Paediatrics and Child Health April2012
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Transcript of Paediatrics and Child Health April2012
EgyptianPediatrics Yahoo Group
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Paediatrics andChildHealthPaediatrics and Child Healthisthecontinuouslyupdatedreviewofpaediatricsandchildhealth(formerlyCurrent Paediatrics)
Paediatrics and Child Health isanauthoritativeandcomprehensiveresourcethatprovidesallpaediatriciansandchildhealthcarespecialistswithup-to-datereviewsonallaspectsofhospital/communitypaediatricsandneonatology,includinginvestigationsandtechnicalproceduresina4-yearcycleof48issues.Theemphasisofthejournalisontheclear,concisepresentationofinformationofdirectclinicalrelevancetobothhospitalandcommunity-basedpaediatricians.Contributorsarechosenfortheirrecognizedknowl-edgeofthesubject.ThejournalisabstractedandindexedinCurrentAwarenessinBiologicalSciences.Thelayoutofthejournal,includingthedesignandcolour,enablesfastassimilationofkeyinformation.Foreaseofreference,Paediatrics and Child Healthisavailableinprintandonlineformats.
Editor-in-ChiefPatrick Cartlidge DM FRCP FRCPCH
SeniorLecturerinChildHealthandHonoraryConsultantNeonatologist,WalesCollegeofMedicine,CardiffUniversity,Cardiff,UK
Visitourwebsiteat:www.paediatricsandchildhealthjournal.co.ukforpreviousissues,subscriptioninformationandfurtherdetails.
Paediatrics and Child Health hasaneminenteditorialboardandawidearrayofauthors,allofwhomarerecognizedexpertsintheirfield.
International Advisory BoardR Adelman (Phoenix,USA) A Bagga(NewDelhi,India)
Z Bhutta (Karachi,Pakistan) H Buller (Rotterdam,TheNetherlands)
MC Chiu (Kowloon,HongKong) M Hassan (Islamabad,Pakistan)
P Malleson (Vancouver,Canada) A Martini (Genova,Italy)
A Moosa(Saffat,Kuwait) C Morley(Carlton,Australia)
BJC Perera(Colombo,SriLanka) J Pettifor(Johannesburg,SouthAfrica)
M Uchiyama(Niigata,Japan) M van de Bor(Nijmegen,TheNetherlands)
Founding EditorRichard WilsonMB FRCP FRCPCH DCH
Associate EditorsAllan ColverMA MD FRCPCH
ProfessorofCommunityChildHealth,SirJamesSpenceInstitute,NewcastleUniversity,Newcastle,UK
Harish VyasDM FRCP FRCPCHProfessorinPICUandRespiratoryMedicine,Queen’sMedicalCentre,NottinghamUniversityHospital,UK
Doug SimkissBMedSci MBChB DCH DTMH MSc FRCP (Ed) FRCPCH FHEA
AssociateProfessorinChildHealth,WarwickMedicalSchool,Warwick,UKHonoraryConsultantPaediatrician,BirminghamCommunityHealthCareNHSTrustandSandwellandWestBirminghamNHSTrust,Birmingham,UK
Nicholas MannMD FRCP FRCPCH DCHConsultantPaediatrician,DepartmentofPaediatrics,RoyalBerkshireHospital,Reading,UK
Alistair ThomsonMA MD BChir FRCPCH FRCP DCH DRCOGConsultantPaediatrician,LeightonHospital,Crewe,UK
Colin PowellMBChB DCH MRCP FRACP FRCPCH MD
ConsultantPaediatrician,UniversityHospitalofWales,Cardiff,UK
Peter HeinzMD State Exam Med FRCPCH
ConsultantPaediatrician,Addenbrooke’sHospital,Cambridge,UK
SYMPOSIUM: NEONATOLOGY
Temperature monitoring andcontrol in the newborn babyYvonne Freer
Andrew Lyon
AbstractThe importance of keeping the newborn baby warm has been known for
centuries but worldwide in the 21st century hypothermia remains a major
contributor to neonatal mortality. Although less of a problem in high
income countries there is evidence that low temperatures have an impact
on outcome at vulnerable times, particularly in the baby born preterm. It
is clear that if we are to see further improvements in mortality and
morbidity in the most immature babies there must be careful attention
given to all aspects of basic neonatal care, including thermoregulation.
Continuous dual temperature monitoring has advantages over intermit-
tent measurements and is the method of choice in the immature and
sick newborn. There is no evidence of any differences in outcome
between radiant heaters or incubators. Whichever device is used fluid
and heat loss from evaporation due to high transepidermal water loss
remains a problem. This is best managed by increasing environmental
humidity but the optimum level of added humidity, and the length of
time that this should be applied, is still unknown.
Keywords temperature monitoring: devices and methods; temperature
support: devices and techniques
Introduction
Outcome for the newborn, and in particular the preterm, baby
improved dramatically in the latter half of the 20th century. There
were many contributory factors with the understanding of
temperature control being one of the major influences. Since the
mid 1990s there has been much slower, if any, change in overall
rates of mortality or morbidity. It is unlikely that the dramatic
changes of the past will be seen again and further improvements in
outcomewill bemore difficult to achieve and of a smaller scale. It is
increasingly important that careful attention is given to the basics
of neonatal care and that lessons from the past are not forgotten.
Thermoregulation
Heat is produced as a by-product of cell metabolism and is lost or
gained with the environment through conduction, radiation,
Yvonne Freer RGN RM RSCN BSc Midwifery PhD is Clinical Reader in the
Neonatal Intensive Care Unit at the Simpson Centre for Reproductive
Health, The Royal Infirmary of Edinburgh, Edinburgh, UK. Conflict of
interest: none.
Andrew Lyon MA MB FRCP FRCPCH is Consultant Neonatologist in the
Neonatal Intensive Care Unit at the Simpson Centre for Reproductive
Health, The Royal Infirmary of Edinburgh, Edinburgh, UK. Conflict of
interest: none.
PAEDIATRICS AND CHILD HEALTH 22:4 127
convection and evaporation. Children and adults are homeo-
thermic, maintaining a constant deep body temperature over
a wide range of ambient thermal conditions. The newborn infant,
by comparison, can only achieve control of temperature over
a narrower range of ambient conditions. The preterm infant has
even greater difficulty and the most immature behave at times as
if they are poikilothermic e their body temperature drifting up
and down with the ambient temperature. The range of ambient
temperature over which an infant can maintain body tempera-
ture, with minimal energy expenditure [thermoneutral range
(NTR)], is very narrow in the immature infant. As environmental
temperature moves outside this range, the infant adopts different
strategies to maintain normothermia.
If the environment is cooler than the body, metabolic heat
production increases. Catecholamine release stimulates the
oxidation of brown adipose tissue distributed in the neck,
between the scapulae and along the aorta (non-shivering ther-
mogenesis). The term baby can alter body posture and skin blood
flow reduces as the superficial capillaries constrict. As environ-
mental temperature falls further outside the NTR, heat produc-
tion reaches a maximum and below this point deep body
temperature falls. If the environment is hotter than the body,
heat is gained through conduction and radiation, as in the use of
skin to skin care and radiant heaters. When above the NTR,
sweating occurs in the term infant.
Heat production is delayed during adaptation to extrauterine
life, especially if there is immaturity, asphyxia, hypoxia or
maternal sedative administration. The preterm infant, particu-
larly below 28 weeks’ gestation, has lower heat production per
unit area and a more prolonged impairment of non-shivering
thermogenesis. The immature infant is further disadvantaged
because of increased evaporative heat losses e a consequence of
high transepidermal water loss (TEWL) due to passive diffusion
of water through a thin, poorly keratinized epidermis. The ability
to alter skin blood flow and change posture are also impaired in
the preterm infant as well as in the presence of illness. Sweating
is delayed in the most immature newborns by 2e3 weeks,
a result of neurological rather than glandular immaturity.
Thermoregulation and outcome
William Silverman and others showed, in a series of randomized
controlled trials, that keeping small babies warm could result in
an absolute reduction in mortality of at least 25% of that seen in
the 1950s.This improvement was seen over all gestation and
birthweight groups. The importance of humidity was recognized
and, in the 1970s, Hammarlund and Sedin published data on the
heat fluxes due to transepidermal water losses in the preterm
baby. Recommendations for optimum environmental tempera-
ture settings, based on the concept of the neutral thermal envi-
ronment, were developed and technological advances have
improved the devices used to keep small babies warm.
By the 1990s the impression was that thermoregulation of the
newborn was understood and well managed but, worldwide
today, hypothermia is still a major cause of death after birth. The
extent of this problem is such that the World Health Organization
(WHO) has published guidelines on the management of the
newborn aimed at reducing the deaths from hypothermia (http://
whqlibdoc.who.int/hq/1997/WHO_RHT_MSM_97.2.pdf).
Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Recent evidence has shown that poor management of temper-
ature in the baby at vulnerable times can impact on outcome.
Whether as a cause or consequence, low body temperature in
newborns lead to increased metabolism and hypoglycaemia,
reduced tissue perfusion, ischaemia and metabolic acidosis and
has been shown to be inversely related to mortality.
The effects of hyperthermia are less well understood but in
infants with moderate-to-severe hypoxic ischaemic encephalop-
athy, hyperthermia is associated with an increased risk of death
or moderate-to-severe disability. There is little data on the effects
of hyperthermia and the human preterm infant but in the preterm
animal model, hyperthermia is associated with severe lung injury
and increased inflammatory cytokine expression.
It is clear, more than 50 years after the work of Silverman, that
thermal control, particularly of the immature infant, is still an
important issue in need of further thought and study. Given the
importance of thermoregulation two questions are paramount:
how best to measure temperature and how best to maintain
thermal balance.
Temperature measurement
The normal temperature
In day-to-day care the only means of assessing the thermal state of
a baby is by measuring body temperature. Defining a ‘normal’
body temperature is difficult as this will depend on where, how,
and the time of day/nightwhenmeasured. The temperaturewithin
the tissues of the body varies with metabolic rate and there is no
such thing as a single central body temperature. Normal temper-
ature ranges for newborns have not been clearly established but
published ranges for both term and preterm infants are:
� rectal at 36.5e37.5 �C� axillary at 35.6e37 �C.It has been suggested that conditions for thermoneutrality are
met in very low birthweight infants when core temperature is
between 36.7 and 37.3 �C and the central-skin temperature
difference fluctuates less than0.2e0.3 �C/hour.An infant may expend a large amount of energy to maintain
a ‘normal’ central temperature. The preterm baby is at higher risk as
a consequence of the very narrow NTR when compared with those
bornat term.Despite anapparentnormal temperature the infantmay
well be thermally stressed and at increased risk of adverse outcome.
How, where and frequency of temperature measurement
Theprimary purpose ofmeasuring the newborn’s temperature is to
detect cold stress as fever is an unusual symptom of illness and
most often influenced by environmental factors. Treatment is often
initiated on relatively small changes in temperature so devices
used for measurement must be accurate, reliable and easy to use.
In the newborn sites of measurement are: rectum, axilla or skin,
although these all offer only an estimate of body core temperature.
Devices
Mercury in-glass thermometers were used for many years
however with concerns about accuracy, the length of time to
reach a stable point and risk of harm posed by mercury they are
no longer used in most high income countries, except as
a research tool for comparing new devices. More automated
thermometers have become available that utilize electronic,
infrared, chemical and liquid crystal technologies.
PAEDIATRICS AND CHILD HEALTH 22:4 128
Electronic thermometers have temperature sensors inside the
tip and are covered with a sheath. They are used in monitoring or
predictivemode. In themonitormode the temperature is displayed
once a steady state has been achieved, usually about 3e5 min.
With predictive mode the temperature is ‘predicted’ by a calcula-
tion based on the rate of rise in the few seconds of use. Tympanic
thermometers have an infrared sensor that records heat radiated
from the tympanic membrane. Temporal artery thermometers
work by detecting changes in heat emitted from the superficial
temporal artery (STA). The thermometer is moved across the
forehead and as it passes over the STA there is a peak in the emitted
temperature which is captured by the sensor. Chemical/liquid
crystal thermometers work by placing a plastic strip, impregnated
with temperature sensitive chemicals/crystals, against the skin.
These change colour in response to variations in temperature.
Site and frequency
Intermittent rectal thermometry is used infrequently (the excep-
tion is during monitoring of therapeutic hypothermia where
a continuous readout is given). As well as concerns about rectal
trauma the reproducibility under clinical conditions is uncertain.
This is affected by differences in the depth of insertion, dwell
time, whether the baby has just passed stool and on the flow and
temperature of the blood returning from the lower limbs. Axillary
temperature is usually measured intermittently. There is little
associated risk but error in measurement is observed depending
on placement of the probe, adequate closure of the axillary pit,
blood flow to the axillary region and possibly activation of non-
shivering thermogenesis. Electronic probes and chemical/crystal
strips attached to the skin have little associated risk and are used
for both intermittent and continuous temperature monitoring.
Accuracy of these techniques may be affected by environmental
temperature, approximation of probe to skin and peripheral
perfusion.
Continuous monitoring using electronic probes, if placed
correctly, offer a close approximation to deep body temperature,
particularly when using the ‘zero heat flux’ principle. With this
technique a probe is placed over an area of skin from which no
heat can be lost. The skin under the probe equilibrates with the
deep body temperature as heat moves down the temperature
gradient from core to skin. In practice this can be achieved when
the baby is lying on its back on a non-conducting mattress with
a probe placed between the scapulae. Measuring temperature
intermittently gives a ‘snapshot’ of the baby’s temperature; it
tells nothing about the energy the baby may be expending to
maintain that temperature. The continuous measurement and
display of central (abdominal, axilla or zero heat flux) and
peripheral (sole of the foot) temperatures gives an early indica-
tion of thermal stress by showing a change in the centrale
peripheral difference which occurs before any alteration in
central temperature.
The preterm baby who appears to be comfortable in its
environment has a central temperature in the normal range for
whichever site is being used and a centraleperipheral tempera-
ture difference of 0.5e1 �C. An increasing centraleperipheral
temperature difference, particularly above 2 �C, is usually due to
cold stress (Figure 1), and occurs before any fall in central
temperature. A high central temperature, particularly if unstable,
along with a wide centraleperipheral gap is seen in septic babies.
Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved.
Figure 1 Central temperature shown in green; peripheral temperature shown in blue. At 01.45 h the incubator door is opened, the peripheral temperature
falls dramatically with little change in the central temperature.
SYMPOSIUM: NEONATOLOGY
Variation due to device and measurement method
Accuracy of thermometers has been reviewed and according to
manufacturing standards, devices should be within �0.2 �Cacross a wide temperature range. However, many manufactures
indicate an accuracy of �0.6 �C when used in predictive mode.
Such differences could result in some intervention if the infant’s
temperature is at the margins of the normal range.
Many factors may be responsible for the failure to develop
a consensus recommendation for temperature monitoring in
neonatal care. Studies differ in thermometer, population case mix
and sample size and the external heat sources used. There are
major problems with the variation in statistical methods used
when comparing devices. Use of the correlation coefficient is
inappropriate, when comparing any device ormethod of recording
a physiological parameter, as this measures strength of a relation-
ship rather than agreement. Bland and Altman propose that by
comparing the individual differences between twomeasurements,
in the context of the mean of their combined readings, will better
assess the agreement of the device/technique. Recent studies have
compared temperature measurements comparing electronic rectal
and axillary thermometers, an infrared temporal artery thermom-
eter and an electronic axillary thermometer against an indwelling
rectal probe and an electronic and an infrared axillary skin ther-
mometer against a glass mercury thermometer using this tech-
nique in the neonatal population. The mean difference between
devices range from 0.1e0.3 �C however there are wide 95% limits
of agreement giving a variability of between 0.8 and 1.7 �C.These few small studies suggest that there is a large variation
betweenmethodsand this is of concern in clinical practice.Although
the mean difference is small, and of no consequence to clinical
PAEDIATRICS AND CHILD HEALTH 22:4 129
decision-making, the degree of variability suggests that interven-
tionsmay be carried out unnecessarily in some infants and not at all
in others when they would be appropriate. These concerns further
strengthen the argument in favour of using continuous monitoring
of dual temperatures as a means of following trends rather than
concentrating on absolute values of intermittent measurements.
How best to maintain temperature
Simplemethods for preventing heat loss are well knowne awarm
delivery room, drying, wrapping and applying a hat, skin to skin
care or lying baby on a non-conducting mattress, breastfeeding,
warm resuscitation and transportation. Despite this knowledge
there are still reports of ‘cold’ babies in both high and low income
countries. Most trials on temperature maintenance have focused
primarily on how best to keep immature infants warm. Although
the lowest acceptable admission temperature is not known, it is
suggested that temperatures should be above 36 �C in this group.
Trials have generally looked at two approaches, barriers to heat
loss or supplemental heat application.
At birth the baby will lose heat rapidly, particularly due to
evaporation.Heat losses canbeminimized, as described above, but
many preterm babies are cold on arrival in the neonatal unit. Heat
fromradiant heaters is often insufficient to compensate for the large
losses due to evaporation. To overcome this, babies arewrapped in
polyethylene occlusive skin wraps or placed into plastic bags to
reduce TEWL. One systematic review of five studies utilizing
plasticwraps/bags and stockinet hats showed that infants less than
28 weeks gestation whowere wrapped were warmer on admission
to the NICU (WMD 0.76 �C; 95% CI 0.49, 1.03) but no such effect
was seen in the stockinet trial. However, two of the trials included
Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
in the systematic review showed that, although admission
temperature had increased with the use of plastic wraps, over
a third of babies were still admitted with a temperature less than
36.5 �C. Another technique, the use of gel warmingmattresses, has
also been trialled. In each of these trials the warming mattress
contributed to an increase in the admission temperature of the
baby. While this is seen as an improvement, between 3 and 55%
babies were admitted to the NICU with hypothermia (temperature
less than 36.5 �C) and 1e28% of babies had an admission
temperature of more than 37.5 �C. Despite the recognized associ-
ation between low temperature and poor outcome no trial to date
has shown that measures to improve admission temperature has
resulted in lower morbidity or death before discharge.
The optimum management of the thermal environment
during ongoing neonatal care has been discussed in the litera-
ture. No study has shown any significant difference in outcome
for babies nursed using either radiant heater or incubator. It is
important that units consider seriously the management of the
thermal environment of the preterm baby but the choice of
device used is a matter of individual preference. However,
whichever method is adopted, evaporative fluid losses remain
a major challenge in the management of the preterm baby.
The skin barrier of the preterm baby is immature and there is
a high water concentration gradient between the body and the
external environment. This results in TEWL with the gradient
being very steep if the ambient water vapour pressure is low. The
more immature the baby the steeper the gradient and higher the
losses, and this is exacerbated if the skin is further damaged
during neonatal care procedures. The skin matures rapidly after
birth and, in practical terms, TEWL falls to around that of the
term baby within 10e14 days of age. The most effective method
of reducing TEWL is by an increase in environmental humidity
around the baby. In the baby under 28 weeks’ gestation this
should be maintained for at least the first 10 days of life and is
most easily achieved by the use of humidified incubators. A
plastic cover can be used with radiant heaters but it must be
remembered that there will be rapid fluid losses whenever this is
removed for any procedure. Covering the skin with a semi-
permeable/impermeable membrane, or the use of emollients,
creates a barrier reducing TEWL. Whilst these have been shown
to reduce TEWL, in some studies they have been associated with
an increased incidence of bacterial and fungal infection.
Movement of water through the skin is important in the
maturation process however the optimum level of environmental
humidity is as yet unknown as prolonged exposure to relatively
high ambient humidity delays the establishment of an effective
skin barrier structure and function.
Practice points
C Methods of measuring temperature are not interchangeable and
it is vital that staff understand the limitations of the devices they
use if unnecessary treatment changes are to be avoided.
Conclusions
The importance of keeping babies warm has been recognized for
centuries. However, even in the 21st century, our understanding of
what is a normal temperature and how best to measure it still
remains a challenge. In clinical practice decisions must be made on
which method of measurement to use, whether intermittent or
continuous monitoring is appropriate and how the data are inter-
preted and acted upon. There are, as yet, no good data to guide us in
deciding on the optimum management of the baby’s external envi-
ronment. What is clear is that this important area of care can no
PAEDIATRICS AND CHILD HEALTH 22:4 130
longer be considered to be a ‘problem solved’. A practical approach
is to try and understand what it is that you are trying to achieve,
knowing the advantages, disadvantages and limitations of the
instruments and techniques that are available to you andnot assume
approaches for assessing a temperature are interchangeable. A
FURTHER READING
Almeida PG, Chandley J, Davis J, Harrigan RC. Use of the heated gel
mattress and its impact on admission temperature of very low birth-
weight infants. Adv Neonatal Care 2009; 9: 34e9.
Crawford DC, Hicks B, Thompson MJ. Which thermometer? Factors influ-
encing best choice for intermittent clinical temperature assessment.
J Med Eng Technol 2006; 30: 199e211.
Flenady VJ, Woodgate PG. Radiant warmers versus incubators for regu-
lating body temperature in newborn infants. Cochrane Database Syst
Rev 2003; 4: CD000435.
Hafis Ibrahim CP, Yoxall CW. Use of self-heating gel mattresses eliminates
admission hypothermia in infants born below 28 weeks gestation. Eur
J Pediatr 2010; 169: 795e9.
Hissink Muller PCE, van Berkel LH, de Beaufort AJ. Axillary and rectal
temperature measurements poorly agree in newborn infants.
Neonatology 2008; 94: 31e4.
Jirapaet V, Jirapaet K. Comparisons of tympanic membrane, abdominal
skin, auxiliary, and rectal temperature measurements in term and
preterm neonates. Nurs Health Sci 2000; 2: 1e8.
Lee G, Flannery-Bergey D, Randall-Rollins K, et al. Accuracy of temporal
artery thermometry in neonatal intensive care infants. Adv Neonatal
Care 2011; 11: 62e70.
LeslieA,WardleSP,BudgeH,MarlowN,BrocklehurstP. Randomised controlled
trial of gel warming mattresses to prevent hypothermia during the resus-
citation at birth of premature infants. In: http://www.neonatalsociety.ac.uk/
abstracts/lesliea_2007_gelwarmingmattressesresuscitation.shtml
Lyon AJ, Freer Y. Goals and options in keeping preterm babies warm. Arch
Dis Child Fetal Neonatal Ed 2011; 96: F71e4.
McCall EM, Alderdice F, Halliday HL, Jenkins JG, Vohra S. Interventions to
prevent hypothermia at birth in preterm and/or low birthweight
infants. Cochrane Database Syst Rev 2010;(3). Art. No.: CD004210.
McCarthy LK, O’Donnell CP. Warming preterm infants in the delivery room:
polyethylene bags, exothermic mattresses or both? Acta Paediatr
2011. doi:10.1111/j.1651-2227.2011.02375.x.
Rosenthal HM, Leslie A. Measuring temperature of NICU patients-A
comparison of three devices. J Neonatal Nurs 2006; 12: 125e9.
Singh A, Duckett J, Newton T, Watkinson MJ. Improving neonatal unit
admission temperatures in preterm babies: exothermic mattresses,
polythene bags or a traditional approach? J Perinatol 2010; 30: 45e9.
Simon P, Dannaway D, Bright B, et al. Thermal defense of extremely low
gestational age newborns during resuscitation: exothermic mattresses
vs polyethylene wrap. J Perinatl 2011; 31: 33e7.
Watkinson M. Temperature control of premature infants in the delivery
room. Clin Perinatol 2006; 33: 43e53.
Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Investigation, prevention andmanagement of neonatalhypoglycaemia (impairedpostnatal metabolicadaptation)Jane M Hawdon
AbstractBlood glucose levels fall in the hours after birth in all babies but for most
babies the normal process of neonatal metabolic adaptation mobilizes alter-
native fuels (eg ketone bodies) from stores so that the physiological fall in
blood glucose is tolerated. However, some babies are at risk of impaired
neonatal metabolic adaptation and for these babies it is important to prevent
hypoglycaemia, to recognize clinically significant hypoglycaemia, and to treat
it without causing unnecessary separation of mother and baby or disruption
of breast feeding. Investigations for underlying cause of hypoglycaemia
should be performed if hypoglycaemia is persistent, resistant or unexpected.
Keywords alternative fuels; blood glucose monitoring; breast feeding;
hypoglycaemia; neonatal metabolic adaptation
Introduction
Much debate surrounds neonatal hypoglycaemia in terms of the
definition of the condition, its clinical significance and its optimal
management. This is in part because there is a continuum
between the normal postnatal metabolic changes, with a physio-
logical fall in blood glucose after birth accompanied by protective
metabolic responses, and the more worrying situations where
there is delay or failure of the normal metabolic adaptation to
birth. Therefore, hypoglycaemia cannot strictly be applied as
a pathological diagnostic term and it is preferable to consider
a diagnosis of impaired metabolic adaptation. Invariably
“neonatal hypoglycaemia” is used as a shorthand term for this. It
is important to prevent potentially damaging hypoglycaemia in
vulnerable babies, but this must be balanced against the risks of
overly invasive management e separation of mother and baby,
placing at risk the establishment of breast feeding, and unnec-
essary administration of formula or intravenous glucose which in
turn impair metabolic adaptation to postnatal life.
Metabolic changes at birth
During pregnancy, the human fetus receives from its mother via
the placental circulation a supply of substrates necessary for
Jane M Hawdon MA MBBS MRCP FRCPCH PhD is Consultant neonatologist
with the University College London Hospitals NHS Foundation Trust,
London, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 22:4 131
growth, for the deposition of fuel stores which are essential after
birth, and for energy to meet the basal metabolic rate and
requirements for growth. When the continuous flow of nutrients
from the placenta is abruptly discontinued at birth, immediate
postnatal metabolic changes preserve fuel supplies for vital organ
function. The newborn infant must adapt to the fast-feed cycle and
to the change in major energy source, from glucose transfer across
the placenta to fat released from adipose tissue stores and ingested
withmilk feeds. After birth, plasma insulin levels fall and there are
rapid surges of catecholamine and pancreatic glucagon release.
These endocrine changes switch on the essential enzymes for
glycogenolysis (the release of glucose stored as glycogen in liver,
cardiac muscle and brain), for gluconeogenesis (glucose produc-
tion from 3-carbon precursor molecules by the liver), lipolysis
(release of fatty acids from adipose tissue stores), and ketogenesis
(the b oxidation of fatty acids by the liver). Some tissues, for
example the kidney, are obligate glucose users but others burn
fatty fuels to provide energy. Of the organs that utilize alternative
fuels to glucose, the brain is the most important in that it takes up
and oxidizes ketone bodies at higher rates than seen in adults, and
the neonatal brain uses ketone bodies more efficiently than
glucose. Lactate has also been identified as an alternative fuel.
In clinical terms, low blood glucose concentrations are
commonly found during the first postnatal days in healthy AGA
term neonates, particularly those who are breast fed. However,
these infants have high ketone body levels when blood glucose
concentrations are low, and it is likely that these alternative fuels
protect them from neurological injury.
Clinical significance of impaired metabolic adaptation
In some circumstances (see below), such as following preterm
delivery, intrauterine growth restriction, perinatal hypoxia-
ischaemia or suboptimal control of diabetes in pregnancy, there
may be impaired ketone body production and in these babies
circulating blood glucose concentrations acquire greater clinical
significance and hypoglycaemia, if present, must be diagnosed
and treated effectively.
No study has yet satisfactorily addressed the duration of
absent or reduced availability of metabolic fuels which is harmful
to the human neonate. Animal studies indicate that hours (rather
than minutes) of hypoglycaemia are required to cause injury, and
that injury is unlikely to occur if there are no abnormal clinical
signs. For babies in whom prolonged neonatal hypoglycaemia
has been associated with abnormal clinical signs (most usually
hypotonia, reduced level of consciousness or fits) adverse long-
term outcomes have been reported. There is evidence from
case reports that profound and prolonged hypoglycaemia is
associated with both transient and permanent structural changes
in the brain. Grey matter damage is most commonly reported
with the parieto-occipital regions being most affected.
Causes of impaired neonatal metabolic adaptation
Insufficient availability of glucose and alternative fuels
Preterm birth: the preterm baby has not had sufficient time in
utero to lay down glycogen and adipose tissues stores. In addi-
tion, hormonal and enzyme adaptive responses may by imma-
ture or the baby may have systemic conditions which affect
hepatic function and glucose production, eg severe infection.
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Intrauterine growth restriction (IUGR): it is important to use
this term rather than “small for gestational age” because not all
IUGR infants will have birthweights on a low centile. Conversely,
not all small for gestational age infants will have been subject to
placental insufficiency e they may be constitutionally small and
will not experience impaired postnatal metabolic adaptation. The
baby who has experienced IUGR has reduced stores of carbo-
hydrate and fat, these fuels were required for metabolism in fetal
life. Therefore, the IUGR baby is at risk of hypoglycaemia prior to
the successful establishment of milk feeds and may have reduced
availability of alternative fuels for cerebral metabolism.
However, it has been shown that healthy breast fed IUGR babies
can mount a ketogenic response, and that excessive formula milk
supplementation is associated with a suppressed response.
Perinatal hypoxia-ischaemia: the high metabolic requirement for
anaerobicmetabolismwill reduceendogenous fuel stores if the fetus
is exposed to significant hypoxia-ischaemia. In addition, hypoxic
liver damage will reduce the activity of the counterregulatory
metabolic responses. Although concurrent hypoglycaemia and
hypoxia-ischaemia are more damaging than either insult alone,
there is no evidence that hypoglycaemia following cessation of
a hypoxic-ischaemic insult worsens hypoxic-ischaemic injury.
Systemic conditions: any condition which increases metabolic
demands (eg hypothermia, systemic infection), or which affects
adequacy of feeding, or which affects perfusion or function of the
gut of liver places the baby at risk of impairedmetabolic adaptation.
If hypoglycaemia is diagnosed, there must be urgent investigation
for underlying conditions and appropriate management of these.
Inborn errors of metabolism and endocrine insufficiency:
these conditions are rare, but for affected individuals frequently
present in the neonatal period when nutrient intake is low. The
most common metabolic disorders presenting at this time are
defects of b oxidation of fatty acids. The most common
congenital endocrine disorders presenting with neonatal hypo-
glycaemia are defects in cortisol production.
Maternal medication: maternal beta blocker therapy has been
associated with impaired neonatal metabolic adaptation,
although passage across the placenta and in breast milk is vari-
able. This is not a contraindication to breast feeding. Often, the
baby of the mother with hypertension also has IUGR, thus
increasing the risk.
Prolonged starvation: as described above, various factors affect
the sufficiency of endogenous fuel stores at the time of birth. If
exposed to prolonged inadequacy of nutrient intake, even the
healthy well grown baby will run out of endogenous stores and
metabolic adaptation will fail.
Neonatal hyperinsulinism
If the fetal insulin levels are raised and do not fall after birth, or if
there is excessive insulin release from the neonatal pancreas, the
actions of insulin are to increase glucose uptake into cells,
suppress endogenous glucose production, and suppress release of
fat from adipose tissue stores. In these circumstances the baby is at
risk of hypoglycaemia and an absence of alternative metabolic
PAEDIATRICS AND CHILD HEALTH 22:4 132
fuels. Clinical features are that glucose requirements to maintain
normoglycaemia are high, in excess of 8 mg/kg/min, as compared
to the 4e6 mg/kg/min usually required by neonates, and the
infant may be macrosomic if hyperinsulinism was of fetal origin.
Maternal diabetes mellitus: for babies born after diabetes in
pregnancywhich has not beenwell controlled, the postnatal fall in
blood glucose concentration is more prolonged or becomes clini-
cally significant and this is the most common cause of neonatal
hyperinsulinaemic hypoglycaemia. Fetal and neonatal hyperin-
sulinism may occur after maternal type 1 or type 2 diabetes or
diabeteswhose onset is in pregnancy, and is the result of increased
placental transfer of glucose and other nutrients stimulating
increased fetal insulin secretion. For affected babies, plasma
insulin levels usually fall to normal within 12e24 h of birth and
this form of hypoglycaemia presents early and is self-limiting.
Congenital hyperinsulinaemic hypoglycaemia (HH): although
a rare condition, this is the most common cause of recurrent and
persistent hypoglycaemia in infancy and childhood. There are
a number of underlying pathologies and understanding of the
molecular and genetic basis of these is becoming more clear. HH
is usually associated with macrosomia and high glucose
requirements. The condition may be self-limiting in the neonatal
period or extend beyond this time. As there is no protective
ketone body response to hypoglycaemia, there are usually
neurological signs and the risk of brain injury is high. Therefore,
urgent treatment is required (see below).
BeckwitheWiedemann syndrome: this condition is character-
ized by exomphalos, macroglossia, visceromegaly, earlobe
abnormalities and an increased later incidence of malignancies.
Hyperinsulinism is a common but not invariable feature which
usually resolves in the days after birth.
Other causes: transient hyperinsulinism has also been reported
in association with perinatal hypoxia-ischaemia, intrauterine
growth restriction and rhesus haemolytic disease, although the
mechanisms for this have not been determined. Maternal thia-
zide diuretic use may cause neonatal hyperinsulinism.
Iatrogenic or factitious hyperinsulinism: hyperinsulinism may
result from erroneous or malicious administration of insulin.
Although rare, these circumstances should be suspected if
hypoglycaemia is unexpected, profound or resistant to treatment.
Diagnosis of clinically significant hypoglycaemia
Much controversy and confusion has surrounded the definition
of hypoglycaemia. Factors which should be considered are the
blood glucose concentration considered to be the minimum safe
level, the duration beyond which the low blood glucose level is
considered to be harmful, the presence of clinical signs, the
group of infants studied, the consideration of alternative fuel
availability, the conditions of sampling and the assay methods.
Most of these have not been adequately addressed in scientific
studies. Therefore, a pragmatic approach based upon thresholds
for intervention has been proposed. If there are neurological
signs in association with low blood glucose levels there should be
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
urgent investigation for underlying cause (Table 2) and institu-
tion of treatment. For infants without clinical signs but at risk of
impaired metabolic adaptation (Table 1), intervention to raise
blood glucose should be considered if two consecutive blood
glucose levels are below 2 mmol/litre (measured using accurate
device) or a single blood glucose level is below 1 mmol/litre.
Detection and management of neonatal hypoglycaemia
Clinical scenario A
Sick baby or very preterm in NNU A
I
Any baby with neurological signs A
- Abnormal tone F
- Decreased activity A
- Lethargic/reduced level of consciousness I
- Abnormal cry
- Seizures
Babies “at risk”: E
R
c
- SGA (<2nd centile)
- Clinically wasted infants
- Infants of diabetic mothers where antenatal glucose
control suboptimal and/or if baby macrosomic
- Post mature infants if wasted
- Perinatal hypoxia-ischaemia
- Severe Rhesus disease
- Preterm infants (<37/40)
- Congenital heart disease
- Infection
- Hypothermia
- Fluid restriction
- Maternal beta blocker (eg labetalol)
What to do if “at risk” and: E
C No abnormal signs and feeding well, BG> 2.0 mmol/l N
p
What to do if “at risk” and: C
AC No abnormal signs and feeding well, BG 1.0e2.0 mmol/l
on 2 consecutive pre-feed measurements
C
T
What to do if “at risk” and: A
t
C BG< 1.0 mmol/l
Healthy term infants N
Includes LGA babies who are not: E
- Macrosomic appearance or I
w
c
- Infants of diabetic mothers
NNU, neonatal unit; EBM, expressed breast milk; BG, blood glucose; LGA, large for g
Table 1
PAEDIATRICS AND CHILD HEALTH 22:4 133
It is well known that glucose reagent strips, commonly used in
neonatal and maternity units, are insufficiently reliable for the
diagnosis. If samples are to be sent to a distant laboratory, blood
glucose levels diminish with time, even in fluoridated tubes.
Therefore, a ward based accurate glucose analyser should be
available to allowprompt and accurate blood glucosemeasurement.
ction
im to maintain BG> 2.5 mmol/l
f hyperinsulinism suspected aim to maintain glucose >3 mmol/l
dmit to NNU
ull investigations including BG
im to maintain glucose >2.5 mmol/l
f hyperinsulinism suspected aim to maintain glucose >3 mmol/l
ncourage breastfeeding as soon as possible after birth (if appropriate)
egular BG measurements e approximately 3e4 hourly pre-feed,
ommencing before the second feed after birth
ncourage breast feeding and observe
o formula supplements if breast fed. Check pre-feed BG 3e4 h later
re-feed or sooner if abnormal signs (as above)
ontinue breast feeding.
dd EBM and/or formula supplement (initially 10 ml/kg/feed)
heck pre-feed 3e4 h later or sooner if abnormal signs
itrate volume of supplements against 3e4 hourly pre-feed BG
dmit to NNU for investigations and IV glucose, continue feeds if
olerated
o glucose monitoring
ncourage and support breast feeding
f concerns around feeding assess for abnormal signs and clinical
ellbeing. Investigate (including infection screen and BG) only if clinical
oncerns
estational age; IV, intravenous; SGA small for gestational age.
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Prevention and management of neonatal hypoglycaemia
Healthy, full-term appropriate weight for gestational age
(AGA) neonates
As described above, healthy full-term AGA neonates often have
low blood glucose concentrations in the first postnatal days, but
are protected by the presence of ketone bodies and lactate as
alternative fuels. These babies do not need routine blood glucose
monitoring or formula supplementation of breast feeds. However,
staff should be alert to systemic conditions (eg neonatal infection)
which may impact upon feeding and the risk of neonatal hypo-
glycaemia, or the very rare risk that a baby who is apparently
healthy at birth may have an underlying metabolic disorder.
Appropriate investigations, including blood glucose measurement,
should be carried out for any baby who presents with abnormal
clinical signs.
Babies at risk of impaired metabolic adaptation (Table 1)
The first step in management is to identify these babies. Some
risk factors will be clear, for example the preterm baby, others
may require more detailed clinical evaluation (for example
fat and muscle wasting arising from intrauterine growth
restriction).
At-risk babies should have regular clinical monitoring to
include feeding behaviour and pre-feed blood glucose moni-
toring (approximately 4 hourly). It is imperative that any infant
with neurological signs should have urgent, accurate blood
glucose measurement. Monitoring should commence before the
second feed (ie not so soon after birth that the physiological fall
in blood glucose level causes confusion and over-treatment) and
pre-feed monitoring should be continued until the infant has had
at least two satisfactory measurements. Monitoring should be
recommenced if the infant’s clinical condition worsens or energy
intake decreases. If monitoring is by reagent strip, low levels
must be confirmed promptly by accurate measurement (see
above).
The importance of early milk feeding has been appreciated for
many years. Both breast and formula milks provide important
gluconeogenic precursors and fatty acids for b oxidation.
Therefore, all infants who are expected to tolerate enteral feeds
should be fed with milk as soon as possible after birth, and at
frequent intervals thereafter. Babies who are capable of sucking
should be offered the breast at each feed (if this is the mother’s
wish). If it is likely that babies will need supplementary formula
feeds, maternal breast milk expression should be encouraged.
The requirement for formula feeds must be titrated against the
clinical condition of the baby, blood glucose monitoring, and the
supply of maternal breast milk. In the breast fed baby, formula
intake should be kept to the minimum necessary, so as to
enhance breast feeding and avoid suppression of normal meta-
bolic adaptation.
In the at-risk baby who is establishing oral feeds there is
a potential nadir at which body stores are steadily reducing but
milk feeds have not yet started to replenish these stores. For this
reason, vulnerable babies should not be transferred to the
community at less than 48 h, and only when experienced staff
are satisfied that feeding is effective.
If a baby requires intravenous glucose from birth (for example
if extremely preterm), usually 10% dextrose at 3 ml/kg/h (5 mg
PAEDIATRICS AND CHILD HEALTH 22:4 134
glucose/kg/min) is sufficient to prevent hypoglycaemia. If fluid
restriction is required, a central line should be inserted for
infusion of more concentrated dextrose solutions.
If low blood glucose levels persist or are associated with
clinical signs in the milk-fed infant despite the above measures,
it may be possible to increase further the volumes and/or
frequencies of feeds. If this is not possible, or if the hypo-
glycaemia is resistant to this strategy, intravenous glucose
will be required. If the infant is tolerating milk feeds these
should be neither stopped nor reduced (unless HH is suspected,
see below). The initial rate of 10% glucose infusion should be
3 ml/kg/h (5 mg/kg/min), but adjusted according to frequent
accurate blood glucose measurements. Boluses of concentrated
glucose solution should be avoided because of the risk of
rebound hypoglycaemia and cerebral oedema, and if boluses are
required (for example if there are neurological signs of hypo-
glycaemia) they should be of 10% dextrose (3e5 ml/kg), given
slowly, and always followed by an infusion. All reductions in
infusion rate should be gradual, and any interruption of infusion
should be promptly remedied.
Specific treatments
The baby born after maternal diabetes mellitus in pregnancy:
significant hypoglycaemia is very rare if control of maternal
diabetes has been good. In these circumstances and if the baby is
well and feeding effectively, there is no requirement to intervene
if a single blood glucose level is low. If early blood glucose
measurements are satisfactory, continued blood glucose moni-
toring is not required.
If significant hypoglycaemia occurs this will be in the hours
after birth and only in rare cases will this be prolonged. If the
baby has presented with abnormal clinical signs and requires
intravenous glucose, the target blood glucose level should be 3
mmol/litre and high rates of glucose delivery may be required.
A single injection of glucagon (0.03e0.1 mg/kg), which has
a temporary hyperglycaemic effect by releasing glucose from
glycogen stores, is a useful measure in the event of delay in siting
intravenous lines.
Congenital hyperinsulinaemic hypoglycaemia (HH): recogni-
tion of hyperinsulinism and early prevention and treatment of
hypoglycaemia, with advice from or referral to a specialist centre,
is essential to reduce the incidence of permanent neurological
damage which has been widely reported.
Milk feeds should be stopped, pending discussion with the
specialist centre, as in some case of HH milk feeds further
stimulate insulin release. Intravenous glucose should be
prescribed to maintain blood glucose levels above 3 mmol/litre,
and this may require siting of a central line to deliver concen-
trated glucose solutions. If hypoglycaemia is still resistant to high
glucose delivery rates, diazoxide (10e20 mg/kg/day) and
chlorthiazide (7e10 mg/kg) may be given. Some cases respond
to the calcium channel blocker, nifedipine. Glucagon (200 mg/kg
bolus i.v. or i.m. or infusion 5e10 mg/kg/h), has a temporary
glycaemic effect but its prolonged use is limited because
glucagon further stimulates insulin release. Somatostatin
analogue (octreotide) administered intravenously or subcutane-
ously at a dose of 10 mg/kg/day also suppresses insulin release.
These additional treatments should only be given after
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
discussion with a specialist centre, and pending transfer of the
baby to the specialist centre.
Inborn errors of metabolism and endocrine insufficiency:
where possible diagnostic samples should be taken before
correction of hypoglycaemia, but should not delay treatment
(Table 2). Emergency management is to ensure adequate blood
glucose levels are sustained, usually requiring intravenous
glucose. If cortisol deficiency is suspected, replacement dose
hydrocortisone may be given empirically pending investigation.
The specialist management of these individual conditions is
beyond the scope of this article and should be discussed with
appropriate teams.
Investigations for persistent, resistant or unexpectedneonatal hypoglycaemia
Blood glucose
Blood gas
Blood lactate
Infection screen
Liver function/blood clotting studies
Urea and electrolytes
Blood b hydroxybutyrate and/or acetoacetatea
Plasma fatty acidsa
Plasma insulina
Plasma cortisola
Plasma/urine amino acid profile
Urine organic acidsa
Blood acyl carnitines
a Samples only informative if taken at the time of hypoglycaemia.
Table 2
Practice points
C Blood glucose levels fall after birth in all babies, and most
compensate for this by mobilizing alternative fuels
C Identification of babies at risk of impaired neonatal metabolic
adaptation and prevention of hypoglycaemia is important to
avoid brain injury
C Unnecessary separation of mother and baby or formula feeding
of the baby should be avoided
C Investigations for underlying cause of hypoglycaemia should
be carried out if hypoglycaemia is persistent, resistant or
unexpected
Summary
Many babies are at risk of impaired metabolic adaptation and
clinically significant hypoglycaemia. Fortunately with prompt
recognition of risk factors and attention to adequacy of energy
intake, it is rare for babies to present with clinical signs or to
sustain brain injury as a result of hypoglycaemia. However, in
rare cases hypoglycaemia is resistant to standard management or
there is serious underlying pathology and specialist advice must
be sought.
Finally, the impact of hypoglycaemia and its treatment on the
mother and baby must be considered. The early neonatal period
is an emotionally sensitive time, and the diagnosis of hypo-
glycaemia may create or add to anxiety for the parents. Treat-
ment of the infant with intravenous glucose involves separation
of the baby and mother with a negative impact on breast feeding,
and may be perceived as invasive or painful. Formula supple-
mentation also disrupts breast feeding and appears to have
a negative effect on normal neonatal metabolic adaptation, so
should be avoided unless there is a clear clinical indication.
Emphasis should be on the early prevention of hypoglycaemia
and strategies of management that do not involve the separation
of mother and baby. A
PAEDIATRICS AND CHILD HEALTH 22:4 135
FURTHER READING
1 Auer RN, Siesjo BK. Hypoglycaemia: brain neurochemistry and
neuropathology. Bailli�eres Clin Endocrinol Metab 1993; 7: 611e25.
2 Boluyt N, van Kempen A, Offringa M. Neurodevelopment after neonatal
hypoglycaemia: a systematic review and design of optimal future
study. Pediatrics 2006; 117: 2231e43.
3 Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding
definition of neonatal hypoglycemia: suggested operational thresh-
olds. Pediatrics 2000; 105: 1141e5.
4 de Rooy LJ, Hawdon JM. Nutritional factors that affect the postnatal
metabolic adaptation of full-term small- and large-for-gestational-age
infants. Pediatrics 2002; 109: E42.
5 Eidelman AI. Hypoglycemia and the breastfed neonate. Pediatr Clin
North Am 2001; 48: 377e87.
6 Hawdon JM. Care of the neonate. In: McCance DR, Maresh M,
Sacks DA, eds. Practical management of diabetes. Oxford: Wiley-
Blackwell, 2010.
7 Hawdon JM, Ward Platt MP, Aynsley-Green A. Patterns of metabolic
adaptation for preterm and term infants in the first neonatal week.
Arch Dis Child 1992; 67: 357e65.
8 Hay Jr WW, Raju TN, Higgins RD, Kalhan SC, Devaskar SU. Knowledge
gaps and research needs for understanding and treating neonatal
hypoglycaemia: workshop report from Eunice Kennedy Shriver
National Institute of Child Health and Human Development. J Pediatr
2009; 155: 612e7.
9 Kapoor RR, James C, Hussain K. Advances in the diagnosis and
management of hyperinsulinaemic hypoglycaemia. Nat Clin Pract
Endocrinol Metab 2009; 5: 101e12.
10 Medical Devices Agency. Extra-laboratory use of blood glucose
meters and test strips: contraindications, training and advice to the
users. Safety Notice MDA SN 9616 1996.
11 National Childbirth Trust. Hypoglycaemia of the newborn. Mod
Midwife 1997; 7: 31e3.
12 Persson B. Neonatal glucose metabolism in offspring of mothers with
varying degrees of hyperglycaemia during pregnancy. Semin Fetal
Neonatal Med 2009; 14: 106e10.
13 Rozance PJ, Hay WW. Hypoglycaemia in newborn infants: features
associated with adverse outcomes. Biol Neonate 2006; 90: 74e86.
14 Srinivasan G, Pildes RS, Cattamanchi G, Voora S, Lilien LD. Plasma
glucose values in normal neonates: a new look. J Pediatr Surg 1986;
21: 114e7.
15 Vanuucci RC, Vannucci SJ. Hypoglycaemic brain injury. Semin
Neonatal 2001; 6: 147e55.
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Resuscitation of the term andpreterm infantAngela E Hayward
AbstractThe vast majority of newborn infants make the transition from intra-
uterine to extrauterine life uneventfully, however there are a significant
number who do require some assistance to make this transition. The
unique physiology at this time needs to be taken into account when
commencing resuscitation efforts. When a newborn infant requires assis-
tance to make the transition to extrauterine life this usually takes the form
of basic airway and breathing management, with more advanced airway
management and chest compressions needed in fewer cases and pharma-
cological support only needed in rare cases.
Keywords guidelines; neonatal; newborn; premature; resuscitation
Background
In 2010 the European Resuscitation Council (ERC) guidelines for
Cardiopulmonary resuscitation (CPR) were updated and pub-
lished. The guideline for resuscitation of babies at birth was
developed based on the most recent International Consensus on
CPR Science and Treatment Recommendations (CoSTR). These 5
yearly reviews have culminated in a several new guideline
recommendations for the resuscitation of newborn infants.
In the UK in 2010, there were 807,272 live births. Approxi-
mately 10% of these newborn infants will have required some
form of assistance to make the transition to extrauterine life and
less than 1% will have required more extensive resuscitation
efforts. The need for resuscitation can often be anticipated;
however there are instances when a baby is born in unexpectedly
poor condition. It is important to ensure that all personnel who
are present at the time of delivery are able to provide basic
newborn resuscitation. In cases where it is predicted the baby
may require newborn resuscitation, the appropriate skilled
personnel should be summoned to attend the delivery.
Normal newborn physiology
There are a number of unique physiological events that occur to
enable a fetus to make the transition to extrauterine life. Most
babies establish their independent breathing and circulation
within a few minutes of being born and quickly become pink.
This transition begins with lung expansion created by a large,
negative intrathoracic pressure and expiration against a partially
closed glottis i.e. generating a cry. Physiological experiments
have shown this initial inspiratory pressure is at least 20 cm of
Angela E Hayward MBBS MRCPCH is Consultant Neonatologist at the
University Hospital of Wales, Heath Park, Cardiff, UK. Conflict of
interest: none.
PAEDIATRICS AND CHILD HEALTH 22:4 136
water and may be as high as 70 cm of water in some newborns.
This has the effect of clearing the lung liquid from the trachea
and alveoli to establish a functional residual volume. The
umbilical cord is clamped and the systemic blood pressure
increases. With regular respiration the pulmonary vascular
pressure falls allowing pulmonary perfusion to the now air filled
lungs, and hence gas exchange. There is a more gradual transi-
tion from the fetal to adult circulation with the closure of the
ductus arteriosus, foramen ovale and ductus venosus.
Physiology of newborn asphyxia
In the 1960s an animal model for neonatal hypoxia was devel-
oped allowing physiological data to be analysed; this now forms
part of the basis for resuscitation management of the newborn. In
these animal experiments, the uterus of a pregnant animal under
anaesthesia was opened, the fetal head was placed in a bag of
fluid and the fetoplacental circulation was obstructed. It was
found that at the onset of the obstruction to the fetoplacental
circulation the fetus attempted to breathe, however due to the
plastic bag the fetus was unable to aerate the lungs. This resulted
in the fetus becoming hypoxic. After a few minutes these
breathing movements would cease and the fetus would enter
a period of primary apnoea. The heart rate was maintained at
a normal level for a period of time before rapidly dropping to
approximately half of its normal level. The heart continued to
beat at this lower rate due to the less efficient anaerobic
metabolism. The blood pressure was maintained due to the
circulation being shut down to all but the most essential areas. If
the hypoxic event continued, the fetus entered a period of deep
gasping movements that were driven by the primitive spinal
centres. After a time of increasing respiratory and metabolic
acidosis the fetus would stop all gasping movements and would
enter a phase described as terminal apnoea. The heart muscle
would no longer function and the fetus would die. This whole
process would take approximately 20 min.
Clearly, total asphyxia of a human infant is rare, more
commonly there is a prolonged partial asphyxia. However, these
experiments have provided us with important information to
help us to understand the physiological process that may occur in
an asphyxiated human infant around the time of birth. A baby
that has not commenced any breathing movements following
delivery may be in primary or terminal apnoea; we need a clear
strategy to attempt to reverse this apnoeic process. See Figure 1.
Resuscitation at birth
Initial actions
Preparation: as with many things, preparation is the key to
a successful outcome. The type of preparation that should occur
will vary with the clinical situation. Resuscitation is far more
likely to be required in situations where there is known fetal
compromise, preterm delivery, vaginal breech delivery and for
multiple pregnancies. However, not all resuscitations can be
predicted so it is important personnel trained in newborn
resuscitation are ready available, with the necessary equipment
to institute initial resuscitation efforts, whilst summoning
personnel trained in advanced resuscitation techniques. Local
guidelines should indicate who is most suitable to attend the
different deliveries and what equipment should be available.
� 2011 Elsevier Ltd. All rights reserved.
Newborn Life Support
Dry the baby
Remove any wet towels and cover
Start the clock or note the time
2010 Resuscitation Guidelines
Resuscitation Council (UK)
Reassess heart rate every 30 s
If heart rate is not detectable or slow (< 60 min-1)
consider venous access and drugs
Assess (tone), breathing and heart rate
If gasping or not breathing:
Open the airway
Give 5 inflation breaths Consider SpO2 monitoring
Re-assess If no increase in heart rate look for chest movement
If chest not moving:
Recheck head position
Consider 2-person airway control and other airway manoeuvres
Repeat inflation breaths Consider SpO2 monitoring
Look for a response
If no increase in heart rate look for chest movement
When the chest is moving:
If heart rate is not detectable or slow (< 60 min-1)
Start chest compressions 3 compressions to each breath
Birth
30 s
60 s
AT
ALL
STAGES
ASK:
DO
YOU
NEED
HELP?
Acceptable pre-ductal SpO2
2 min 60% 3 min 70% 4 min 80% 5 min 85% 10 min 90%
Figure 1 Newborn Life Support Algorithm 2010. With kind permission of the Resuscitation Council (UK).
SYMPOSIUM: NEONATOLOGY
PAEDIATRICS AND CHILD HEALTH 22:4 137 � 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
When there is a planned high-risk delivery, there needs to be
adequate communication between the multi-disciplinary teams
caring for the mother and neonate. This allows for the environ-
ment and equipment to be prepared. If time allows, the team
responsible for the neonatal care should introduce themselves to
the parents, revisit and outline the plan and invite any questions.
Cord clamping: in the uncompromised term infant there is
evidence that suggests delaying of cord clamping for at least 1
min is beneficial. This practice results in the baby having
increased iron stores at 3 months but may result in an increased
need for phototherapy in the immediate neonatal period. In the
preterm baby delayed cord clamping of at least 30 s has been
associated with a suggestion of an increase in postnatal blood
pressure, less need for postnatal blood transfusion, decreased
rates of intraventricular haemorrhage and reduced late onset
sepsis. It is also associated with increased rates of jaundice. For
babies requiring active resuscitation and stabilization there is not
sufficient evidence to suggest delayed cord clamping is beneficial
and commencing resuscitation should remain the priority.
The environment and temperature control: all babies are born
naked and wet and thus have the potential to become cold.
Preterm babies are at particular risk of hypothermia. It is known
that cold stress lowers arterial oxygen tension, increases meta-
bolic acidosis and inhibits surfactant production. The delivery
room should be kept warm and draught free. Following delivery
the term baby should be dried and then wrapped in a warm dry
towel. Alternatively, the baby can be dried and then placed skin
to skin with the mother, covering the baby with a dry towel. If
the term baby is judged to be compromised, the baby should be
dried, wrapped and placed on a warm flat surface directly under
a radiant heater.
For babies delivering at 28 weeks gestation and below, the
delivery room should be kept at 26 �C. Drying and wrapping the
preterm baby is often not sufficient to maintain body tempera-
ture. Placing the wet baby directly into a polyethylene bag or
wrapping in a polyethylene sheet (food or medical grade) up to
the neck and then placing the baby directly under a radiant
heater has been shown to be effective at maintaining tempera-
ture. Resuscitation and stabilization can occur with the plastic
cover in place. The baby should then be kept wrapped in poly-
ethylene until admission to the neonatal unit and the tempera-
ture checked.
Assessment: APGAR scores are not calculated to guide resusci-
tation efforts. The initial assessment for a newborn baby consists
of assessing the heart rate, respiratory effort, colour and tone. The
heart rate should be assessed using a stethoscope, palpating the
base of the umbilical cord is not as reliable. Colour is a poor guide
to oxygenation. Accuracy in assessing heart rate and oxygen
saturations are improvedwith pulse oximetry. Studies have shown
that if a neonatal pulse oximeter probe is attached preductally and
then connected to the pulse oximeter, reliable results will be
available in approximately 90 s. Pulse oximetry has the additional
benefit of providing a continuous measurement of heart rate and
oxygen saturations. An improving heart rate will indicate that
resuscitation efforts are being successful. If the heart rate is not
improving further resuscitation efforts may be required.
PAEDIATRICS AND CHILD HEALTH 22:4 138
Airway and breathing support
Neutral head position: a baby is in primary or terminal apnoea if
there are no signs of respiratory effort at birth. If a baby is
gasping, provided the airway is patent, the baby will aerate the
lungs and subsequently develop regular respiratory movements.
To maintain a patent airway the baby should be placed on a flat
surface with the head in a neutral position. This may be difficult
to achieve in a floppy baby due to the baby’s relatively large
occiput. A rolled towel or padding of not more than 2 cm may be
placed under the baby’s shoulders to assist with neutral posi-
tioning of the airway. A patent airway may also be provided by
using jaw thrust or the insertion of an appropriate sized
oropharyngeal airway, endotracheal tube or laryngeal mask.
Airway suctioning and meconium: obstruction of the airway
may be caused by particulate meconium, vernix, blood clots and
mucus. However, most newborn babies do not need to have their
airway suctioned to remove clear secretions. Suctioning of the
airway has been shown to lower oxygen tension and induces
bradycardia.
In circumstances of meconium stained liquor, the practice of
suctioning the mouth and nose of the baby on the perineum has
been shown to be ineffective at preventing meconium aspiration
syndrome. In addition, routine intubation and suctioning of the
trachea of the vigorous baby has also been shown to be inef-
fective at preventing meconium aspiration syndrome. In the case
of the non-vigorous baby, the available evidence does not
support or refute routine suctioning of the trachea. This is an
area where further randomized clinical trials would be helpful to
inform clinical practice.
Positive pressure ventilation: if the newborn baby is showing
inadequate or no spontaneous respiratory efforts, the lungs need
to be inflated. In the term newborn, giving five inflation breaths
each lasting 2e3 s at a pressure of 30 cm of water should result in
the establishment of the functional residual volume. Occasion-
ally, higher pressures may be required. The effectiveness of these
inflations should be judged by an increase in the heart rate. If
there is no improvement in the heart rate, chest wall movement
should be examined and face-mask seal technique should be
checked to ensure there are no leaks. Once the functional
residual volume has been established the lungs should be
ventilated at a rate of 30e40 breaths/min.
Inflation and subsequent ventilation breaths are given by face
mask in the majority of cases. The face mask may be attached to
a bag/valve system or T-piece system. The benefits of the
bag/valve system are that it does not require a gas supply and is
portable. However, its limitations include the inability to give set
pressures or continuous positive airway pressure (CPAP). The
bag/valve system comes with a pressure limiting valve usually
set to 40 cm of water; if the bag is squeezed vigorously pressures
far in excess of this may be generated. The benefits of the T-piece
system are varying inflation times may be given and the peak
inspiratory pressure (PIP) and peak expiratory end pressure
(PEEP) may be set to the desired level. The T-piece is limited
by the fact that in order to operate the system it requires
a compressed gas supply.
Preterm term lungs are damaged by large volume inflations
following birth. Animal studies have shown the benefit of
� 2011 Elsevier Ltd. All rights reserved.
0
Ox
yg
en
sa
tura
tio
n (
%)
Minutes after birth
a
1 2 3 104 5 6 7 8 9
100
90
80
70
60
50
40
30
20
10
0
0
Ox
yg
en
sa
tura
tio
n (
%)
Minutes after birth
b
1 2 3 104 5 6 7 8 9
100
90
80
70
60
50
40
30
20
10
0
0
Ox
yg
en
sa
tura
tio
n (
%)
Minutes after birth
c
1 2 3 104 5 6 7 8 9
100
90
80
70
60
50
40
30
20
10
0
3rd 10th 25th
75th 90th 97th
50th
Figure 2 Oxygen saturation percentiles for newborn infants with no medical
intervention after birth. (a) Third, 10th, 25th, 50th, 75th, 90th and 97th Spo2
SYMPOSIUM: NEONATOLOGY
PAEDIATRICS AND CHILD HEALTH 22:4 139
maintaining a PEEP to prevent this damage, improve lung
compliance and gas exchange. However, excessive PEEP may
reduce pulmonary blood flow and cause pneumothorax. It is
thought that initial inflation pressures of 20e25 cm of water are
adequate in preterm deliveries. Very obvious chest wall move-
ment in preterm infants undergoing positive pressure ventilation
may indicate excessive tidal volumes and pressures should be
adjusted accordingly. A preterm infant who is spontaneously
breathing may benefit from CPAP in the delivery room. The
COIN and SUPPORT trials have reported that there is no signif-
icant reduction in death or bronchopulmonary dysplasia in
infants treated with either early CPAP or intubation and surfac-
tant in the delivery room. They also reported preterm infants
exposed to CPAP following delivery had fewer days of ventilation
and oxygen requirement.
Air versus oxygen: in term newborn infants who require posi-
tive pressure ventilation, air has been shown to be as effective as
100% oxygen. There is now compelling evidence showing that
hypoxic tissues when exposed to high concentrations of oxygen
come to additional harm from oxygen free radicals and antioxi-
dants. Hyperoxaemia has been shown to be damaging to the
brain and other organs at the cellular level, particularly after
a hypoxic event. Pulse oximetry studies have provided us with
data for an uncompromised population of newborns making the
transition from intrauterine to extrauterine life. Babies born at
term and at sea level have saturations of approximately 60% in
utero and this rises to more than 90% by 10 min of age. When
born at higher altitude or by Caesarean section, these values are
found to be lower. It therefore seems reasonable to start resus-
citating in room air and any need for supplementary oxygen to be
guided by the pulse oximeter readings and heart rate.
In preterm infants resuscitating in air or 100% oxygen results
in hypoxaemia or hyperoxaemia respectively. There is not yet
sufficient data to indicate what oxygen concentration should be
used when commencing resuscitation in preterm infants. It
seems reasonable to aim for saturations resembling those of
healthy term infants and adjust the oxygen blender whilst being
guided by the pulse oximeter readings and heart rate. There are
now reference ranges for oxygen saturations in the first few
minutes following delivery for both term and preterm infants.
See Figure 2.
Endotracheal intubation: endotracheal intubation is of benefit
when face-mask ventilation has proved ineffective, tracheal
suction is required, ventilation is prolonged or there are special
circumstances e.g. congenital anomalies or administration of
surfactant. The timing of endotracheal intubation may depend on
operator skill and experience. Once the endotracheal tube has
percentiles for term infants at more than 37 weeks of gestation with no
medical intervention after birth. (b) Third, 10th, 25th, 50th, 75th, 90th and
97th Spo2 percentiles for preterm infants at 32e36 weeks of gestation with
nomedical intervention after birth. (c) Third, 10th, 25th, 50th, 75th, 90th and
97th Spo2 percentiles for preterm infants at less than 32 weeks of gestation
with no medical intervention after birth.
Dawson JA, Kamlin CO, VentoMet al. Defining the reference range for oxygen
saturation for infants after birth. Pediatrics 2010; 125(6): e1340ee1347withkind permission of the American Academy of Pediatrics.
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
been inserted, its position in the trachea needs to be confirmed.
There is an increasing body of evidence indicating detection of
exhaled carbon dioxide confirms tracheal intubation in neonates
with an adequate cardiac output faster than clinical assessment
alone. Clinical assessment includes seeing the tip of the endo-
tracheal tube pass through the vocal cords, prompt increase in
heart rate, equal chest wall movement, equal breath sounds
bilaterally and condensation (misting) in the endotracheal tube.
Oesophageal intubation should be suspected if the carbon
dioxide detection device fails to detect carbon dioxide. These
devices are suitable for use in term and preterm infants, but their
use has not been studied sufficiently in situations of circulatory
arrest where poor or absent pulmonary blood flow may prevent
carbon dioxide detection. False positives have also been docu-
mented in colorimetric devices when they have been contami-
nated with adrenaline, surfactant and atropine. Once the
endotracheal tube has been confirmed to be in the trachea, it is
important to ensure that it is secured at the correct depth. See
Table 1.
Laryngeal masks: in the newborn setting, a laryngeal mask that
fits over the laryngeal inlet has been used successfully in babies
requiring positive pressure ventilation with a gestation greater
than 34 weeks and weight more than 2000 g. They have also
been used successfully when face-mask ventilation and endo-
tracheal tube placement have proved unsuccessful. There is very
limited data for their use in smaller preterm infants. There is no
or insufficient evidence for the use of the laryngeal mask in the
setting of meconium stained liquor, during chest compressions or
during the administration of tracheal medications.
Circulation support
Chest compressions: chest compressions to provide circulatory
support are only effective if the lungs have been successfully
inflated. In the presence of a low heart rate, effective ventilation is
judged by the observation of chest wall movement. If the heart rate
remains below 60 beats per minute and there has been chest wall
movement, compressions should be commenced. There is no
scientific data that supports a given ratio of ventilations and
compressions in the neonatal population. Currently, the recom-
mended compression to ventilation ratio is 3:1. Chest compressions
Tracheal tube lengths by gestation and weight
ETT length at lips (cm) Gestation (weeks) Weight (kg)
5.5 23e24 0.5e0.6
6.0 25e26 0.7e0.8
6.5 27e29 1.9e1.0
7.0 30e23 1.1e1.4
7.5 33e34 1.5e1.8
8.0 35e37 1.9e2.4
8.5 38e40 2.5e3.1
9.0 41e43 3.2e4.2
Kempley ST, Moreiras JW, Petrone FL. Endotracheal tube length for neonatal
intubation. Resuscitation 2008; 77: 369e373.
Table 1
PAEDIATRICS AND CHILD HEALTH 22:4 140
are more effectively and efficiently provided when the two thumb
encircling method is used rather than the two finger method. The
chest should be compressed one-third of its anterioreposterior
diameter above the xiphisternum and just below the nipple line. In
1 min the aim should be to deliver 90 compressions and 30 venti-
lations. The chest wall should be allowed to return to its relaxed
position in between compressions to allow the heart to refill
passively after the compression. Compressions that are delivered
effectively will generate a pulsation seen on a pulse oximeter. The
heart rate should be assessed every 30 s and the chest compressions
should be discontinued once the heart is beating spontaneously
above 60 beats/min.
Medication and fluid: the use of medication or fluid is very
rarely required in neonatal resuscitation. Bradycardia is usually
secondary to hypoxia, therefore ensuring adequate ventilation
and chest compressions should result in the reversal of the
bradycardia. If the heart rate remains below 60 and the above
interventions are being performed correctly, the use of medica-
tion may be required.
Adrenaline e there is insufficient neonatal data to indicate
the most appropriate dose and route for adrenaline usage and the
data we do have is based on case series and case reports. From
the limited information available, the dose via the tracheal route
would need to be higher than that by the intravenous route to
obtain a similar clinical effect. When extrapolating data from
animal and paediatric studies, high doses of adrenaline given
intravenously, may cause cardiac and neurological dysfunction.
The current recommendations state that adrenaline should be
given intravenously via an umbilical venous catheter at a dose of
0.01e0.03 mg/kg. If the intravenous route is not available
tracheal adrenaline may be considered using a higher dose of
0.05e0.1 mg/kg.
Sodium bicarbonate e the use of sodium bicarbonate is
controversial and current guidance suggests that it is only
appropriate to use in prolonged resuscitation when other
methods have failed. The dose suggested for sodium bicarbonate
is 1e2 mmol/kg intravenously. The animal studies in the 1960s
showed that giving a mixture of alkali and glucose when the fetal
animal was known to be in terminal apnoea resulted in the return
of gasping and an increase in heart rate in the absence of any
other resuscitation efforts. In a number of studies sodium
bicarbonate has been shown to have a number of potential side
effects including depression of myocardial function, paradoxical
intracellular acidosis and decreased cerebral blood flow.
Fluid e it is rare that fluid is given during a neonatal resus-
citation and again there is limited neonatal data. It would seem
sensible to give volume when there is known or suspected blood
loss. In this situation it would be more appropriate to give
emergency blood to improve intravascular volume. If there is
a delay in obtaining suitable blood, isotonic crystalloid is
advised. A bolus of 10 ml/kg fluid should be given in the first
instance and its effect assessed prior to any further volume
administration.
Ongoing care following resuscitation
Newborns who have responded to resuscitation efforts remain at
risk for further deterioration. It is essential for them to have
� 2011 Elsevier Ltd. All rights reserved.
Practice points
C The need for resuscitation is not always predictable.
C Effective airway management is vital.
C Pulse oximetry readings should guide the need for supple-
mentary oxygen.
C Where there is evidence of hypoxiceischaemic encephalop-
athy, cooling should be considered.
C Ongoing clinical research is required to further our knowledge.
SYMPOSIUM: NEONATOLOGY
further observation and clinical care, usually within the neonatal
unit. After resuscitation, it is important to consider whether the
newborn meets the criteria for induced hypothermia (cooling).
There are several, good quality trials showing that infants born at
a gestation greater than 36 weeks, suffering from moderate to
severe hypoxiceischaemic encephalopathy, who are cooled,
have significantly reduced death and neuro-disability at 18
months. Cooling should be commenced as soon as possible after
resuscitation is completed; the current evidence suggests that
cooling is unlikely to be beneficial if delayed for greater than 6 h.
In centres where there are no facilities for cooling, the local
cooling centre should be contacted and arrangements for trans-
port made. Whilst awaiting transport, passive cooling should be
commenced.
Failure to respond to resuscitation
If a baby fails to respond to good quality resuscitation efforts and
the heart rate continues to be undetectable after 10 min, it is
appropriate to consider stopping resuscitation efforts. The deci-
sion to continue the resuscitation attempts may be affected by
a number of considerations, including, the newborns gestation,
the underlying aetiology and the parents expressed wishes. This
is a very difficult clinical situation for the resuscitation team and
experienced senior advice should aid decision making. A
FURTHER READING
Cramer K, Wiebe N, Hartling L, Crumley E, Vohra S. Heat loss prevention:
a systematic review of occlusive skin wrap for premature neonates.
J Perinatol 2005; 25: 763e9.
Davis PG, Tan A, O’Donnell CP, Schulze A. Resuscitation of newborn
infants with 100% oxygen or air: a systematic review and meta-anal-
ysis. Lancet 2004; 364: 1329e33.
Dawson JA, Kamlin CO, Vento M, et al. Defining the reference range for
oxygen saturation for infants after birth. Pediatrics 2010; 125:
e1340e7.
Finer NN, Waldemar AC, Walsh MC, et al. Early CPAP versus surfactant in
extremely preterm infants. N Engl J Med 2010; 362: 1970e9.
Hosono S, Inami I, Fujita H, Minato M, Takahashi S, Mugishima H. A role of
end-tidal carbon dioxide monitoring for assessment of tracheal intu-
bations in very low birth weight infants during neonatal resuscitation
at birth. J Perinat Med 2009; 37: 79e84.
PAEDIATRICS AND CHILD HEALTH 22:4 141
Kempley ST, Moreiras JW, Petrone FL. Endotracheal tube length for
neonatal intubation. Resuscitation 2008; 77: 369e73.
McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of
term infants on maternal and neonatal outcomes. Cochrane Database
Syst Rev 2008. CD004074.
Milner AD, Lagercrantz H. Adaptation at birth. In: Greenough A, Milner AD,
eds. Neonatal respiratory disorders. Arnold, 2003; 59e66.
Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP
or intubation at birth for very preterm infants. N Engl J Med 2008; 358:
700e8.
Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-
analysis of a brief delay in clamping the umbilical cord of preterm
infants. Neonatology 2008; 93: 138e44.
Richmond S, ed. Newborn life support: resuscitation at birth. London:
Resuscitation Council (UK), 2011.
Richmond S, Wyllie J. European Resuscitation Council guidelines for
resuscitation 2010 section 7: resuscitation of babies at birth. Resus-
citation 2010; 81: 1389e99.
Vain NE, Szyld EG, Prudent LM, Wisewell TE, Aguilar AM, Vivas NI.
Oropharyngeal and nasopharyngeal suctioning of meconium-stained
neonates before delivery of their shoulders: multicentre, randomised
controlled trial. Lancet 2004; 364: 597e602.
Wiswell TE, Gannon CM, Jacob J, et al. Delivery room management of the
apparently vigorous meconium stained neonate: results of a multi-
center, international collaborative trial. Pediatrics 2000; 105: 1e7.
Wyllie J, Perlman JM, Kattwinkel J, et al. Part 11: neonatal resuscitation
2010 International Consensus on Cardiopulmonary Resuscitation and
Emergency Cardiovascular Care Science with treatment recommenda-
tions. Resuscitation 2010; 81S: e260e87.
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Understanding blood gases/acidebase balanceNitin Goel
Jennifer Calvert
AbstractAcidebase balance is regulated by intracellular & extracellular buffers and
by the renal and respiratory systems. Normal pH is necessary for the
optimal function of cellular enzymes and metabolism. Disorders of acide
base balance can interfere with these physiological mechanisms leading
to acidosis or alkalosis and can be potentially life threatening. Blood
gas analysis is a routine procedure performed in the neonatal unit and
combined with non-invasive monitoring, aids in the assessment and
management of ventilation and oxygenation and provides an insight
into the metabolic status of the patient. The following discussion details
the basic terminology and pathophysiology of acidebase balance and the
main disorders. It aims to provide a logical and systematic approach to
the understanding and interpretation of blood gases in the newborn
period. The application of these concepts, together with relevant history
and examination, will help the clinician assess the medical condition,
make therapeutic decisions and evaluate the effectiveness of any inter-
vention provided.
Keywords acidebase balance; acidosis; alkalosis; anion gap; base
deficit; blood gas analysis; pH
Introduction & terminology
Acidebase balance is the complex physiological process, which
acts to maintain a stable extracellular pH within the body. It is
regulated by intracellular & extracellular buffers and by the renal
and respiratory systems. Any derangement in this balance can
interfere with physiological processes and can be potentially life
threatening. An understanding of acidebase balance is required
for the interpretation of blood gases, to assess both the respira-
tory and metabolic status of patients and thereby enable their
effective clinical management.
Normal pH is maintained between 7.35 and 7.45, which
creates an optimal environment for cellular metabolism. The pH
is inversely related to the concentration of Hþ ions.
pH a 1=Hþ
Nitin Goel MBBS MD MRCPCH is a Neonatal Registrar at the Neonatal
Intensive Care Unit in the University Hospital of Wales, Cardiff, UK.
Conflict of interest: none.
Jennifer Calvert BA BM BCh MRCP(UK) MRCPCH is a Consultant Neonatologist
at the Neonatal Intensive Care Unit, University Hospital of Wales,
Cardiff, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 22:4 142
An acid (HA) is a substance that donates Hþ ions (e.g. carbonic
acid). In contrast, a base (A�) accepts Hþ ions, (e.g. hydroxyl
ions, ammonia) and in solution combines with the acid to
neutralize it. An acid can dissociate into Hþ and a conjugate
base.
HA4Hþ þA�
Equilibrium is maintained based on the above equation.
Thus addition of acid (HA) increases Hþ and A� and shifts the
equation towards the right. During normal metabolism, Hþ ions
are constantly being produced and neutralized to maintain pH
homeostasis. Neonates produce higher levels of Hþ due to their
rapid growth and metabolism and therefore maintaining balance
can be challenging in newborn period.
Normal acidebase regulation
The process of maintaining pH balance during normal metabo-
lism involves buffer systems and compensatory mechanisms in
the respiratory and renal systems.
Buffer systems
Buffers are substances that attenuate the change in pH when
acid/base levels increase. On addition of acid, they bind to
any extra Hþ ions and prevent decline in pH. Similarly when
base is added, the buffers prevent a rise in pH by releasing Hþ
ions. The best buffers are weak acids and bases and work best
when they are 50% dissociated. The pH at which this happens
is called pK and is close to 7.40 for some buffers. The
HendersoneHasselbalch equation expresses the relationship
between pH, pK and concentrations of an acid and its conju-
gate base.
pH¼ pKþ log½A��=½HA�
Extracellular buffers: the bicarbonate system is the principal
buffer in the extracellular fluid (ECF) and is based on the rela-
tionship between carbon dioxide (CO2) and bicarbonate
(HCO3�), where the former combined with water acts as an acid
(carbonic acid H2CO3) and the latter as base.
Hþ þHCO�3 4H2CO34CO2 þH2O
The pK for this buffer is 6.1. For bicarbonate buffer, the
HendersoneHasselbalch equation is:
pH¼ 6:1þ log½HCO�3 �=½CO2�
Mathematical manipulation of the above equation produces the
following relationship,
½Hþ� ¼ 24� pCO2=½HCO�3 �
which emphasizes that Hþ ion concentration and hence pH is
determined by the ratio of pCO2 and HCO3� concentration, and
not their absolute values.
When Hþ ions are added to the system, the equation shifts to
right and pH is maintained at the expense of HCO3� ions, referred
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
to as ‘Base Deficit’. There is also an increase in dissolved CO2
levels (as H2CO3), which can be clinically estimated by measuring
the partial pressure of CO2 (pCO2). Thus with addition of Hþ ions,
the pH decreases with a decrease in base and an increase in CO2
levels. The lungs then excrete the excess CO2. With addition of
base, there is a decrease in CO2 and the lungs then reduce CO2
excretion. In this way the bicarbonate buffer system works as an
open system and plays an important role in pH homeostasis.
Intracellular buffers: these are non-bicarbonate buffers and
include various proteins and organic phosphates. The proteins
consist of acid histidine, with a side chain, which accepts Hþ ions
in exchange for intracellular potassium (Kþ) and sodium (Naþ)ions. In acute metabolic acidosis, hyperkalaemia can develop due
to the exchange of Kþ for Hþ.Phosphate can bind up to three Hþ ions and in its mono- and
di-hydrogen forms acts as an effective buffer in the urine.
H2PO1�4 4Hþ þHPO2�
4
Bone is also an important buffer and releases base on dissolution,
so can buffer an acid load, but at the expense of bone density.
During bone formation, it also consumes base thus buffering any
excess.
Compensatory mechanisms
Although buffers represent the first line of defence against pH
changes, they cannot maintain acidebase balance in disease
states for prolonged periods of time or with sudden significant
alterations of Hþ ion production. Instead, compensatory physi-
ological changes by the renal and respiratory systems are
employed. In a primary metabolic disorder, the respiratory
system provides the compensation, whereas in a primary respi-
ratory disorder, the regulation is by the renal system. Respiratory
responses occur more rapidly (minutesehours) than renal
mechanisms, which take about 3e4 days, with renal base
excretion more rapid than acid excretion. These compensatory
mechanisms must be followed by corrective measures to
normalize the acidebase balance, by treating the primary cause
of the imbalance.
Respiratory compensation: the respiratory system modifies pH
by balancing the production of Hþ with excretion of CO2.
During normal metabolism CO2 is generated, which is a weak
acid. Any increase in physical activity leads to an increase in
metabolism and thus an increase in pCO2. The lungs respond
by increasing ventilation and excreting excess CO2, thus
maintaining a normal pCO2 (4.5e6 kPa). Conversely, hypo-
ventilation causes CO2 retention and thus an increase in pCO2.
The resulting increase in Hþ ions directly stimulates chemore-
ceptors in the brain causing an increase in respiratory rate.
Thus changes in alveolar ventilation can alter pH and vice
versa.
Renal compensation: the kidneys prevent loss of HCO3� in the
urine and maintain plasma levels by excreting acid and gener-
ating new bicarbonate. They can thus respond to acidebase
imbalance by acidifying or alkalinizing the urine. This is
accomplished by:
PAEDIATRICS AND CHILD HEALTH 22:4 143
(1) Reabsorption of filtered HCO3, which takes place in the
proximal tubules (85%) and in the thick ascending loop of
Henle (15%).
Normally large amounts of bicarbonate enter the proximal
tubules (PT) daily and if this bicarbonate is not reclaimed by the
nephrons, severe acidosis can result. In the proximal tubular
cells, CO2 derived from cell metabolism or diffusion through the
tubular lumen, combines with water to form carbonic acid. This
dissociates into Hþ ions and bicarbonate via carbonic anhydrase.
The bicarbonate is transported back to the circulation, while the
Hþ ions are secreted into the tubular lumen, where they combine
with the filtered bicarbonate to form H2O and CO2. The CO2
diffuses back in the PT cells to repeat the cycle. The net effect is
that for each Hþ ion secreted, one HCO3� is retained, so that
bicarbonate reserves are continuously regenerated.
Factors causing an increase in Hþ ion secretion and thus
increased bicarbonate reabsorption include increased filtered
bicarbonate, volume depletion due to any cause and resulting
activation of renineangiotensin system, increased plasma pCO2
and hypokalaemia. Conversely Hþ ions secretion and thus
bicarbonate reabsorption is decreased in conditions with reduced
filtered bicarbonate, expansion of ECF volume and decreased
plasma pCO2. Hyperparathyroidism and disease states such as
proximal renal tubular acidosis (RTA), cystinosis, or neph-
rotoxins can also affect proximal tubules and limit bicarbonate
reabsorption.
Newborn infants and in particular preterm babies have
a lower glomerular filtration rate, immature tubular function and
limited capacity to retain bicarbonate and are therefore predis-
posed to metabolic acidosis.
(2) Excretion of Hþ ions which takes place at the distal tubules
and the collecting duct, thus acidifying the urine. The prin-
cipal buffers at these sites are phosphate and ammonia.
In normal conditions large amounts of phosphate ions are
present in the tubular fluid, which combine with Hþ ions,
forming titratable acid, thus reducing urinary pH. However,
phosphate buffering capacity is limited as there is no mechanism
for increasing urinary phosphate excretion in response to acide
base status.
Ammonia is generated in the cells of the proximal tubules,
diffuses into the tubular fluid and combines with the intra-
luminal Hþ ions to form ammonium ion, which cannot diffuse
back into the tubular cells, thus making ammonia an effective
buffer.
These two processes reduce free Hþ in the tubular fluid,
thereby increasing Hþ excretion into the urine and allowing the
generation of new bicarbonate in the cells, which can then
enter the plasma to replenish depleted levels. The major
regulator of Hþ secretion in the distal tubule is aldosterone with
other influencing factors being pCO2 and the sodium concen-
tration delivered to these segments. Sodium is reabsorbed in
exchange for either potassium or Hþ ions, under the influence
of aldosterone. These mechanisms may be impaired by intrinsic
defects in the tubules causing primary distal renal tubular
acidosis (RTA), or by various insults including nephrocalci-
nosis, vitamin D intoxication or Amphotericin B administra-
tion, which produce secondary distal RTA. Patients with distal
RTA cannot acidify their urine and have a urine pH more than
5.5, despite acidosis.
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Disturbances of acidebase balance
Abnormalities in blood pH, due to an increase in Hþ ions above
normal, is called ‘acidaemia’ (pH less than 7.35), and due to
a decrease is termed ‘alkalaemia’ (pH more than 7.45). The
clinical process, which causes the acid or alkali to accumulate, is
called ‘acidosis or alkalosis’, respectively.
As shown in Figure 1, acidosis is caused by conditions
resulting in either a reduction in HCO3� or an increase in pCO2,
leading to an increase in Hþ ions and decreased pH. Alkalosis is
caused when the primary disturbance causes either an increase
in HCO3� or a decrease in pCO2, leading to a decrease in Hþ ions
and an increased pH.
Metabolic acidosis
This results from an alteration in the balance between production
and excretion of acid; by increased exogenous intake or endoge-
nous production of Hþ ions, inadequate excretion, or by excessive
loss of bicarbonate in urine or stools (Table 1). Premature infants
less than 32 weeks gestation, frequently manifest a proximal or
distal RTA. In proximal RTA, there is limited secretion of Hþ ions
and incomplete bicarbonate reabsorption. Urine pH remains less
than 5, but becomes alkaline after a bicarbonate infusion, even
without normal serum bicarbonate levels. In distal RTA, the distal
tubules cannot secrete Hþ ions and thus the urine pH remains
alkaline (more than 7), rarely falling below 5.5.
Carbohydrate, fat and protein metabolism in the body
generate about 2e3 mEq/kg/day Hþ ions. Normally the CO2,
resulting from complete oxidation of carbohydrates and fats is
removed by the lungs. However anaerobic metabolism, as in
tissue hypoxia, produces lactic acid from glucose metabolism
and ketoacids from triglycerides, leading to acidosis.
pH < 7.
pH > 7.
CO + H O ↔ H CO
↑PCO
↓PCO
Respiratory acidosis
Respiratory compensation
Hyperventilation
↓PCO
Hypoventilation
↑PCO
Respiratory alkalosis
Figure 1 Acidebase regulation: interplay of bicarbon
PAEDIATRICS AND CHILD HEALTH 22:4 144
Systemic acidosis stimulates the respiratory centre directly,
the rate of breathing is increased and CO2 is excreted. The
acidosis also stimulates the kidneys to increase Hþ ion excre-
tion, accompanied by bicarbonate reabsorption. In renal insuf-
ficiency, the ability of kidneys to generate ammonia and secrete
Hþ ions is limited, leading to acidosis. In unstable neonates,
respiratory compensation is limited and because of tubular
immaturity, the acidosis worsens rapidly if the underlying cause
is not treated.
Anion gap: an important tool in evaluating the cause of meta-
bolic acidosis is the ‘anion gap’, the difference in the measure-
ment of the most abundant serum cation (Naþ) and the sum of
two most abundant serum anions (HCO3� and chloride, Cl�).
½Naþ� � ð½Cl�� þ ½HCO�3 �Þ
This gap also represents the difference between unmeasured
anions (phosphate, sulphate, proteins, acids e.g. lactate, ketoa-
cids) and unmeasured cations (potassium, magnesium, calcium).
It should not be interpreted in isolation but in conjunction with
other laboratory abnormalities and the clinical history. The
normal anion gap for neonates is 5e15 mEq/litre.
An elevated anion gap represents an increase in unmeasured
anions (Figure 2) and can result from overproduction or under
excretion of acids. Normal anion gap acidosis results from the net
loss of bicarbonate. In these cases Cl� reabsorption is increased
and it becomes the major anion accompanying Naþ and so the
sum of anions in plasma remains normal. Thus, normal anion
gap acidosis is also referred to as hyperchloraemic metabolic
acidosis.
35
45
↔ H+ + HCO –
↓HCO –
↑HCO –
Metabolic compensation
↑Bicarbonate
reabsorption
↑HCO –
↓Bicarbonate
reabsorption
↓HCO –
Metabolic acidosis
Metabolic alkalosis
ate buffer, respiratory and renal systems.
� 2011 Elsevier Ltd. All rights reserved.
Acidebase disorders, blood gas findings and common causes in neonates
Disorder Blood gas analysis (normal range) Causes
pH
(7.30e7.45)
pCO2
(4.5e6 kPa)
HCO3L
(19e24 mmol/l)
BE
(L3 to D3)
Metabolic acidosis
Uncompensated Y Normal Y Y Increased anion gap (more than 16 mEq/l)
Hypoxaemia/lactic acidosis: sepsis, shock, respiratory or cardiac disorders, anaemia, intraventricular haemorrhage,
perinatal asphyxia, necrotizing enterocolitis
Renal failure
Inborn errors of metabolism
Total parenteral nutrition
Normal anion gap (8e16 mEq/l)
Prematurity: hyperchloraemic acidosis
Renal tubular acidosis: proximal/distal
Gastrointestinal bicarbonate losses: ileostomy, diarrhoea
Compensated Low Y Y Y
Normal
Metabolic alkalosis
Uncompensated [ Normal [ [ Decreased urinary chloride (<10 mEq/l)
Gastric losses: vomiting, pyloric stenosis, excess naso-gastric aspirates
Diuretics
Chloride losing diarrhoea
Hypokalaemia
Increased urinary chloride (>20 mEq/l)
Hyperaldosteronism
Adrenal hyperplasia
Excess alkali administration
Compensated High [ [ [
Normal
Respiratory acidosis
Uncompensated Y [ Normal Normal Respiratory abnormalities: respiratory distress syndrome, chronic lung disease, pneumothorax, meconium aspi-
ration, transient tachypnoea of newborn, pneumonia, pulmonary hypoplasia, congenital lung malformations
Central nervous system depression: hypoxic ischaemic encephalopathy, excess opioids, raised intracranial pres-
sure, central hypoventilation, meningitis, malformations
Neuro-muscular disorders: congenital myopathies, neuropathies, spinal and neuro-muscular junction disorders
Upper airway obstruction: Pierre-Robin sequence, choanal atresia, laryngeal oedema/spasm/mass etc.
Iatrogenic: inadequate ventilator settings in mechanically ventilated patient
Compensated Low [ [ [
Normal
Respiratory alkalosis
Uncompensated [ Y Normal Normal Increased sensitivity of respiratory centre: hypoxia due to any cause
Medications: Caffeine
Extra pulmonary CO2 losses: ECMO, dialysis
Iatrogenic: over-ventilation of mechanically ventilated patient
Compensated High Y Y Y
Normal
Table 1
SYMPOSIUM:NEONATOLO
GY
PAEDIATRICSANDCHILD
HEALTH22:4
145
�2011Elsevie
rLtd
.Allrig
hts
reserve
d.
Normalplasma
UC
UC, unmeasured cations; UA, unmeasured anions.
The anion gap
UA
HCO
Na
UCUA
UC
UA
Cl
HCO
Cl
NaHCO
Cl
Na
Acidosis(no gap)
Acidosis(increased gap)
Figure 2 Anion gap.
SYMPOSIUM: NEONATOLOGY
Metabolic alkalosis
This results from increased bicarbonate and/or excessive loss of
Hþ ions. It is uncommon in the neonatal period. Causes are
related to increased renal reabsorption of HCO3, loss of Hþ ions
or increase addition of bicarbonate (Table 1).
The buffers try to minimize the changes, but bicarbonate and
pH rise, respiration is depressed, and there is an increase in
pCO2. Respiratory compensation is limited by increasing
hypoxia, so cannot normalize the pH. The kidneys respond
to this by increasing base excretion, with urine pH increasing to
8.5e9.0. The alkalosis can worsen if there is co-existing ECF
contraction and hypokalaemia, as it conversely increases bicar-
bonate reabsorption. This can only be corrected by treating the
underlying disorder.
Hypochloraemia and hypokalaemia are usually present, due
to increased urinary losses. Measurement of urinary chloride can
help differentiate the causes of metabolic alkalosis (Table 1). If
urine chloride levels are less than10 mEq/litre, the underlying
cause is generally volume depletion from extra-renal losses, with
loss of Naþ, Kþ and chloride. These cases are responsive to
sodium chloride. The use of diuretics in neonates can lead to
increased fluid and Naþ losses in the kidneys, stimulating Naþ
reabsorption in exchange for Hþ ions, thus leading to bicarbonate
reabsorption and metabolic alkalosis. If metabolic alkalosis is
secondary to excessive mineralocorticoid activity or potassium
depletion, the urine chloride is more than20 mEq/litre, and is
resistant to sodium chloride treatment.
Respiratory acidosis
This occurs due to inadequate pulmonary excretion of
CO2 leading to increases in pCO2 and H2CO3, with a resulting
rise in Hþ ions. This occurs both acutely and in a chronic
form, in conditions affecting the respiratory or neurological
systems (Table 1). The rise in pCO2 is initially buffered by
PAEDIATRICS AND CHILD HEALTH 22:4 146
non-bicarbonate buffers, protein & phosphate. If the rise is
sustained, as in preterm babies with chronic lung disease, the
kidneys are stimulated to excrete Hþ ions and to generate &
reabsorb bicarbonate. This causes plasma bicarbonate levels to
increase above normal and the pH returns to normal. This is
the compensated phase of respiratory acidosis and occurs over
days.
Respiratory alkalosis
This occurs with excessive pulmonary losses of CO2 and result-
ing fall in pCO2. This occurs with hyperventilation due to any
cause (Table 1). It is often iatrogenic, related to mechanical
ventilation. A rapid decrease in pCO2 has been associated with
periventricular leukomalacia and intraventricular haemorrhage,
so timely intervention is critical.
With decreased pCO2, pH rises and a rapid buffering occurs
with release of Hþ ions to decrease the plasma bicarbonate.
There is also increased renal excretion of HCO3�. This results
in a decrease in plasma bicarbonate and pH normalizes. Final
correction is achieved by treatment of the underlying
disorder.
Mixed disorders
In certain conditions, more than one disturbance can co-exist.
This should be suspected if the compensatory response falls
outside the expected range. For example, in respiratory
distress syndrome or pneumonia with sepsis, respiratory
acidosis (due to ventilatory failure) and metabolic acidosis
(due to lactic acidosis) often co-exist. The respiratory disease
prevents the compensatory fall of pCO2 and the metabolic
component prevents compensatory rise of plasma bicar-
bonate, resulting in a greater fall in pH. Similarly in chronic
lung disease with the use of loop diuretics, respiratory
acidosis and metabolic alkalosis can result. Thus the plasma
bicarbonate and pH are higher than expected. Patients with
hepatic failure can have metabolic acidosis and respiratory
alkalosis, with a greater than usual drop in plasma bicar-
bonate & pCO2 and little change in pH.
Implications of acidebase disorders
The effects of pH changes at a cellular level are poorly
understood. A low pH can reduce myocardial contractility and
impair catecholamine action, increasing the risk of
arrhythmia. The metabolic activity of proteins is pH depen-
dent and any changes may adversely affect enzyme activity.
An increase in Hþ ions can also cause disturbances in ion
transport within the kidneys. With acidosis, a decrease in
carbohydrate tolerance is observed and with alkalosis, an
increase in neuro-muscular irritability can occur, either in
a latent form or manifesting as tetany.
Invasive & non-invasive blood gas analysis in the neonatal unit
Blood gas analysis is routinely performed in the neonatal unit.
In conjunction with non-invasive monitoring, it enables
clinicians to appropriately assess & monitor the respiratory
status and modify ventilation strategy accordingly. It can also
provide information on metabolic status, acidebase
� 2011 Elsevier Ltd. All rights reserved.
Guide for blood gas values in neonates
Analyte Normal reference ranges
(arterial sample)
pH 7.30e7.45
PaCO2 (kPa) 4.5e6.0
PaO2 (kPa) 6.0e8.0
HCO3� (mmol/l) 19e24
BE (mmol/l) �3 to þ3
Table 2
SYMPOSIUM: NEONATOLOGY
imbalance and whether any respiratory or renal compensation
is taking place.
Blood gas values vary depending on the site of the sample,
i.e., arterial, capillary or venous; arterial samples are the most
informative. The technique of sampling is equally important; the
sample site should be warm if capillary, the sample itself should
be free flowing, un-diluted with no air bubbles and processed in
a timely manner (less than 15 min). Arterial gases provide
information about pulmonary gas exchange, while central
venous samples give information regarding the acidebase status
of tissues in conditions of severe hypoperfusion. If the sample is
taken from an arterial line running heparinized saline solution,
there is a risk of dilution with erroneously low pCO2 and bicar-
bonate values. Central venous pH is lower than arterial pH by
approximately 0.03 units and venous pCO2 is higher by 0.8 kPa.
These differences increase in hypoventilation and circulatory
failure, with a pH difference up to 0.1 units and pCO2 difference
of up to 3.2 kPa.
Capillary blood samples are commonly used in the neonatal
unit for blood gas estimation. The capillary values for pH and
pCO2 are usually within 1 kPa of the corresponding arterial
values. However, they have their limitations and are less reli-
able for babies with hypotension, poor perfusion or cold
peripheries. Capillary blood samples also cannot reliably
monitor oxygenation status or predict the degree of hypo-
xaemia. In these settings, an arterial blood gas is more useful,
although invasive.
Non-invasive monitoring using pulse oximetry to monitor
oxygen saturation in blood (SpO2) and transcutaneous moni-
toring are useful adjuncts to blood gas measurements. Pulse
oximeters work on the principle that oxygenated and deoxy-
genated haemoglobin absorb different wavelengths of light. The
oximeter provides a measure of the oxygen saturation of pulsatile
arterial blood compared with that from non-pulsatile venous
blood. It can be unreliable in hypoperfusion or with movement
artefacts. Transcutaneous electrodes measure oxygen (TcPO2)
and CO2 pressures (TcPCO2). They rely on diffusion from vaso-
dilated vessels in heated skin, so are particularly useful in the
newborn period when the skin is thin, but can be unreliable in
hypoperfusion. Transcutaneous levels usually match arterial
blood levels closely, thus careful application can be used to
monitor trends and may allow the frequency of blood gas
sampling to be reduced. Continuous end tidal CO2 monitors can
also be useful for monitoring CO2 levels in infants with stable
ventilation.
Clinical interpretation of blood gases
Blood gas analyzers measure pH, pCO2, PO2 and HCO3� (Table
2). They measure ‘actual’ HCO3� in the blood sample from
which they calculate ‘actual’ BE. Normally all the bicarbonate in
blood is produced by the ‘metabolic’ system, i.e., liver and
kidneys. However hypercapnia increases H2CO3 dissociation into
bicarbonate. ‘Standardised’ figures therefore calculate bicar-
bonate derived from CO2 and subtract this from the actual
measurements to reflect metabolic function. Thus in patients
with respiratory problems, it is advisable to use the ‘standard-
ized’ HCO3� and BE. Normal ranges vary slightly with gestation
& postnatal age and the desired values of these parameters for
PAEDIATRICS AND CHILD HEALTH 22:4 147
any specific medical condition can vary with clinical practice, for
example with approaches such as “permissive hypercarbia” or
“gentle ventilation”. Understanding that pH is maintained by the
ratio of HCO3�/pCO2, a patients’ acidebase status can be readily
ascertained from a blood gas.
The following steps can be used as a guide for blood gas
interpretation (see Table 1):
1. Is there acidaemia or alkalaemia, i.e., pH less than 7.30 or pH
more than 7.45?
2. Is it primarily metabolic, i.e., HCO3� less than 19 or more
than 24 mmol/litre & BE less than �3 or more than þ3? OR
Is it primarily respiratory, i.e., pCO2 less than 4.5 or more
than 6 kPa?
3. Is there any compensation?
4. Is there a mixed disorder present, i.e., values outside the
normal compensation?
Blood gases should always be interpreted in conjunction with
information from a detailed history and thorough clinical
examination, the type of sample and non-invasive monitoring.
The prudent use of blood gas analysis in conjunction with
continuous monitoring allows optimal assessment of the patient
and prompt intervention when required, the response to which
can then be monitored and the blood gas repeated after an
appropriate time period to ensure clinical improvement.
Management should always be directed at the underlying cause
and an understanding of the processes involved in acidebase
balance aids this interpretation. A
FURTHER READING
1 Greenbaum Larry A. Chapter 52.7. Acidebase balance. In:
Kleigman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson text-
book of paediatrics. 18th Edn. WB Saunders, 2007.
2 Quigley R, Baum M. Neonatal acid base balance and disturbances.
Semin Perinatol 2004 Apr; 28: 97e102.
3 Adelman RD, Solhaug MJ. Chapter 52. Hydrogen ion. In: Behrman RE,
Kleigman RM, Jenson HB, eds. Nelson textbook of paediatrics. 16th
Edn. WB Saunders, 2000.
4 Modi N. Chapter 39. In: Rennie JM, Roberton NRC, eds. Textbook of
neonatology. 3rd Edn. Churchill Livingstone, 1999.
5 Cloherty JP, Eichen EC, Stark AR, eds. Manual of neonatal care.
6th Edn. Lippincott Williams & Wilkins, 2008.
6 Woodrow P. Essential principles: blood gas analysis. Nurs Crit Care
2010 MayeJun; 15: 152e6.
� 2011 Elsevier Ltd. All rights reserved.
Practice points
C A stable pH is essential for optimal cellular metabolism and
can be challenging in the newborn period
C Acidebase balance is regulated by buffers, the respiratory &
renal systems
C When the compensatory response falls outside the expected
value, a mixed acidebase disorder is likely
C Blood gases can be used to monitor acidebase balance
C Blood gases should always be interpreted in conjunction with
information from the clinical history & examination and non-
invasive monitoring
SYMPOSIUM: NEONATOLOGY
7 Lorenz JM, Kleinman LI, Markarian K, Oliver M, Fernandez J.
Serum anion gap in the differential diagnosis of metabolic
acidosis in critically ill newborns. J Pediatr 1999 Dec; 135:
751e5.
8 Brouilette RT, Waxman DH. Evaluation of the newborn’s blood gas
status. Clin Chem 1997 Jan; 43: 215e21.
9 Edwards SL. Pathophysiology of acid base balance: the theory practice
relationship. Intensive Crit Care Nurs 2008; 24: 28e40.
10 Williams AJ. ABC of oxygen: assessing and interpreting
arterial blood gases and acidebase balance. BMJ 1998 Oct 31;
317: 1213e6.
11 Foxall F. Arterial blood gas analysis: an easy learning guide. 1st Edn.
London: M&K Update Ltd, 2008.
12 Hennessey IAM, Japp AG. Arterial blood gases made easy. 1st Edn.
Edinburgh: Churchill Livingstone, 2007.
PAEDIATRICS AND CHILD HEALTH 22:4 148 � 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
Recognition andmanagementof neonatal seizuresVaishali Patel
Amit Kandhari
Shobha Cherian
AbstractSeizures in the neonate are frequent and often the only sign of neurological
dysfunction. They can be caused by a variety of conditions ranging from the
benign and self-limiting to life threatening disorders. Several unresolved
issues remain concerning when to initiate treatment, duration of therapy
and what anticonvulsant medications should be used. Recent insights
into the pathophysiology may provide the foundation for better treatment.
Keywords neonatal; seizures; treatment
Introduction
Seizures occur more frequently in the neonatal period than at any
other time during the human lifespan. The overall incidence is 1e3
per 1000 live births. The incidence in high-risk premature infants
maybeashigh as 57e132per 1000 live births. 80%of seizures occur
in the first week of life and are often the first sign of neurological
dysfunction. Rapid diagnosis of the underlying cause is important in
order to institute specific therapy. Although the present treatment of
neonatal seizures is often unsatisfactory, considerable progress has
been made in understanding the pathogenesis of seizures and the
response by the neonate to anticonvulsant therapy.
Pathophysiology
Seizures in both term and preterm infants differ considerably
from those in older children and adults both in frequency and
clinical presentation. Understanding the probable mechanisms
for the genesis of seizures within the immature central nervous
system will lead to an understanding of its varied clinical
presentation and the conundrums associated with treatment.
Biochemical basis of neonatal seizures
A seizure is a sudden, excessive, synchronous electrical discharge
of a group of neurons within the central nervous system. This
Vaishali Patel MBBS MD MRCPCH is Paediatric Registrar in the Neonatal
Intensive care unit at the University Hospital of Wales, Cardiff, UK.
Conflict of interest: none.
Amit Kandhari MBBS MRCPCH is Paediatric Registrar in the Department of
Paediatrics at the Princess of Wales Hospital, Bridgend, UK.
Conflict of interest: none.
Shobha Cherian MB BS MD MRCP(UK) MRCPCH is Consultant Neonatologist in
the Neonatal Intensive care unit, University Hospital of Wales, Cardiff, UK.
Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 22:4 149
electrical discharge is due to depolarization of neurons, resulting
from an influx of sodium ions. Negative potential across neuronal
cells ismaintained by anATP (adenosine triphosphate) dependant
Naþ (sodium)e(Kþ) potassium pump. Depolarization can result
from one of four mechanisms:
1 Decreased energy production and failure of ATP dependant
NaþeKþ pump e.g. following hypoxia-ischaemia and hypog-
lycaemia
2 Excessive release of the excitatory neurotransmitter gluta-
mate and reduced (energy dependant) uptake into cells e.g.
following hypoxia-ischaemia
3 Deficiency of inhibitory neurotransmitters: gamma-amino
butyric acid (GABA) is the predominant inhibitory neuro-
transmitter in the brain. A deficiency of pyridoxine,
a cofactor for GABA synthesis, will lead to reduced levels of
GABA and consequently to seizures
4 Hypocalcaemia and hypomagnesaemia also cause seizures
as both calcium and magnesium inhibit Naþ movement
across neuronal cells.
Neurodevelopmental basis for neonatal seizures
Anatomical: neonates rarely develop easily recognizable tonic-
clonic seizures. Motor phenomena are often asynchronous and
not well propagated. Subtle seizures presenting with sucking,
occulomotor phenomenon and apnoea are more frequent. This
may be because myelination, dendritic outgrowth and formation
of synaptic junctions in the cerebral cortex are relatively
incomplete, while the development of subcortical and limbic
structures are relatively advanced.
Physiological: glutamate is the major excitatory neurotransmitter
in the central nervous system, while GABA is the major inhibitory
neurotransmitter. Glutamate receptors are located at synapses, on
non-synaptic sites, on neurons and on glia. There are three types
of ionotropic (i.e. linked to calcium and sodium ion channels)
glutamate receptors; the NMDA receptor (N-methyl-D-aspartate),
the AMPA receptor (alpha-amino-3 hydroxy-5-methyl-4-iso-
xazolepropionic acid) and the kainite receptor. Experimental
evidence has shown that in the neonatal brain, both NMDA and
AMPA receptors are over expressed and their subunit composition
renders them susceptible to enhanced excitability. NMDA
receptor antagonist drugs (ketamine, meperidine) suppress
seizures, however they cause deep sedation and induce apoptotic
cell death in the immature brain. AMPA receptor antagonists
(topiramate) appear to be potentially highly effective against
neonatal seizures.
To compound the relative excess of ‘excitability’ of the perinatal
brain, GABA receptor expression is low in early life. In addition,
GABA receptor activation produces excitation rather than inhibi-
tion of neurotransmission. This paradoxical action of GABA in the
neonate is due to age related differences in chloride homeostasis.
Chloride transport is a function of two membrane pumps. In the
neonate NaþeKþeCl� co-transporter (NKCC1) imports large
amounts of chloride into the neuron. Chloride levels within
the neuron remain high because of relative under expression of
KþeCl� co-transporter, (KCC2) which is a Kþ exporter. When the
chloride permeable GABA receptors are activated, chloride flows
out of the cell depolarizing it. As a result GABA activation is
excitatory rather than inhibitory. This explains why in the
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
neonatal period, GABA agonists e.g. barbiturates and benzodiaz-
epines, are relatively ineffective. With maturation, NKCC1
expression diminishes and KCC2 expression increases. GABA
activation then causes chloride to flow into the cell and hyperpo-
larize it (Figure 1). Maturation of these chloride co-transporters
occurs in a caudal to rostral direction with maturation of spinal
cord and brain stem receptors occurring before that of the cerebral
cortex. This explains why treatment with GABA agonists often
results in suppression of motor manifestations with persisting
electrical seizures. Early clinical trials have shown the NKCC1
inhibitor, bumetanide, to be effective against neonatal seizures.
Clinical features
There are four major types of neonatal seizures. Their incidence,
clinical manifestations and EEG (electroencephalograph) corre-
lates are shown in Table 1. Seizures must be differentiated from
three types of non-convulsive movements: jitteriness, benign
sleep myoclonus and hyperekplexia.
Jitteriness: jitteriness is tremulousness. It is not accompanied by
ocular, orobuccal or autonomic phenomenon and can be elimi-
nated by gentle passive flexion of the affected limb. Jitteriness
may occur with hypoglycaemia, hypocalcaemia, drug with-
drawal and hypoxic-ischaemic encephalopathy.
Benign sleep myoclonus: is characterized by bilateral, repetitive,
myoclonic movements involving the upper or lower limbs that
occur only during sleep. Myoclonus may be provoked by gentle
rocking of the mattress that stops abruptly on arousal of the infant.
The episodes can last for several minutes. The interictal EEG is
either normal or shows minor non-specific changes. It resolves
within about 2 months and the neurological outcome is normal.
Figure 1 Transmission of electrical impulses at synapses in the neonatal perio
neuron (left panel) by activating NMDA and AMPA receptors. GABA release (righ
in the immature CNS. NKCC1: sodium-chloride co-transporter, KCC2: potassiu
alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid, Naþ: sodium, Ca2
PAEDIATRICS AND CHILD HEALTH 22:4 150
Hyperekplexia: also known as ‘startle disease’, is characterized
by an exaggerated startle response and sustained tonic spasm to
handling and to unexpected auditory, visual stimuli. Nocturnal
myoclonus and generalized hypertonia may occur which can
interfere with bathing, diaper change and feeding. Forced truncal
flexion can terminate an episode. The EEG is invariably normal.
It is an autosomal dominant disorder caused by increased
excitability of reticular neurons in brain stem. Hyperekplexia
disappears spontaneously by about 2 years of age.
Aetiology
The main causes of seizures are listed in Table 2. Asphyxia is the
commonest cause and accounts for up to 40% of all neonatal
seizures. Other frequent causes are cerebral arteriovenous
infarction (20%), intracranial haemorrhage (12e20%), infection
(3e20%), hypoglycaemia and hypocalcaemia (3e19%),
congenital cerebral anomaly (5e10%). The aetiology remains
unknown in 10e13% cases.
Epilepsy syndromes: are of unclear aetiology and unlike the
non-convulsive movements detailed earlier have documented
EEG abnormalities.
Benign idiopathic neonatal seizure (fifth day fits) e seizures
begin by day 3e5 and may last for 2 weeks. The diagnosis is one
of exclusion. The interictal neurological examination and EEG
are normal. The cause remains unknown, however low CSF zinc
deficiency has been demonstrated in a few cases. The develop-
mental outcome is favourable.
Benign familial neonatal convulsions e this rare condition
has an autosomal dominant inheritance involving mutations in
voltage-gated potassium channel genes. Seizures occur in
an otherwise healthy neonate on day 2e3 of life and may last for
d. Presynaptic release of glutamate results in excitation of post synaptic
t panel) results in hyperpolarization in the mature CNS and depolarization
m-chloride co-transporter, NMDA: N-methyl-D-aspartate, AMPA:þ: calcium, Cl�: chloride.
� 2011 Elsevier Ltd. All rights reserved.
Incidence, clinical characteristics and EEG correlates in various forms of neonatal seizures
Clinical seizure Incidence Clinical manifestation EEG activity
Subtle 50%
- More common in premature infants
- Orobuccal: sucking, chewing, lip smacking,
hiccups
- Ocular: blinking, staring, horizontal devia-
tion of eyes
- Limbs: cycling, rowing
- Autonomic: alteration in heart rate, blood
pressure, apnoea, colour change
þ/�
Clonic 25e30% - Repetitive jerking
- Focal, multifocal or generalized (rare)
þ
Tonic 5% - Sustained posturing of limbs/trunk
- Deviation of head/eyes
- Focal, generalized
- Generalized may mimic decerebrate or
decorticate posturing
Focal: þGeneralized: �
Myoclonic 15e20% - Rapid isolated jerks
- Common in flexor group of muscles
- Focal, multifocal, generalized, axial
Focal and multifocal: �Generalized:þ
Table 1
SYMPOSIUM: NEONATOLOGY
1e6 months. There is often a family history of neonatal seizures
and development is normal. However, secondary epilepsy may
occur in 10e15%.
Early myoclonic encephalopathy e is characterized by severe
recurrent myoclonic and focal clonic seizures, which then prog-
resses to tonic spasms. Onset is in the first weeks of life, however
intrauterine onset has been documented. The underlying cause
may be an inborn error of metabolism e.g. nonketotic hyper-
glycinemia but in 50% cases the cause is unknown. The EEG
shows burst suppression that is enhanced by sleep and persists
beyond 1 year of age. Prognosis is poor and seizures are resistant
to treatment needing multiple anticonvulsant drugs.
Early infantile epileptic encephalopathy (Ohtahara
syndrome) e seizures begin in the first 3 months of life as tonic
spasms that progress to myoclonic spasms. Seizures are resistant
to treatment and are often accompanied by severe encephalop-
athy. The EEG shows burst suppression like early myoclonic
encephalopathy, but is not altered by sleep or waking. The
prognosis of this syndrome is also poor with death or severe
psychomotor retardation occurring in the first few years of life.
Management of neonatal seizures
There are several fundamental controversies regarding the
diagnosis and treatment of neonatal seizures:
1 Recognition of seizures
2 Why treat?
3 When to treat?
4 What is appropriate treatment?
5 How long to treat?
Recognition of seizures
Neonatal seizures are difficult to recognize, as there are often no
clinical manifestations of electrographic seizures; a phenomenon
PAEDIATRICS AND CHILD HEALTH 22:4 151
called electro clinical dissociation. This is believed to occur as
connectivity within the nervous system is not fully developed
and myelination is incomplete. Infants may show no signs or
very subtle signs of electrical seizures. As up to 80% of EEG
documented seizures are not accompanied by clinically observ-
able seizures, full channel EEGs are essential for diagnosis and
for assessing efficacy of treatment. Video-EEG monitoring, where
continuous EEG monitoring is accompanied by contempora-
neous video recording documenting suspicious clinical behav-
iours, is considered the neurophysiological ‘gold standard’.
Several subtle seizures, tonic seizures and myoclonic jerks have
no EEG correlates and are believed to be generated at a deep
subcortical level.
In viewof this diagnostic complexity, some argue that diagnosis
of neonatal seizures should not be based on clinical observation
alone. As EEGs are difficult to obtain round the clock on the
neonatal unit, initial diagnosis and treatment is based on clinical
observation. Several centres are now using amplitude integrated
EEG (aEEG) as a readily available bedside tool. This device uses
a single or dual channel EEG and acute variations in spectral width
to detect seizures. Several reports show that aEEG detects
approximately 75% of seizures detected by conventional EEGs.
The complete list of investigations to be performed would
vary with aetiology but should include blood glucose, serum
electrolytes, calcium, magnesium, full blood count, C reactive
protein, blood gas analysis, blood culture and lumbar puncture.
Urine toxicology, TORCH screen and a metabolic screen should
be performed if indicated. Neuroimaging in the form of a cranial
ultrasound scan, magnetic resonance imaging or computed
tomography are often indicated.
Why treat?
The impact of convulsions on the immature brain has long been
debated. Although the immature brain is more prone to seizures,
� 2011 Elsevier Ltd. All rights reserved.
Aetiology of neonatal seizures
Hypoxic Ischaemic encephalopathy
Cerebro-vascular
Arterial and venous stroke
Sinus thrombosis
Intracranial haemorrhage
Intraventricular/periventricular
Subarachnoid
Subdural/epidural
Trauma
Birth trauma
Non accidental injury
Intracranial infection
Bacterial meningitis (Group B Strep, E. coli, Listeria)
Viral encephalitis (Herpes simplex, Enterovirus)
Intrauterine TORCH infection
Malformations of cerebral development
Polymicrogyria
Pachygyria
Lissencephaly
Neurocutaneous syndromes
Tuberous sclerosis, incontinentia pigmenti
Electrolyte and metabolic abnormalities
Hypoglycaemia
Hypocalcaemia
Hypomagnesaemia
Hyponatraemia, Hypernatraemia
Neonatal drug withdrawal
Kernicterus
Inborn errors of metabolism
Amino acid, organic acid, urea cycle disorders
Mitochondrial and peroxisomal disorders
Pyridoxine dependency
Inadvertent injections of local anaesthetics during delivery
Epilepsy syndromes
Benign idiopathic neonatal convulsions (fifth day fits)
Benign familial neonatal convulsions
Early myoclonic encephalopathy
Early infantile epileptic encephalopathy (Ohtahara syndrome)
Table 2
SYMPOSIUM: NEONATOLOGY
it is more resistant to post seizure damage than the mature brain.
However, evidence from several animal models and a few studies
on human infants has shown that prolonged and recurrent
seizures have widespread effects, which are deleterious to the
developing brain.
The proposed mechanisms for brain injury are shown in
Figure 2. Animal studies have shown that seizures result in
reduced density of dendritic spines in hippocampal pyramidal
neurons, delayed neuronal loss, decreased neurogenesis,
synaptic reorganization and changes in hippocampal plasticity.
Magnetic resonance spectroscopy studies on human infants with
seizures have shown disturbances in cerebral metabolism and
adverse long-term neurological sequelae. This suggests that seizures
might cause or exacerbate cerebral injury by increasing cerebral
PAEDIATRICS AND CHILD HEALTH 22:4 152
metabolic demands above that of energy supply. Infants with
hypoxia-ischaemia and clinical seizures have been shown to have
a significantly worse outcome than those without seizures, inde-
pendent of the severity of hypoxia-ischaemia.Also, post-hoc analysis
of data from theCool-Caphypothermia trial revealed that theabsence
of seizures was an independent predictor for better outcomes.
Unfortunately there is insufficient evidence from randomized
controlled trials to either support or refute the use of anticon-
vulsants for the treatment of neonatal seizures. The question of
whether aggressive treatment of seizures, most of which occur
against the background of pre-existing brain injury, confers
benefit requires further clinical investigation.
When to treat?
Poorly controlled and prolonged seizures are associated with poor
neurodevelopmental outcome, however the severity of the
underlying disease may account for both the poor seizure control
and outcome. Several questions remain unanswered. How long
must a seizure last before it leads to brain injury? Does the degree
of CNS injury vary with type of seizure, particularly those without
documented EEG changes? Does treatment with anticonvulsants
alter developmental outcome when the underlying disorder is
controlled for? Should electrical seizures be treated or should only
clinical seizures be treated? There are no randomized trials that
answer all these questions. Some feel it is reasonable to treat
frequent and prolonged seizures especially if they are associated
with cardiorespiratory compromise. As there is no agreed defini-
tion of ‘prolonged’ seizures, many neonatologists take a pragmatic
approach and treat seizures by the ‘rule of 3’ i.e. treat if there are
more than three seizures per hour or if any one seizure lasts more
than 3 min. Others feel that all seizures, both electrical and clin-
ical, should be treated to prevent further brain injury.
What is appropriate therapy?
The evaluation and initial management of the infant with clinical
seizures should not await EEG confirmation. The following basic
principles should be followed:
1 Support airway, breathing and circulation
2 Check blood glucose and secure vascular access. If hypo-
glycaemia is present in a convulsing infant, give 2 ml/kg of
10% dextrose intravenously and start maintenance dextrose
solution to achieve normal blood glucose levels.
3 Investigate and treat the underlying cause
4 Balance the benefits of controlling some or all of the seizures
with anticonvulsant drugs against risks of potential side
effects from the medications.
Anticonvulsant therapy:
Phenobarbitone e is a GABA agonist. It controls approximately
70% of clinical seizures and 50% of electrical seizures. This is
probably because many GABA receptors are excitatory and have
immature chloride channels. (See Pathogenesis) However, it
continues to be the drug of choice in neonates as it has been well
studied, has a longhalf-life (2e4days) andenters theCSF rapidly. It is
given as a loading dose of 20 mg/kg (which may be repeated if the
initial dose is ineffective) andachieves therapeutic levels (20e40mg/
litre) in the serum within a short time.
Phenytoin e acts by reducing electrical conductance in
neurons by stabilizing sodium channels. Both phenytoin and
� 2011 Elsevier Ltd. All rights reserved.
Prolonged/ repeated seizures affects
Respiratory system Cardiovascular system Energy metabolism Neuro-transmitters
Brain injury
Po2 Pco2 BP Glycolysis ADPRe-uptakeof EAA
Releaseof EAA
EAABrain glucose
Haemorrhage
CBF CBFLactate+ H+
ATP/
Figure 2 Mechanisms for the development of brain injury following prolonged or repeated seizures. PO2: oxygen pressure, PCO2: carbon dioxide pressure,
BP: blood pressure, ATP: adenosine triphosphate, ADP: adenosine diphosphate, EAA: excitatory amino acid, Hþ: hydrogen ion, CBF: cerebral blood flow.
SYMPOSIUM: NEONATOLOGY
phenobarbitone are equally but incompletely effective in
achieving complete control of clinical and electrographic
seizures. Their combination achieves control of 85% of clinical
seizures and up to 80% of electrical seizures. Phenytoin should
be given in the dose of 20 mg/kg intravenously slowly, under
cardiac monitoring, as it can cause hypotension and arrhythmias
especially in the presence of myocardial damage accompanying
hypoxia-ischaemia. Skin rashes have also been reported.
Benzodiazepines e are GABA agonists and are used to control
seizures where the combination of phenobarbitone and phenytoin
has been ineffective. Both clonazepam and midazolam are widely
used. Clonazepam has a long half-life (24e48 h) and is given as
a bolus dose of 100 mg/kg. It causes increased respiratory and oral
secretions that may interfere with respiratory function. Midazolam
has a shorter half-life (approximately 6 h in sick and premature
infants) and is administered as a bolus dose of 200 mg/kg followed
by infusion of 60e300 mg/kg/h. It has been reported to cause
myoclonic jerks and dystonic posturing in premature infants.
Lorazepam has been used in neonates in the dose of 100 mcg/kg
given intravenously and has duration of action of 6e24 h.
Lidocaine e suppresses seizures by suppressing sodium entry
into the neuron. It has been shown to decrease seizure burden in
up to 60e75% infants who have not responded to phenobarbi-
tone and benzodiazepines. A loading dose of 2 mg/kg is followed
by an infusion of 6 mg/kg/h for 6 h, 4 mg/kg/h for 12 h and then
2 mg/kg/h for 12 h. It has a narrow therapeutic range and can
induce seizures in high doses. As it can induce cardiac arrhyth-
mias and hypotension, it should not be given with phenytoin and
must be administered under continuous cardiac monitoring.
Levetiracetam (Keppra) e is a commonly prescribed anti-
convulsant medication in older children and adults. Its anticon-
vulsant action is not well understood but is believed to impede
PAEDIATRICS AND CHILD HEALTH 22:4 153
nerve conduction across synapses. Pharmacokinetic and safety
data in neonates is lacking, however it has been tried with some
success in seizures resistant to other medications.
Topiramate e has multiple proposed mechanisms of action. It
acts as a glutamate antagonist by blocking AMPA receptors, is
a Naþ channel blocker and has been shown to be neuroprotective
following hypoxia-ischaemia in animal models. It has not yet
been studied for safety, dosing or efficacy in neonates, however,
a recent retrospective, cohort study reported good results in six
newborn infants with seizures refractory to standard agents.
Bumetanide e is commonly used as a diuretic. It inhibits the
NKCC1 co-transporter, creating a Cl� gradient more like the adult
neuron. In animal models this switches the GABA equilibrium
potential from excitatory to inhibitory. Although it has been
shown to be a promising therapy in the laboratory, there are no
reported clinical trials.
Other drugs:
Paraldehydeewas used as an effective adjunct anticonvulsant.
It has a short half-life and is eliminated by the lungs and liver and is
not affected by altered renal function. However, as it must be
administered per rectally, is reported to cause pulmonary oedema,
hepatic necrosis and hypotension, it is no longer widely used.
Sodium valproate e has been used to treat intractable
seizures. Due to serious concerns regarding hyperammonaemia
and hepatotoxicity its value is uncertain.
Carbamazepine e has been reported to be effective in the
treatment of neonatal seizures. However it must be administered
orally and blood levels are very variable.
Pyridoxine e diagnosis of pyridoxine dependent seizures is
suspected when an infant develops multifocal clonic seizures
resistant to conventional anticonvulsants soon after birth. 50e100
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
mg of pyridoxine should be administered intravenously under EEG
monitoring. Seizure activity stops within minutes and the EEG
normalizes.
How long to treat?
Practice points
C The neonatal brain is more prone to seizures than the mature
brain due to an over expression of glutamate receptors (NMDA,
AMPA) and under expression of GABA receptors. In addition
GABA receptors are excitatory in the neonate
C Electrical seizures may occur without any clinical manifesta-
tion, a phenomenon known as electro clinical dissociation
C The need to treat electrical seizures is controversial
C Phenobarbitone remains the mainstay of therapy despite
being ineffective in a significant proportion
C Levetiracetam, topiramate and bumetanide may have a role in
the future
Once seizures are controlled, should maintenance therapy be
administered and if so for how long? Once again, there is no
consensus on this issue. Antiepileptic drugs have a deleterious
effect on the developing brain. Animal studies have demon-
strated that systemic therapy with phenobarbitone, benzodiaze-
pines, phenytoin and valproate increase apoptotic neuronal
death. Combination therapy produced greater adverse effects.
Abnormal cognitive development has been documented in
infants and children that have received phenobarbitone.
The risk of developing recurrent seizures once seizure
control is achieved and anticonvulsants discontinued is under
10% in infants with normal EEG background activity. In infants
with both abnormal neurological examination and EEG back-
ground activity, it may be as high as 50%. It would therefore be
prudent to administer maintenance therapy (phenobarbitone 3
e5 mg/kg) only if the neurological examination or EEG back-
ground activity is abnormal. Once neurological examination is
normal, phenobarbitone should be withdrawn. In most cases
this can be done before discharge from the neonatal unit. If
neurological examination remains abnormal, obtain an EEG and
discontinue phenobarbitone if there is no electrical seizure
activity.
Prognosis
The long-term neurodevelopmental outcome in infants with
seizures varies with aetiology, gestational age, seizure type and
interictal EEG. The prognosis following benign familial seizures
is excellent while 30e50% of infants with hypoxia-ischaemia,
hypoglycaemia and meningitis have abnormal developmental
outcome. Nearly all infants with CNS malformations have a poor
outcome. When seizures occur with normal EEG background
activity, the outcome is good, while those with low voltage EEG,
burst suppression or electrocerebral silence are associated with
neurodevelopmental deficits in more than 90% cases. Only 20%
premature infants with a birth weight less than 1500 g and
seizures have a normal outcome as compared to 60% of term
infants. Intractable seizures, generalized myoclonic and tonic
seizures are often associated with poor outcome. A
PAEDIATRICS AND CHILD HEALTH 22:4 154
FURTHER READING
1 Lawrence R, Inder T. Neonatal status epilepticus. Semin Pediatr
Neurol 2010; 17: 163e8.
2 Glass HC, Glidden D, Jeremy RJ, Barkovich J, Ferriero DM, Miller SP.
Clinical neonatal seizures are independently associated with
outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr
2009; 155: 318e23.
3 Levene M. The clinical conundrum of neonatal seizures. Arch Dis
Child Fetal Neonatal Ed 2002; 86: 75e7.
4 Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant
treatment of neonatal seizures: a video-EEG monitoring study.
Neurology 2004; 62: 486e8.
5 Volpe JJ. Neonatal seizures. In: Neurology of newborn. 5th Edn. W. B.
Saunders, 2009; 203e244.
6 Silverstein FS, Ferriero DM. Off-label use of antiepileptic drugs for the
treatment of neonatal seizures. Pediatr Neurol 2008; 39: 77e9.
7 Dzhala VI, Talos DM, Sdrulla DA, et al. NKCC1 transporter facilitates
seizures in the developing brain. Nat Med 2005; 11: 1205e13.
8 Booth D, Evans DJ. Anticonvulsants for neonates with seizures.
Cochrane Database Syst Rev 2004; 18: CD004218.
9 Bassan H, Bental Y, Shany E, et al. Neonatal seizures: dilemmas in
workup and management. Pediatr Neurol 2008; 38: 415e21.
10 El-Dib M, Chang T, Tsuchida TN, Clancy RR. Amplitude-integrated elec-
troencephalography in neonates. Pediatr Neurol 2009; 41: 315e26.
11 Jensen FE. Neonatal seizures: an update on mechanisms and
management. Clin Perinatol 2009; 36: 881e900.
� 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NEONATOLOGY
The role of brain MRIscanning in the newbornPia Wintermark
AbstractVery sick newborns are at high risk for brain injuries and adverse neuro-
developmental outcomes. Accurate diagnosis of these injuries and
adequate prognostication of future outcome is one of the most difficult
tasks confronting caregivers in neonatal intensive care units. In the
past several years, there have been tremendous advancements in the
development of magnetic resonance imaging (MRI) technologies devoted
to studying the newborn brain. MRI is now slowly becoming the new stan-
dard of care for evaluating the exact nature and extent of brain injuries in
sick newborns, as well as reliably predicting the future prognosis of these
newborns. In addition, it is giving unique insights about how brain
injuries develop in these patients and how they further impact brain
maturation. This will probably help in the future to refine therapeutic
strategies offered to these patients, and to evaluate the efficiency of
such changes. In this article, we thus review some of the current and
future roles of brain MRI scanning in the newborn.
Keywords brain injuries; magnetic resonance imaging; newborn brain
Diseases leading to brain injuries in newborns
Hypoxic-ischaemic encephalopathy
Stroke
Cerebral sinovenous thrombosis
Prematurity
Congenital cardiopathy
Infection: Cytomegalovirus, Enterovirus, Parechovirus, Herpes
Simplex Virus, .
Introduction
Very sick newborns are at high risk for brain injuries and adverse
neurodevelopmental outcomes. A major issue confronting care-
givers who work with these children is to provide the most
accurate prognosis about their future to their families. The major
challenge of researchers in the neonatal neurology field is to find
innovative treatments to prevent or repair brain injuries in these
newborns. Nowadays, advances in modern neuroimaging are
continuously ongoing, allowing us to improve our understanding
of how neonatal brain injuries develop and how they impact on
further brain development. Among the available neuroimaging
techniques for these patients, magnetic resonance imaging (MRI)
is proving more and more to be useful, even if more expensive
and more challenging to obtain compared to head ultrasounds.
Brain MRI is slowly becoming the new standard of care for
evaluating the exact nature and extent of brain injuries in sick
newborns, as it provides good spatial resolution and thus accu-
rate anatomical details that cannot be obtained by any other
imaging modality. Furthermore, more and more studies are
Abbreviations: DTI, diffusion-tensor imaging; DWI, diffusion-weighted
imaging; MRI, magnetic resonance imaging; NICU, neonatal intensive care
unit; SWI, susceptibility-weighted imaging.
Pia Wintermark MD is an Assistant Professor in the Department of
Pediatrics in the Division of Newborn Medicine, Montreal Children’s
Hospital, McGill University, Montreal, Canada, an associate Member in
the Department of Neurology and Neurosurgery at McGill University and
an Associate Member of the Integrated Program in Neurosciences at
McGill University. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 22:4 155
demonstrating the role of MRI as a reliable predictor of the future
prognosis of newborns with brain injuries, as well as its potential
to give further insights into maturation, destruction and repair
processes occurring concurrently in a newborn brain. In this
article, we review some of the current and future roles of brain
MRI scanning in the newborn.
The newborn brain
The human brain begins forming very early in prenatal life (just
three-four weeks after conception), but continues to develop
years postnatally. Especially very active and complex processes
such as elaboration of dendritic and axonal ramifications,
establishment of synaptic contacts, selective elimination of
neuronal processes and synapses, proliferation and differentia-
tion of glia, and myelination, start during gestation, but continue
for several years after birth. This plasticity explains why the
newborn brain is more vulnerable to insults. Brain injuries in the
newborn occur thus against these active developmental events.
After the acute damage, neuronal circuits pursue develop-
mental processes with a significant cell loss, leading to disruption
of normal developmental processes. This can cause dramatic
deterioration of subsequent brain development and brain func-
tions. The key issue is to understand better the molecular and
cellular mechanisms of these processes and their timing. This is
of utmost importance for developing new strategies to improve
prevention and repair of brain injuries in the newborn.
Diseases leading to brain injuries in newborns
Many different diseases can lead to brain injuries in newborns.
This review does not present an exhaustive list, but rather
discusses those most frequently encountered in the neonatal
intensive care unit (NICU) (Table 1).
Newborns with hypoxic-ischaemic encephalopathy displayed
heterogeneous brain injuries. Patterns of these injuries have been
associated with varying clinical presentations and different
neurodevelopmental outcomes. They have been classically
Neonatal hypoglycemia
Other metabolic diseases: inborn errors of metabolism, .
Malformation of brain development: focal cortical dysplasia,
hemimegalencephaly, .
Anomalies of cerebral vasculature
Phakomatoses: tuberous sclerosis, neurofibromatosis, .
Brain tumours
Perinatal brain trauma
Table 1
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SYMPOSIUM: NEONATOLOGY
described as basal ganglia injury pattern, boundary zone injury
pattern (watershed injury pattern) and total cortical injury
pattern, according to the injured parts of the brain. Perinatal
stroke (Figure 1) is another not-uncommon clinical entity
affecting the newborn with impact on long-term neurological
outcome. It is characterized by focal infarction of the brain
parenchyma, which is most often ischaemic in nature in
newborns rather than hemorrhagic. Newborns are also at higher
risk to develop cerebral sinovenous thrombosis, which is often
complicated by intraventricular haemorrhage associated with
unilateral thalamic haemorrhage or bilateral white matter
involvement.
Premature newborns are prone to germinal matrix haemor-
rhage, intraventricular haemorrhage and periventricular hae-
morrhagic infarction, but also white matter and grey matter
injuries. They may display a large spectrum of white matter and
grey matter injuries, including white matter signal abnormality,
decreased white matter volume, cystic abnormalities in white
matter, ventricular dilatation, decreased myelination in the
posterior limb of the internal capsule, thinning of the corpus
callosum, grey matter signal abnormality, simpler gyral pattern,
increased subarachnoid space and cerebellar injuries. Newborns
with congenital cardiopathy are another population of newborns
at high risk of developing brain injuries. Even before cardio-
vascular surgery, these newborns have been shown to have
delayed third trimester brain growth, impaired white matter
maturation, reduced N-acetyl-aspartate and increased lactate,
suggesting an early onset of impaired brain growth and
development.
Among congenital infections leading to brain injuries,
congenital Cytomegalovirus infection is probably one of the most
devastating. Depending on the timing of the infection, it can
cause different types of brain injuries, i.e. ventriculomegaly,
subependymal cysts, intraventricular septa, calcifications,
cortical migrational disturbances, cerebellar hypoplasia and
temporal white matter injuries. White matter changes resembling
periventricular leukomalacia have been seen in cases of neonatal
meningoencephalitis with Enterovirus and Parechovirus, and an
infection by these viruses should be excluded when scattered
white matter injuries are present in term newborns without clear
explanations. Neonatal Herpes Simplex Virus Type 2 typically
causes multifocal brain injuries that are mostly located to
temporal lobes, brainstem and cerebellum. Bacterial meningitis
Figure 1 Stroke in a term newborn. MRI performed at 42 4/7 weeks of correcte
image, (c) Axial apparent diffusion coefficient (ADC) map, and (d) Axial diffus
territory.
PAEDIATRICS AND CHILD HEALTH 22:4 156
may also lead to focal (single or multiple) diffuse and/or
hemorrhagic infarcts, with associated meningeal enhancement.
Symptomatic neonatal hypoglycemia is associated with
involvement of parietal and occipital cortex, subcortical white
matter, posterior limb of internal capsule, basal ganglia, and
thalami. Other metabolic diseases, especially inborn errors of
metabolism, are often very difficult to diagnose for the physician. In
these cases, brain MRI may play a useful role in diagnosis, as there
are few neuroradiological features for differentiating these errors.
Imaging appearance of inborn errors of metabolism includes white
matter injuries (true leukodystrophy or Wallerian degeneration),
grey matter injuries and involvement of basal nuclei.
Malformations of brain development, anomalies of cerebral
vasculature, phakomatoses (Figure 2), brain tumours and peri-
natal brain trauma are other potential diseases associated with
brain injuries in newborns. For each of these entities, brain MRI
plays an important role for diagnosis, treatment planning and
prognosis.
MRI sequences available for brain newborn imaging
A dedicated imaging protocol should be developed for scanning
the newborn brain. Standardized protocols are now available
through literature. The typical imaging protocol should include
all the essential MRI sequences to evaluate brain injuries in the
newborn, including high spatial resolution T1- and T2-weighted
imaging, diffusion-weighted imaging (DWI) and spectroscopy, as
well as fluid attenuated inversion recovery (FLAIR) imaging, MR
angiography, MR venography and susceptibility-weighted
imaging (SWI) if required. It may also include newer MRI
adjuncts, such as diffusion-tensor imaging (DTI) and diffusion
tractography, functional MRI and perfusion-weighted imaging.
Conventional T1- and T2-weighted imaging are the most
widely used sequences, specifically differentiating fat from water.
Perinatal lesions are typically at their most obvious on conven-
tional imaging between 1 and 2 weeks from birth, explaining
why this timing is most often chosen to perform an MRI in
newborns with hypoxic-ischaemic encephalopathy to define the
extent of the brain injuries and give a prognosis. DWI explores
micromovements of water molecules and can detect changes in
water diffusion associated with cellular dysfunction. It can
differentiate between cytotoxic and vasogenic oedema in cases of
early brain hypoxic-ischaemic infarcts. DWI is very useful for the
early identification of ischaemic tissue in the neonatal brain
d age (5 days of life). (a) Axial T1-weighted image, (b) Axial T2-weighted
ion-weighted image showed the infarction within the left cerebral artery
Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved.
Figure 2 Tuberous sclerosis in a term newborn. MRI performed at 42 3/7 weeks of corrected age. (a) Sagittal T1-weighted image showed multiple
subependymal hamartomas (thin arrows) along the wall of the lateral ventricle. (b) Sagittal T1-weighted image showed a mass, presumably a giant cell
tumour (thick arrow) located at the level of the foramen of Monro. (c) Axial FLAIR image showed the cortical tubers (curved arrows) as hyperintense
signals. (d) Axial FLAIR image showed the white matter tracts (black arrowheads) extending from the tubers to the ventricular surface.
SYMPOSIUM: NEONATOLOGY
(Figure 1) but may underestimate the final extent of injuries,
particularly basal ganglia and thalamic lesions. DWI enables
quantitative measurements of apparent diffusion coefficient
(ADC) values in brain tissue. Spectroscopy allows exploration of
the molecular composition of the tissue and monitor biochemical
changes over time. Proton spectroscopy especially permits the
study of metabolites which can be altered in newborns devel-
oping brain injuries, such as lactates (product of anaerobic
glycolysis), N-acetyl-aspartate (NAA) (neuronal marker), gluta-
mine/GABA (neurotransmitter), creatine (energy metabolism),
choline (cell membrane marker) and myo-inositol (glial cell
marker). Early elevation of lactate and later reduction of N-
acetyl-aspartate have for example been demonstrated in cases of
newborns with hypoxic-ischaemic brain injuries. Metabolic data
from proton MR spectroscopy might also be a useful adjunct to
more conventional sequences, especially in helping to diagnose
an inborn error of metabolism (e.g. neonatal maple syrup urine
disease with specific peak at 0.9 ppm representing branched
chain amino acids and ketoacids).
Fluid attenuated inversion recovery (FLAIR) images are
T2-weighted images with the cerebrospinal fluid signal sup-
pressed. This imaging technique is more sensitive than T1- and
T2-weighted imaging for detecting pathologies specifically
located periventricular or subcortical within the brain paren-
chyma, such as for example tubers in tuberous sclerosis
(Figure 2). MR angiography might be added to the imaging
protocol for newborns, in order to look at the anatomic varia-
tions of the neonatal circle of Willis and to explore possible
vascular-related abnormalities, such as arteriovenous malfor-
mations. MR venography should be added to study possible
neonatal cerebral sinovenous thrombosis. SWI, another MR
imaging technique, accentuates the paramagnetic properties of
blood products such as deoxyhemoglobin, intracellular meth-
aemoglobin and haemosiderin. It is particularly well suited for
detecting intravascular venous deoxygenated blood as well as
extravascular blood products, especially for visualizing even
very small normal or abnormal veins or parenchymatous
haemorrhage.
More advanced MR-based neuroimaging approaches are now
also becoming available for newborns. DTI, functional connec-
tivity MRI (fcMRI), volumetric MR analysis, and surface based
morphometry (SBM) are now providing insight into structural
and functional brain maturation and the impact of brain injuries
on this development. Perfusion-weighted imaging, and more
PAEDIATRICS AND CHILD HEALTH 22:4 157
specifically arterial spin labeling (ASL), now enables direct
noninvasive imaging of cerebral perfusion, and this may have
several implications for better understanding how brain injuries
develop in newborns, as abnormal brain perfusion is a key
mechanism in many of them.
Brain MRI for clinical purposes
Brain MRI currently has two main clinical applications in the
newborn. The main role of brain MRI is to define the extent of
brain injuries and to give important clues about the cause and
timing of an insult by the combination of the different MRI
sequences. As mentioned above, conventional imaging can
detect patterns of injuries that provide valuable information
about prognosis. The addition of DWI and spectroscopy might
provide guidance as to the timing of the event or help to diagnose
the aetiology of some brain injuries. All this information cannot
be obtained by any other neuroimaging modality in the newborn.
The second important clinical application of brain MRI in the
newborn is to provide valuable information about the long-term
prognosis. For example, abnormal findings on MRI at term
equivalent in very preterm infants have been shown to strongly
predict adverse neurodevelopmental outcomes at 2 years of age,
permitting the use of MRI at term equivalent in risk stratification
for these infants. Similarly, the pattern of perinatal lesions in
newborns with hypoxic-ischaemic encephalopathy or stroke
provides valuable information about prognosis in these patients.
Brain MRI for research purposes
MRI techniques offer great potential for further understanding how
brain injuries develop in the newborn brain and how they can be
prevented or repaired. The pattern of injuries seen in the newborn
is unique due to the combination of effective loss of brain tissue
and remodelling of subsequent brain development. The exact
pathogenesis of these lesions in the developing brain is still not
well understood. It is considered to be multifactorial, with impli-
cations of several prenatal, perinatal but also postnatal factors. As
mentioned previously, some of the most recent MRI sequences
adjuncts provide important insights into the trajectory of brain
development and the impact of injuries on this developmental
trajectory. Further results of such ongoing studies should improve
our knowledge and offer us important clues on how to develop
specific and efficient treatments in these newborns. For these
reasons, these more advanced neuroimaging techniques will
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SYMPOSIUM: NEONATOLOGY
probably soon be part of the regular imaging protocol for
newborns, as they already are in adult MRI protocols.
As MR imaging is an excellent predictor of outcome following
perinatal brain injuries, it also has an huge potential to be used as
a surrogate, short-term outcome measure in clinical studies eval-
uating new interventional trials designed to reduce injuries in the
developing brain and improve neurodevelopmental outcome. It
will help in delineating which infants have the most to gain from
these newer therapeutic strategies, but may also act as an early
biomarker to gauge response to these new interventions.
Safety of brain MRI scanning in the newborn
MRI is a noninvasive and nonionizing neuroimaging technique
and does not involve harmful radiation. Thus, when available, it
should be preferred over computed tomography (CT) scan in
newborns, especially as it provides additional detailed imaging of
the brain parenchyma. Obtaining a brain MRI in this population
of sick children might appear challenging, especially when the
NICU is located at distance from the MRI suite. However, brain
MRI in newborns can be safely and easily obtained with
a minimum of requirements and training. A specialized team
should be dedicated to these scans. This team should include
neonatologists, neonatology fellows or neonatal nurse practi-
tioners, NICU nurses and respiratory therapists who care exclu-
sively for the newborn from NICU departure to return, as well as
neuroradiologists and MRI technicians who know how to oper-
ate, acquire and read neonatal neuroimaging. Time inside the
MRI should be balanced between the haemodynamic stability of
the newborn being imaged and the need to obtain optimal data
for analysis, diagnosis, and prognosis, as well as the time
available on the machine for such exam. As mentioned above,
specific imaging protocol should be developed for imaging of
these patients. A dedicated neonatal imaging coil or the best
available coil adapted for this type of imaging should be chosen
in order to optimize the signal-to-noise ratio.
Most of newborns do not need to be sedated for a brain MRI.
Neonates should be placed in a MRI-compatible isolette
or wrapped with one or two thin blankets and placed on
a MRI-compatible pillow containing small polystyrene spheres.
Once the neonate is placed on the pillow, the air in the
MRI-compatible pillow will be removed by suction to mould the
shape of the pillow to the infant’s head and body and further
reduce motion artifacts. If possible, feeding should be adminis-
tered after wrapping the newborn as described above, and some
time should be available to let the baby fall asleep naturally. Ears
should be covered with earmuffs to reduce noise exposure. All
metal objects should be removed form the newborn before
entering the MRI suite. Supportive therapies, including
mechanical ventilation, vasoactive infusions, antiepileptic treat-
ments and sedation, should be maintained throughout the exam
per current clinical practice. Additional sedation should be
administered only if deemed clinically necessary and should be
rarely required. Of note, most of the neonatal treatments, such as
hypothermia, mechanical ventilation and pressor support, can be
continued in the MRI with special precautions. Ventilation by
high-frequency oscillatory ventilation and/or administration of
nitric oxide might be the only treatments that cannot be admin-
istered in some of the MRI suites.
PAEDIATRICS AND CHILD HEALTH 22:4 158
Conclusions
In conclusion, there have been tremendous advancements in the
development of MRI technologies devoted to the newborn brain.
Brain MRI should be the gold standard for neonates who have
encephalopathy or suspected brain injuries in order to clearly
define the extent of the injuries. It should be used to identify the
newborns, who are most at risk for subsequent neuro-
developmental disability and who may benefit from early inter-
vention services. But also, as often as possible, it should be used
to improve our knowledge of these brain injuries to further refine
our therapeutic strategies in these patients and to evaluate the
efficiency of such changes. A
FURTHER READING
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venous thrombosis fromsymptom tooutcome.Stroke2010;41:1382e8.
6 Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cere-
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neonatal hypoglycemia. Pediatrics 2008; 122: 65e74.
7 Counsell SJ, Tranter SL, Rutherford MA. Magnetic resonance imaging of
brain injury in the high-risk term infant.Semin Perinatol 2010; 34: 67e78.
8 De Vries LS, Groenendaall F. Patterns of neonatal hypoxic-ischaemic
brain injury. Neuroradiology 2010; 52: 555e66.
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10 Hagmann CF, De Vita E, Bainbridge A, et al. T2 at MR imaging is an
objective quantitative measure of cerebral white matter signal
intensity abnormality in preterm infants at term-equivalent age.
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11 Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ. Defining the
nature of the cerebral abnormalities in the premature infant: a
qualitative magnetic resonance imaging study. J Pediatr 2003; 143:
171e9.
12 Inder TE, Warfield SK, Wang H, Huppi PS, Volpe JJ. Abnormal cerebral
structures present at term in premature infants. Pediatrics 2005; 115:
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13 Kate R, Atkinson D, Brant-Zawadzki M. Fluid-attenuated inversion
recovery (FLAIR): clinical prospectus of current and future applica-
tions. Top Magn Reson Imaging 1996; 8: 389e96.
14 Kersbergen KJ, Groeneendaal F, Benders MJ, de Vries LS. Neonatal
cerebral sinovenous thrombosis: neuroimaging and long-term follow-
up. J Child Neurol 2011; 26: 1111e20.
15 Kirton A, DeVeber G. Advances in perinatal ischemic stroke. Pediatr
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16 Lawrence RK, Inder TE. Anatomic changes and imaging in assessing
brain injury in the term infant. Clin Perinatol 2008; 35: 679e93.
Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved.
Practice points
C There have been tremendous advancements in the develop-
ment of magnetic resonance imaging (MRI) technologies
devoted to the newborn brain.
C MRI is a noninvasive and nonionizing neuroimaging technique.
When available, it should be preferred over computed
tomography scan in newborns, especially as it provides addi-
tional detailed imaging of the brain parenchyma.
C Brain MRI in newborns can be safely and easily obtained with
a minimum of requirements and training. Most of newborns do
not need to be sedated for a brain MRI. Most of the neonatal
treatments, such as hypothermia, mechanical ventilation and
pressor support, can be continued in the MRI with special
precautions.
C A dedicated imaging protocol should be developed for scan-
ning the newborn brain. The typical imaging protocol should
include all the essential MRI sequences to evaluate brain
injuries in the newborn, including high spatial resolution T1-
and T2-weighted imaging, diffusion-weighted imaging (DWI)
and spectroscopy, as well as Fluid Attenuated Inversion
Recovery (FLAIR) imaging, MR angiography, MR venography
and susceptibility-weighted imaging (SWI) if required. It may
also include newer MRI adjuncts, such as diffusion-tensor
imaging (DTI) and diffusion tractography, functional MRI and
perfusion-weighted imaging.
C Brain MRI should be the gold standard for neonates who have
encephalopathy or suspected brain injuries in order to clearly
define the extent of brain injuries. It should be used to identify
the newborns, who are most at risk for subsequent neuro-
developmental disability and who may benefit from early
intervention services.
C Brain MRI should be used to improve our knowledge of these
brain injuries, to further refine our therapeutic strategies in
these patients and to evaluate the efficiency of such changes.
SYMPOSIUM: NEONATOLOGY
17 Limperopoulos C. Extreme prematurity, cerebellar injury, and autism.
Semin Pediatr Neurol 2010; 17: 25e9.
18 Lodygensky GA, Vasung L, Sizonenko SV, H€uppi PS. Neuroimaging of
cortical development and brain connectivity in human newborns and
animal models. J Anat 2010; 217: 418e28.
19 Malamateniou C, Adams ME, Srinivasan L, et al. The anatomic vari-
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20 Mathur AM, Neil JJ, McKinstry RC, Inder TE. Transport, monitoring, and
successful brain MR imaging in unsedated neonates. Pediatr Radiol
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21 Mathur AM, Neil JJ, Inder TE. Understanding brain injury and neuro-
developmental disabilities in the preterm infant: the evolving role
of advanced magnetic resonance imaging. Semin Perinatol 2010; 34:
57e66.
22 Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in
term neonatal encephalopathy. J Pediatr 2005; 146: 453e60.
23 Miller SP, Ferriero DM, Leonard C, et al. Early brain injury in premature
newborns detected with magnetic resonance imaging is associated
with adverse early neurodevelopmental outcome. J Pediatr 2005;
147: 609e16.
24 Miller SP, McQuillen PS, Hamrick S, et al. Abnormal brain develop-
ment in newborns with congenital heart disease. N Engl J Med 2007;
357: 1928e38.
25 Mukherjee P, McKinstry RC. Diffusion tensor imaging and tractog-
raphy of human brain development. Neuroimaging Clin N Am 2006;
16: 19e43.
26 Owen M, Shevell M, Majnemer A, Limperopoulos C. Abnormal brain
structure and function in newborns with complex congenital heart
defects before open heart surgery: a review of the evidence. J Child
Neurol 2011; 26: 743e55.
27 Rutherford M, Biarge MM, Allsop J, Counsell S, Cowan F. MRI of
perinatal brain injury. Pediatr Radiol 2010; 40: 819e33.
28 Seghier ML, H€uppi PS. The role of functional magnetic resonance
imaging in the study of brain development, injury, and recovery in the
newborn. Semin Perinatol 2010; 34: 79e86.
29 Tong KA, Ashwal S, Obenaus A, Nickerson JP, Kido D, Haacke EM.
Susceptibility-weighted MR imaging: a review of clinical applications
in children. AJNR Am J Neuroradiol 2008; 29: 9e17.
30 Verboon-Maciolek MA, Groenendaal F, Hahn CD, et al. Human
parechovirus causes encephalitis with white matter injury in
neonates. Ann Neurol 2008; 64: 266e73.
31 Volpe JJ. Neonatal encephalitis and white matter injury: more than
just inflammation? Ann Neurol 2008; 64: 232e6.
32 Volpe JJ. Brain injury in premature infants: a complex amalgam of
destructive and developmental disturbances. Lancet Neurol 2009; 8:
110e24.
33 Volpe JJ. The encephalopathy of prematurityebrain injury and
impaired brain development inextricably intertwined. Semin Pediatr
Neurol 2009; 16: 167e78.
34 Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal
MRI to predict neurodevelopmental outcomes in preterm infants.
N Engl J Med 2006; 355: 685e94.
PAEDIATRICS AND CHILD HEALTH 22:4 159
35 Wintermark P, Labrecque M, Warfield SK, DeHart S, Hansen A. Can
induced hypothermia be assured during brain MRI in neonates with
hypoxic-ischemic encephalopathy? Pediatr Radiol 2010; 40: 1950e4.
36 Wintermark P, Hansen A, Gregas MC, et al. Brain perfusion in
asphyxiated newborns treated with therapeutic hypothermia. AJNR
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Acknowledgements
The author thanks Aaron Johnstone and Therese Perreault for their
thorough review of the manuscript.
Crown Copyright � 2011 Published by Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
Cleft lip and palate: currentmanagementTim Goodacre
Marc C Swan
Figure 1 Left complete unilateral cleft of lip, alveolus, hard and soft
palate.
AbstractCleft lip and palate are the most common presenting congenital condi-
tions of the face and cranial bones. This article describes current under-
standing of the aetiology and presentation of the deformity and
management of the child from prenatal diagnosis until maturity. Principle
concerns include correction of the physical defect with the best possible
functional and cosmetic outcome, optimal speech correction, satisfactory
feeding and hearing, and dental and orthodontic health. The value of
comprehensive management of all aspects of care within a multidisci-
plinary team including clinical psychology support for child and family
is discussed.
Keywords alveolar bone graft; cleft lip; cleft palate; naso-alveolar
moulding; orthognathic; pharyngoplasty; postoperative emergencies;
submucous
Definitions
Cleft lip (CL) is defined as a congenital abnormality of the
primary palate (i.e. anterior to the incisive foramen). It may be
complete, incomplete or microform, unilateral or bilateral, and
may involve a palatal cleft (CL � P) (see Figure 1).
A cleft palate (CP) is a congenital abnormality of the
secondary palate and may be complete or incomplete, unilateral
or bilateral, or submucous.
CL � P is epidemiologically and aetiologically distinct from
isolated CP.
Epidemiology
The overall incidence of orofacial clefting is approximately one in
700 live births, amounting to approximately 1000 new cases per
annum in the UK. However, the incidence varies with ethnicity,
geography and the nature of the cleft itself.
In the context of CL � P, the incidence is approximately
0.3 per 1000 in African American populations, 1.0 per 1000 in
Caucasian populations, and 2.1 per 1000 in Japanese
Tim Goodacre BSc FRCS is a Senior Clinical Lecturer at the Nuffield
Department of Surgery, and a Consultant Plastic Surgeon, Spires Cleft
Centre, Children’s Hospital Oxford & Nuffield Department of Surgery,
Oxfordshire, UK. Conflict of interest: none.
Marc C Swan MRCS is a Specialist Registrar in Plastic & Reconstructive,
Surgery at the Oxford & Wessex Deanery, Spires Cleft Centre Children’s
Hospital Oxford & Nuffield Department of Surgery, Oxfordshire, UK.
Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH 22:4 160
populations. The incidence of isolated CP is racially homoge-
neous at approximately 0.5 per 1000 live births.
Unilateral clefts are nine times as common as bilateral clefts,
and occur twice as frequently on the left than the right. The ratio
of left:right:bilateral clefts is 6:3:1. Males are predominantly
affected by CL � P (M:F 2:1) whereas females are more
commonly affected by isolated CP.
Aetiology
Over 300 syndromes are associatedwith orofacial clefting andmost
occur as an isolated abnormalitye the so-called non-syndromic CL
� P. Isolated CP is more likely to be syndromic than CL � P.
The cause of isolated clefting is multifactorial involving
a complex influence of environmental and genetic factors. There
is a predisposition for familial clustering. In one Danish study the
concordance rate for CL � P was 60% in monozygotic twins and
10% in dizygotic twins. There is a doseeresponse relationship
between maternal periconception smoking and orofacial clefting.
Maternal alcohol consumption is also associated with an
increased risk of isolated CP. Other maternal risk factors include
diabetes, nutritional factors (e.g. vitamin A, folic acid), and
anticonvulsant medication.
Genetics
Inheritance may be chromosomal, Mendelian or sporadic
(Table 1).
With respect to non-syndromic clefts, the risk of unaffected
parents with one child with CL � P having a second affected
child is 4%, while with two affected children, this risk increases
to 9%. If one parent has a CL � P, the risk of having an affected
child is 4%, which increases to 17% for a second affected child.
A total of 35% of CL � P patients and 54% of isolated CP
patients are associated with another anomaly, although less than
3% of these is due to a single gene disorder.
Numerous ‘candidate’ genes/loci have been proposed on the
basis of linkage and/or association studies and include TGF-a
TGF-b-3 MSX-1 and IRF-6.
A recent longitudinal population based study from Norway
demonstrated that the risk of recurrence of an isolated cleft in
first degree relatives does not seem to be related to the
anatomical severity of the defect. Furthermore, the relative risk
� 2011 Elsevier Ltd. All rights reserved.
Genetic associations with orofacial clefting
CL � P CP
Chromosomal Trisomy 13 or 21
Single gene Van der Woude (Chromosome 1, AD) EEC (ectrodactyly,
ectodermal hyperplasia and CL � P) Syndrome
(Chromosome 3, AD)
Treacher Collins Syndrome (Chromosome 5, AD) Stickler
Syndrome (Chromosome 12, AD) Velocardiofacial Syndrome
(Chromosome 22, AD) Opitz G/BBB Syndrome (AD)
Sporadic Pierre Robin Sequence
CL � P, cleft lip and palate; CP, cleft palate; AD, autosomal dominant.
Table 1
OCCASIONAL REVIEW
of cleft recurrence in first degree relatives was 32 for any cleft lip
and 56 for isolated cleft palate e thus indicating that genetics
contribute more to cleft palate alone than to cleft lip. There was
a low (three-fold) crossover risk between the incidence of cleft lip
and isolated cleft palate in families, which implies that genes
such as MSX-1 and IRF-6 may participate in all forms of oral
clefting. Several major groups are now investigating the genetic
basis of clefting with genome wide association studies alongside
single family investigation and tissue bank establishment.
However, it is unlikely that this work will influence the
management of the majority of cases for more than a decade.
Antenatal diagnosis
Since first reported in the prenatal diagnosis of facial clefting,
most centres performing 20-week foetal anomaly ultrasound
scanning now include observation of the facial elements as
a routine. Detection of cleft lip and alveolus (gum) is around
70% cases in the best series, but the sensitivity is generally in the
order of 20%, although there is high specificity. Missed cases will
inevitably occur due to foetal movement and adverse position
during the scan. Isolated CP is particularly difficult to diagnose
on account of the acoustic shadow created by the facial bones.
Currently up to 25% of cleft lips (with or without CP) are diag-
nosed antenatally. The addition of three-dimensional (and now
four-dimensional) ultrasound methods gives better quality
a b
Figure 2 Intra-uterine magnetic resonance imaging scan (sagittal view) demon
(red arrow) in (b) is a pathognomic sign of cleft palate.
PAEDIATRICS AND CHILD HEALTH 22:4 161
pictures for parents’ benefit, but do not significantly improve the
ability to predict foetal palate status. To date, only foetal
magnetic resonance imaging offers a realistic means of predicting
important additional information about the palate, which has
a bearing upon the future child’s feeding, speech, and facial
growth capacity (Figure 2).
Prenatal diagnosis has been described as a ‘mixed blessing’.
Psychological studies of parents indicate the appreciation of
preparatory knowledge, but an increased anxiety level during the
remaining pregnancy. Diagnosis, therefore, carries with it
a considerable obligation for parental support and counselling e
now offered routinely by most of the newly configured cleft
teams. Training for ultrasonographers involved in the first
moments of detection has been shown to be beneficial. Outcome
following prenatal diagnosis of clefting across UK maternity units
is unknown, but carefully organized support for parents has
avoided the high levels of termination of pregnancy for isolated
clefting that have been reported elsewhere.
Cleft types
Most clefts fall within the fusion lines of the fronto-nasal process
and lateral maxillary elements and the midline of the palatal
shelves in the mouth once posterior to the incisive foramen.
Clefts in other lines are rare and were classified by Paul Tessier
as craniofacial clefts no. 0e14. They are not the subject of this
strating normal (a) and cleft (b) palates. The absent palatal stripe
� 2011 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
review, and are almost always best managed by referral to
a specialist paediatric craniofacial team.
‘Typical’ clefts may involve all or part of one or both lip philtral
columns, alveolar (gum) bone, hard palate or soft palate. The cleft
can also be complete, incomplete, or a forme fruste involving
muscle dehiscence only. In the lip, these latter ‘near misses’ can
produce asymmetry of smile and nasal shape and thus are of
cosmetic importance. In the soft palate, a forme fruste is of even
greater importance, presenting as a submucous cleft palate.
The approximate distribution of the major cleft types is as
follows:
� cleft lip and palate 46%
� isolated cleft palate 33%
� isolated cleft lip 22%
A total of 86% of bilateral cleft lips and 68% of unilateral cleft
lips are associated with a cleft palate deformity.
Submucous cleft palate
Submucous cleft palate (SMCP) is sufficiently important to merit
further mention. It may present ‘overtly’ with a classical triad of
signs:
� notched hard palate posterior margin (however small)
� bifid uvula
� lucency of midline of palate (the ‘zona pellucida’ e due to
muscular diastasis) (Figure 3).
Even the most marginal of hard palate notches is a hard sign
of possible SMCP, in contrast to the bifidity of the uvula, which is
common in those with no other signs of muscle dehiscence, and
may be of no clinical consequence.
‘Occult’ presentation of SMCP presents with the speech and
swallowing difficulties of SMCP, but none of the classical triad of
signs. It can be confirmed by observing a characteristic ‘grooved’
surface on the dorsum of the soft palate during nasendoscopy.
SMCP presents a management conundrum. Most e detected
by neonatal examination or as a consequence of early feeding
difficulties e will progress to severe speech dysfunction if left
untreated. For these children, the only effective treatment is
surgical muscle repositioning, with subsequent specialist speech
and language therapy together with surgical pharyngoplasty if
required. However, a certain number may develop perfectly
normal speech and feeding, suggesting that careful monitoring of
early babbling patterns and speech development by highly
Figure 3 The midline zona pellucida of a submucous cleft palate.
PAEDIATRICS AND CHILD HEALTH 22:4 162
specialized speech and language therapists is an acceptable early
management plan for these cases.
Diagnosis of SMCP is often delayed. Awareness of the pre-
senting features should enable detection during all neonatal
screening examinations if the mouth is examined correctly.
Casual slipping of a finger into the mouth is not adequate.
Suspicion should always be raised by neonates who fail to suck
with good pressure, and in older toddlers whose speech develops
with cleft type characteristics (see Speech section).
Bilateral clefts
Bilateral cleft lip presents a difficult problem when associated
with alveolar þ/� more posterior clefting. The bony element
(the ‘premaxilla’) may be unrestrained by the normal ring of lip
muscle, and protrude in a much distorted and upwardly rotated
position (Figure 4). Pre-surgical orthopaedics (using a dental
plate, and sometimes lip strapping) is often helpful in such cases
and may make the primary surgery a much easier (and, there-
fore, successful) procedure.
Early care
Pre-surgical orthopaedics and naso-alveolar moulding
There is a long history of the use of dental devices to assist cleft lip
and palate management. Prospective randomized trial data now
shows that there is no benefit to infant feeding with the use of such
treatment. The term ‘feeding plate’ is, therefore, now defunct.
Moulding of the dental arch form with orthopaedic devices is
more controversial, and the subject of a large multicentre trial
still accruing data. Contradictory data exist for whether such
bony manipulation improves outcome, affects growth, or makes
surgery more straightforward. Improved surgical ability is likely
to be the most consistent and valuable effect, especially if it
produces more satisfactory cosmetic outcomes.
A variety of appliances have been described, which if ‘active’
may contain springs or other mechanisms to gently oppose the
gum ridges. No UK unit currently uses the more severe Latham
device, which requires pin fixation to the jaw arch line.
Naso-alveolar moulding (NAM) involves adding an extension
to the orthopaedic device, to exert moulding pressure on the
distorted nasal margin. The principle is similar to that espoused
for ear cartilage moulding in early months (‘ear buddies’). It
requires much additional work (and cost) from the orthodontic
team, and adds considerably to the burden of care for the new
parents. No UK unit currently offers this service routinely, but
the best series in the United States have impressive results, which
would be expected to lead to better cosmetic outcomes. It is also
becoming an established method in China and south east Asia,
and is likely to become the subject of careful benefit analysis in
the UK in the near future.
Postoperative nasal splints
Along similar lines, post lip repair nostril splinting (using
conformers) is thought by many to be beneficial. Use of
progressively enlarging conformers to shape the nostril aperture
and lift the slumped rim has a good evidence base, but again
requires considerable commitment from the parents in conjunc-
tion with good nurse specialist support. The use of such splints is
routine now across south east Asia.
� 2011 Elsevier Ltd. All rights reserved.
Figure 4 Pre-operative views of bilateral cleft lip and palate (a) and (b) with post-operative image (c).
OCCASIONAL REVIEW
Specialist nursing care
One of the indisputable advances in UK cleft care over the past 15
years has been the widespread development of highly skilled
nurse specialists to offer support to expectant parents, peri-natal
care, complex feeding advice, home visits and peri-operative
care. The success of such specialists has improved continuity
of care from the more centralized teams, and raised standards
from previously ad hoc support structures. Arguably, this
development has had a far greater impact on outcomes than any
specific surgical methodological change.
Pierre Robin sequence
The sequence of cleft palate associated with micrognathia, glos-
soptosis, and respiratory difficulty, was described by Robin in
1923. The incidence is approximately one in 14,000 births. Not
indicative of a specific syndrome, the spectrum of severity ranges
greatly. The most severe forms exhibit wide clefts with gross
maxillary shelf and muscle hypoplasia, the tongue prolapsing as
PAEDIATRICS AND CHILD HEALTH 22:4 163
a ‘ball valve’ into the posterior nasopharynx, a minute jaw, and
major problems with airway maintenance. Management of Pierre
Robin sequence is concentrated on establishing a secure airway
at all times and satisfactory oral feeding (Figure 5).
Current best practice is invariably to use a nasopharyngeal
airway for the mainstay of airway protection. The widespread
adoption of this method has obviated the need for more invasive
techniques of the past, such as glossopexy (fixation of the tongue
tip to the lip/jaw) or the Burston frame (a prone positioning
frame to allow forward head projection). Very early surgical
distraction osteogenesis of the hypoplastic mandibular arch has
been advocated by several current authorities in the United
States. However, the method has found few devotees elsewhere,
where surgical enthusiasm is more reasonably balanced by wise,
less invasive, medical support. The most cogent argument for
such mandibular distraction is to reduce the period of time that
a child might require a tracheostomy for the most extreme severe
cases of Pierre Robin sequence.
� 2011 Elsevier Ltd. All rights reserved.
a
b
Figure 5 Child with Pierre Robin sequence a with intra-oral view of wide
cleft palate (b). The child is successfully managed at home with a naso-
pharyngeal airway and nasogastric feeding tube in situ.
OCCASIONAL REVIEW
Feeding support for such children can be problematic.
Nasogastric supplementation may be required, but every effort is
made to prevent the child becoming overly dependent upon
nasogastric feeds in preference to using normal oral sucking.
Postoperative emergencies
Primary surgery: The most commonly encountered problems
after primary cleft surgery are airway obstruction and bleeding.
Airway obstruction usually follows narrowing of the nostril
apertures in lip/anterior palate closure, in the child who is still an
obligate nasal breather. Use of the nostril conforming splint,
together with perhaps a nasogastric tube, can further obstruct the
nasal airway. Relief of such obstruction is usually easy with gentle
exterior suction and use of a nasopharyngeal airway if required.
PAEDIATRICS AND CHILD HEALTH 22:4 164
Airway obstruction following posterior palate repair can be
more difficult. If anticipated, a nasopharyngeal airway can be left
in situ at the end of the procedure, together with placement of
a temporary tongue suture to assist with positioning. If a naso-
pharyngeal airway requires placement on the ward post-
operatively, it should be passed with the utmost care to avoid
suture line disruption with inevitable additional bleeding and
functional consequences for the repair.
Significant postoperative bleeding is a surgical emergency. Some
bleeding in thefirst 12h is expected, although the surgeonshouldbe
alerted if it is fresh or brisk. Later bleeding can be reactionary or
secondary in nature. Either way, the child will require some seda-
tion (usuallymorphine 0.1mg/kg), and a topical adrenaline soaked
gauze swab is used to apply pressure onto the roof of the mouth.
The most common bleeding site is one of the lateral releasing inci-
sions used to close the cleft palate and such digital pressure can
establish control remarkably quickly. Unnecessary staff and/or
parents should be removed from the roomand very great care given
to any suction (avoided if at all possible). The child should be
prepared for urgent return to theatre, although often ward control
obviates the need for any more active surgical intervention.
Secondary surgery: Secondary procedures include phar-
yngoplasty, alveolar bone grafting and osteotomyeorthognathic
surgery. Bleeding is the most common later emergency. It should
be managed with all usual supportive measures (ABC, intrave-
nous fluids and cross matching if appropriate) and early return to
theatre. Airway obstruction can frequently follow the less phys-
iological forms of pharyngoplasty.
Current treatment protocols
Timing of cleft repair
The late 20th century UK-based controversy surrounding the value
of neonatal cleft lip repair has now almost disappeared; the
purported benefit of improved lip scarring from foetal wound
healing patterns is disproven.Work on the impact of early repair as
opposed to more conventional timing of lip closure at 3 months is
now beginning to improve understanding of early neural
development. Further work to investigate the nature of early
mothereinfant interactions and the disruption caused by facial
disfigurement is in progress and may influence surgical timing in
the coming decade. Most UK centres (and similarly almost all
world centres) now undertake first surgery once feeding patterns
have been established and birth weight regained.
The main difference in timing protocol in major centres is
found in the sequence in which the lip and palatal elements are
operated upon. The more frequent pattern used is lip and ante-
rior palate as a primary procedure around 2e3 months, with soft
palate closure once the airway is more secure e from 4 to 12
months. The opposing view (common in France e sometimes
termed the ‘Malek sequence’) aims to avoid any early surgical
interference with the hard palate growth centres, and repairs the
lip þ/� soft palate at around 2e3 months, followed by delayed
hard palate closure at times varying from 6 to 60 months. Those
centres adopting palate repairs later than 12 months frequently
use hard palate cover plates to reduce abnormal airflow and
permit better speech development than would occur in the
presence of an oronasal fistula.
� 2011 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
The dilemma of the mutually opposing benefits of early and
later hard palate repair on palatal growth versus speech devel-
opment remains one of the most controversial and difficult
aspects of cleft management. Robust evidence accounting
adequately for all variables and cleft types is lacking, and many
opinions accept that it is the quality of overall surgical tissue
handling rather than defined technique or timing that has most
influence on long-term outcome for growth and speech.
Cleft lip repair
Lip repairs adopt a form of lengthening of the greater segment
margin, the rotation advancement being the most popular. Almost
all authorities now include some form of primary nasal tip correc-
tion in the primary lip repair, results usually improving upon the
status quo if nothing is done. Radical muscle repositioning is also
widely adopted, and many surgeons now use a subperiosteal
dissection of the muscle away from the maxilla, in order to mini-
mize deep seated scar tissue and offer the potential to generatemore
bone from theunder surface of the periosteum. Subtle corrections of
the lip scarwith the interposition of small flaps above thewhite roll,
and within the dry vermilion mucosa as well as the avoidance of
cuts around the base of the lateral nostril margin are all advances
that improve long-term outcome (Figure 6).
Cleft palate repair
The most significant advance in palate repair over the past
15 years has been the widespread adoption of the radical levator
palate muscle repositioning procedure described by Brian Som-
merlad. The outcome of this procedure appears to have no
adverse growth effect and produces the very best speech
a
Figure 6 Pre-operative (a) and post-operative (b) appearan
PAEDIATRICS AND CHILD HEALTH 22:4 165
capability with lowest incidence of velopharyngeal incompe-
tence. It also has potential benefits on Eustachian tube function.
The technique involves closure of the nasal mucosa, followed by
transposition of the medial insertion of the levator muscles by
90� so that the two mobilized ends can be sutured together to
form a new, extensible muscle ‘sling’, which is capable of velo-
pharyngeal closure (Figure 7).
An alternative procedure adopted widely around the world is
the Furlow palatoplasty, with double opposing Z-plasties to
facilitate the muscle correction as espoused by Sommerlad.
The remaining development in palate surgery is the trend
towards minimizing lateral releasing incisions (as with the Von
Langenbeck procedure, now in use for over 100 years) by radical
undermining of the palatal flaps. Self-inflating tissue expanders
might hold some improvement in this respect in the coming 10years.
Foetal surgery
The advent of improved antenatal diagnosis of intrauterine
pathology has made foetal surgery a feasible option, however the
standard ‘open’ techniques are associated with significant
morbidity and mortality. Thus, the development of less invasive
feto-endoscopic techniques appears encouraging, and has been
demonstrated to be effective in vivo using cleft animalmodels. The
major advantage is the ‘holy grail’ of scarless wound healing,
which has been reported at mid-gestation and would have clear
functional and aesthetic advantages. Consensus criteria exist as to
which congenital malformations are considered appropriate for
intrauterine surgery. At present such surgery is purely experi-
mental with respect to orofacial clefting and there is little prospect
of clinical trials commencing in the foreseeable future.
b
ces of a left unilateral cleft lip and palate.
� 2011 Elsevier Ltd. All rights reserved.
a b
Figure 7 Sommerlad radical muscle-positioning technique for soft palate repair: pre-operative view (a) and intra-operative view (b). (Reproduced with
permission from Plastic & Reconstructive Surgery).
OCCASIONAL REVIEW
Speech
Cleft palate (overt or submucous) carries an inevitable potential
for speech to develop abnormally due to the position of the soft
palate musculature. Of the five known soft palate muscles, the
palatoglossus and palatopharyngeus are principally involved in
swallowing. The tensor and levator veli palatini muscles are
speech motors, acting to extend and lift the soft palate in a ‘knee’
shaped valvular action, which closes the posterior nasopharynx
from the oropharynx. This action is essential if air pressure is to
be raised in the mouth e a necessary component of normal
speech in most languages.
Raised oral pressure is needed particularly for fricative sounds
(such as ‘s’, ‘f ’, ‘sh’) and plosives (‘p’, ‘m’, ‘b’). Failure of this
action results in the speech pattern described as velopharyngeal
incompetence (VPI) the component parts of which are hyper-
nasality, nasal emission and nasal turbulence or resonance.
When young children have incompetent palatal musculature,
somewill develop very substantial compensatorymisarticulations
in order to attempt normal speech. These can lead to severely
compromised intelligibility, and in some places have resulted in
erroneous association with learning disorders.
Recent evidence supports the adoption of therapeutic inter-
vention at an early stage (the babbling phase) to counter adverse
speech development. Once normal speech is developing, it is
essential that specialized speech and language therapists are
involved to monitor and guide speech development. Significant
abnormalities in palatal function can then be identified at an early
stage, and investigated to ascertain whether secondary speech
surgery will offer any benefit to the child.
PAEDIATRICS AND CHILD HEALTH 22:4 166
Audiology
Most children with cleft palate would develop glue ear without
intervention. This relates to the abnormal positioning of the
stylopharyngeus muscle. Some authorities, therefore, advocate
early grommet insertion by way of prophylaxis for this condition,
to improve hearing, and to prevent chronic secretory otitis media
and worse (e.g. cholesteatoma). However, there is no consensus
for early middle ear management for cleft children, other than
agreement that careful audiological prolonged assessment is
mandatory, with appropriate intervention (either grommet
insertion or use of hearing aids) as required. It is possible that the
newer, more radical, palate muscle repositioning techniques will
lead to ‘normalization’ of middle ear Eustachian ventilation and
reduce the need for external ventilating grommets. However, no
published evidence currently exists to support this view.
Secondary speech surgery
Although primary cleft palate repair techniques have improved
early outcomes, a substantial number of children will remain with
deficient palatal function despite optimal speech therapy. Those
demonstrated to have VPI are considered for either palatal muscle
re-repair (along the lines described by Sommerlad for primary
repair) or pharyngoplasty (an operation performed on the pharyn-
geal wall in order to improve closure of the velopharyngeal orifice).
Pharyngeal flap
The oldest, and to some extent most consistently reliable, means
of improving velopharyngeal closure is by elevating a myomu-
cosal flap from the posterior pharyngeal wall and attaching it to
� 2011 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
the posterior soft palate. The static flap acts as a broad ‘wafer’ of
tissue tethering the palate and also obstructing the widest portion
of the airway.
The pharyngeal flap e of which there are numerous anatomic
variations e is also the most obstructive, and can produce
significant sleep apnoea as well as other adverse sequelae, such
as severe snoring, mucous obstruction, and long-term airflow
obstruction (implicated rarely in right heart failure).
Pharyngoplasty procedures
In an attempt to reduce such symptoms, the use of lateral
pharyngeal wall or tonsillar pillar tissue to constrict the
nasopharyngeal valve was developed. Lateral pharyngeal wall
flaps set high in the adenoidal area act as a form of ‘speed
bump’ to bring the posterior pharyngeal wall closer to the soft
palate and assist closure of the valve (the ‘Hynes’ phar-
yngoplasty procedure). Posterior tonsillar pillar flaps, set lower,
act as a form of dynamic sphincter, and tend to be somewhat
more obstructive to airflow (the ‘Orticochoea’ pharyngoplasty
procedure).
Posterior pharyngeal wall augmentation
a
In an attempt to avoid all adverse obstructive consequences of
pharyngoplasty, some authorities create the ‘speed bump’ effect
on the posterior pharyngeal wall entirely by placing a piece of
material (cartilage or alloplastic) beneath the pharyngeal
mucosa.
Such secondary speech procedures are now only performed
with full pre- and postoperative support by a specialized
speech and language therapy team. Additional, non-surgical,
methods for the infrequent severe and resistant cases include
the use of prosthetic devices such as ‘speech bulbs’ attached to
permanently worn dental plates, and biofeedback therapy
techniques.
Alveolar bone grafting
b
Figure 8 Secondary bone grafting of the cleft alveolus: pre-operative
(a) and immediate post-operative (b) views.
Primary cleft repair does not correct the bony deformity in the
gum ridge, although recent work on primary gingivoper-
iosteoplasty is an attempt to address this. Since the 1970s, it has
been understood that the bone defect is best filled with cancel-
lous (marrow) bone graft in the secondary dentition phase,
before the eruption of the secondary canine tooth, which usually
lies adjacent to the cleft gum (Figure 8).
The timing of this procedure is determined by the specialist
orthodontist and relates to dental maturity. It is usually between
the ages of 7 and 11 years and involves reopening the cleft bony
line and packing the mucosally lined cavity with chips of graft
harvested from the iliac crest or tibial plateau. This procedure
also offers the best opportunity to close any residual oronasal
fistula in the anterior palatal region. It is a highly effective
operation, and enables the subsequent orthodontic management
of what are frequently much distorted teeth into a well-corrected
arch form.
The necessity for such bone grafting is well established.
Careful paediatric dental health is a mandatory part of early cleft
care, and later specialist restorative dental expertise enables all
but the most resistant cases to obtain a high level of dental health
and appearance.
PAEDIATRICS AND CHILD HEALTH 22:4 167
Orthognathic surgery
Despite the best outcomes available, a certain proportion of
children with complete cleft lip and palate will develop
secondary maxillary hypoplasia following primary repair. The
characteristic ‘dish face’ appearance is often the subject of severe
teasing and self-consciousness, and is best addressed by
a combination of psychological support with orthognathic (jaw
moving) surgical correction in the late teenage years.
Orthognathic surgery involves moving the maxilla forwards by
means of controlled bone cuts (‘osteotomies’) in patterns
described by Ren�e Le Fort in the 19th century. Maxillary
advancement may be combined with surgical correction of the
mandible by sliding it backwards again using bone cuts. Recent
use of bone distraction osteogenesis has improved the long-term
outcome of such procedures. Orthognathic procedures are
amongst themost effective in thewhole gamut of cleft surgery, and
should be considered even in less severe cases of hypoplasia if the
surgery can be undertaken by a skilled maxillofacial surgeon.
The cause of mid-facial growth failure remains controversial.
The adverse effect of primary surgical intervention is indisput-
able (as shown by careful analysis of adult unrepaired clefts in
Sri Lanka over many years) but the relative impact of various
forms of primary management is still unclear. It would appear
that, despite the best efforts to minimize adverse sequelae of
surgery, some children are ‘poor growers’ with inherent hypo-
plasia, and are destined to require significant secondary surgery
regardless of their primary treatment protocol.
� 2011 Elsevier Ltd. All rights reserved.
OCCASIONAL REVIEW
Clinical psychology
Practice points
Throughout this description of interventional medical care for
cleft lip and palate children, it will be evident that the goal of all
care should be a well-rounded and healthy child able to achieve
his/her full potential in life. They should be able to enjoy
a normal childhood as little disrupted by treatment or adverse
consequences of the cleft as possible.
The input from skilled specialist psychologists to cleft manage-
ment from prenatal diagnosis to adulthood is invaluable, and
essential as a guide to achieve holistic care from all teammembers.
Since the Clinical Standards Advisory Group (CSAG) report and
reorganization, a full psychology service has become a mandatory
part of the team structure. It is probable that the number of
unnecessary or ill-advised secondary procedures is reduced by such
input, as well as demonstrable improvements in individual and
family wellbeing and dynamics. Future developments in the area of
psychological input will focus on the potential value of early inter-
vention in families at high risk of adverse psychological conse-
quences when older. Much evidence is accumulating of the
particular value of very early (before 12 weeks) psychological
support, with a possible ‘sensitive period’ in development influ-
encing subsequent cognitive ability becoming clear.
C Cleft lip and palate are the most commonly encountered
CSAGanomalies of the craniofacial region
C The genetic basis of non-syndromic clefting is complex and
poorly understood. Environmental factors are involved in
a proportion of cases
C Antenatal diagnosis of lip clefts can be expected in about two-
thirds of cases. Palatal clefts cannot be diagnosed before birth
other than with magnetic resonance scanning. Prenatal diagnosis
carries with it a responsibility for rapid access to specialist coun-
selling and advice. Outcome following such support is very good
C The spectrum of cleft types is considerable. Incomplete and
forme fruste conditions include submucous clefting of the
palate, which is frequently missed in postnatal examinations
C The triad of notched posterior hard palate, bifid uvula, and
midline zona pellucida are diagnostic of submucous cleft
palate, which should be referred for specialist opinion
C The role of pre-surgical orthopaedics to improve surgical repair
of wider cleft lips remains controversial. It has no beneficial
effect on feeding, but many surgeons value the outcome
C There is little (if any) role for surgical intervention in early severe
Pierre Robin sequence. Nasopharyngeal airway management is
highly successful in support during the early months
C Cleft care has been centralized into less than 10 units in the UK.
This has enabled coordinated nursing, surgical, and other
specialist service provision, with a rising of standards since
instigated. All newly diagnosed or suspected clefts and related
conditions should be referred to these teamsas early as possible
C Optimal surgical technique remains elusive. However, radical
palatal muscle repositioning has improved speech outcomes
considerably. Mid-facial growth disturbance remains the most
common long-term adverse outcome of surgical intervention
C Comprehensive and ‘holistic’ cleft care involves mandatory
clinical psychology support of children and their families.
Unnecessary surgical interventions can be reduced, and long-
term global health outcomes are improved
Perhaps the single most effective change in cleft care standards in
the UK has been brought about by reorganization and service
centralization stimulated by the 1996 report from the CSAG e
now a defunct organization. Service provision was reduced from
57 centres in the early 1990s to nine centres (some ‘twin site’) in
the UK from 2006. This centralization has been accompanied by
more careful financial investment by regional commissioners,
and has brought UK clinical outcomes to a level that is arguably
among the best in the world. A
FURTHER READING
Ardinger HH, Buetow KH, Bell GI, Bardach J, VanDemark DR, Murray JC.
Association of genetic variation of the transforming growth factoralpha
gene with cleft lip and palate. Am J Hum Genet 1989; 45: 348e53.
Boyne PJ, Sands NR. Secondary bone grafting of residual alveolar and
palatal clefts. J Oral Surg 1972; 30: 87e92.
Calnan J. Submucous cleft palate. Br J Plast Surg 1954; 6: 264e82.
Curtis E, Fraser FC, Warburton D. Congenital cleft lip and palate: risk
factors for counseling. Am J Dis Child 1961; 102: 853e7.
Descamps MJL, Golding S, Sibley J, McIntyre A, Alvey C, Goodacre T. MRI
for definitive in utero diagnosis of cleft palate: a useful adjunct to
antenatal care. Cleft Palate Craniofac J 2010; 47: 578e85.
Jugessur A, Murray JC. Orofacial clefting: recent insights into a complex
trait. Curr Opin Genet Dev 2005; 15: 270e8.
Kobus KF. Cleft palate repair with the use of osmotic expanders:
a preliminary report. J Plast Reconstr Aesthet Surg 2007; 60: 414e21.
Lees M. Familial risks of oral clefts. BMJ 2008; 336: 399.
Masarei AG,WadeA,MarsM, SommerladBC, Sell D.A randomized control trial
investigating the effect of presurgical orthopedics on feeding in infants
with cleft lip and/or palate. Cleft Palate Craniofac J 2007; 44: 182e93.
Pfeifer TM, Grayson BH, Cutting CB. Nasoalveolar molding and gingivo-
periosteoplasty versus alveolar bone graft: an outcome analysis of
costs in the treatment of unilateral cleft alveolus. Cleft Palate Cra-
niofac J 2002; 39: 26e9.
PAEDIATRICS AND CHILD HEALTH 22:4 168
Rice DPC. Craniofacial anomalies: from development to molecular path-
ogenesis. Curr Mol Med 2005; 5: 699e722.
Rollnick BR, Pruzansky S. Genetic services at a center for craniofacial
anomalies. Cleft Palate J 1981; 18: 304e13.
Sivertsen A, Wilcox AJ, Skjaerven R, et al. Familial risk of oral clefts by
morphological type and severity: population based cohort study of
first degree relatives. BMJ 2008; 336: 432e4.
Sommerlad BC, Fenn C, Harland K, et al. Submucous cleft palate:
a grading system and review of 40 consecutive submucous cleft palate
repairs. Cleft Palate Craniofac J 2004; 41: 114e23.
Sommerlad BC. A technique for cleft palate repair. Plast Reconstr Surg
2003; 112: 1542e8.
Tessier P. Anatomical classification facial, cranio-facial and laterofacial
clefts. J Maxillofac Surg 1976; 4: 69e92.
Yazdy MM, Honein MA, Rasmussen SA, Frias JL. Priorities for future public
health research inorofacial clefts.Cleft Palate Craniofac J2007;44:351e7.
Zucchero TM, Cooper ME, Maher BS, et al. Interferon regulatory factor 6
(IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J
Med 2004; 351: 769e80.
� 2011 Elsevier Ltd. All rights reserved.
PERSONAL PRACTICE
ConjugatedhyperbilirubinaemiaJulie Brent
Mansoor Ahmed
What is conjugated hyperbilirubinaemia?
Neonatal jaundice is common in the first 1e2 weeks after birth
and usually resolves spontaneously. In the majority of cases, it is
physiological. Prolonged neonatal jaundice is jaundice lasting for
more than 2 weeks (more than 3 weeks for preterm babies). In an
otherwise healthy and asymptomatic breast fed neonate, this
may reflect breast milk jaundice (unconjugated hyper-
bilirubinaemia). A direct or conjugated bilirubin of more than 1.0
mg/dL if total bilirubin is less than 5 mg/dL or more than 20% if
total bilirubin is more than 5 mg/dL is considered as abnormal
(pathological) at any time and constitutes conjugated hyper-
bilirubinaemia. This personal practice review focuses on the
initial diagnostic approach and management of conjugated
hyperbilirubinaemia during the first few weeks after birth.
How common is conjugated hyperbilirubinaemia?
Neonatal cholestasis effects one in 2500 live births. Due to its
relatively low incidence, it is infrequently seen by most providers
of medical care to infants. Extra hepatic biliary atresia is a rare
disorder with an incidence of approximately 1:15,000 live births
and comprises of approximately 1/3 cases of neonatal
cholestasis. Alpha 1 antitrypsin deficiency is the cause in 5e15%
and other inherited forms of cholestasis occur in 10e20% of
cases. Inborn errors of metabolism and congenital infection
(TORCH) cause 20% and 5% cases respectively. Incidence of
idiopathic neonatal hepatitis has decreased significantly (now
stands at 10e15%) due to improved diagnostic methodologies
and better understanding of genetics of bile acid metabolism.
Bilirubin metabolism and pathophysiology
Conjugated bilirubin accumulates in the blood when there is
impaired bile formation by the hepatocytes or from obstruction of
bile flow through intra or extra hepatic biliary tree (cholestasis).
This leads of accumulation of biliary substances (bilirubin, bile
acids and cholesterol) in the liver, blood and extra hepatic tissues.
The pathway for bilirubin metabolism is shown in Figure 1.
In the liver, water insoluble unconjugated bilirubin is taken
up by hepatocytes at the sinusoidal membrane and conjugated to
Julie Brent MBBS MRCPCH is an ST-5 Paediatrics, at Queen’s Hospital,
Burton Upon Trent UK. Conflicts of interest: None.
Mansoor Ahmed MBBS FRCP FRCPCH is Consultant Paediatrician at Queen’s
Hospital, Burton Upon Trent, UK. Conflicts of interest: None.
PAEDIATRICS AND CHILD HEALTH 22:4 169
become water soluble. Bile production depends upon an active
transport of bile acids (and other substances) into the biliary
canaliculi. Major transporters at the basolateral membrane are
Naþ Taurocholate Cotransporting Polypeptide (NTCP) and
Organic Anion Transporting Proteins (OATP). Bile secretion at
the canalicular membrane is facilitated by Bile Salt Export Pump
(BSEP) and Multidrug Resistant Proteins (MRP2). The role of
these transporters in cholestatic diseases is being increasingly
recognized.
Causes of conjugated hyperbilirubinaemia
There are numerous Intrahepatic and extra hepatic causes of
neonatal conjugated hyperbilirubinaemia (Table 1).
Common causes include biliary atresia, inherited/metabolic
forms of cholestasis idiopathic neonatal cholestasis, and the
multifactorial cholestasis seen in ex-preterm infants requiring
total parenteral nutrition and/or neonatal surgery.
What are the key presenting features?
Neonatal conjugated hyperbilirubinaemia usually presents as
prolonged jaundice in a well infant. Pale acholic stools (cardinal
feature of cholestasis) and dark urine are important pointers in
history but not always recognized by parents. In an unwell
neonate, presentation may include bleeding due to coagulopathy
unresponsive to vitamin K. Conjugated hyperbilirubinaemia may
also present as a feature of systemic conditions in a more unwell
neonate who may have sepsis, shock, seizure, irritability, heart
failure, hypopituitarism or metabolic disorder (such as gal-
actosaemia or tyrosinaemia). Important features in the history
include obstetric history particularly looking for intrauterine
infections or cholestasis of pregnancy, consanguinity, family
history of cholestasis or liver disease, early neonatal course
including resuscitation at birth, neonatal intensive care admis-
sion and details of parenteral/enteral nutrition.
Focussed physical examination
Anthropometric assessment (including weight, length and head
circumference measurement) should be undertaken. In intra-
uterine infections, intrauterine growth restriction and skin rash
may be seen. Stigma of syndromic disorders with congenital
anomalies, facial dysmorphic features, oedema, ascites and
evidence of congenital heart disease should also be carefully
looked for. Abdominal examination often reveals hepatomegaly
and less commonly splenomegaly. A choledochal cyst may be felt
as a mass in the right upper quadrant of abdomen. Formal ocular
assessment (posterior embryotoxin in Alagille syndrome, optic
nerve hypoplasia in panhypopituitarism, chorioretinitis in
congenital infections and cataract in congenital infections/gal-
actosaemia) and cardiac evaluation may also be required.
Diagnostic workup
All babies with prolonged jaundice should have a split bilirubin
(total and conjugated bilirubin) measurement taken. All babies
with conjugated hyperbilirubinaemia should be promptly
referred to a paediatrician for initial investigations.
� 2012 Elsevier Ltd. All rights reserved.
Haemoglobin
Haem
Unconjugated Bilirubin
Conjugated Bilirubinbilirubin diglucuronide
(Water soluble)
Globin
Uridine diphosphoglucuronicacid glucuronyl transferase
Bile
Bile salts
Colonic bacteria
Urobilinogen
Reabsorbed
Urobilin
Stercobilinogen
Stercobilin
Old red blood cells breakdown
spleen
Albumin
Hepatocytes
Kidneyy
Bilirubin-albumin complex(Water insoluble)
Figure 1 Schematic diagram of bilirubin pathway.
PERSONAL PRACTICE
Initial investigations
Taking into account wide range of differential diagnosis (Table 1),
a structured approach to investigate a neonate with cholestasis
should identify conditions or complications (such as coagulop-
athy, neoplastic disorders, acute liver failure, hypoglycaemia,
sepsis, metabolic disorders like galactosaemia and pan-
hypopituitarism) requiring immediate treatment. Once these
disorders have been excluded, the most important differential is to
look for biliary atresia. A paediatric hepatologist should be con-
sulted early as prompt referral for surgery to manage biliary atresia
before 60 days improves prognosis.
Initial investigations in neonates with conjugated hyper-
bilirubinaemia are listed in Table 2. The serum transaminases
(ALT, AST) are sensitive markers for hepatocellular injury but
are non-specific. Alkaline phosphatase is also non-specific
PAEDIATRICS AND CHILD HEALTH 22:4 170
(found in liver, bone and kidney) and is likely to be raised in
biliary obstruction. Gamma glutamyl transpeptidase (GGT), an
enzyme in bile duct epithelium, is a sensitive marker of biliary
obstruction and is raised in most cholestatic disorders. However,
it may be normal or low in progressive familial intrahepatic
cholestasis and disorders of bile acid metabolism. Alpha 1 anti-
trypsin deficiency can be difficult to distinguish from extra
hepatic biliary atresia on clinical and histological findings. Both
alpha 1 antitrypsin level as well as phenotype should be assessed
(serum levels may be falsely normal or raised, as it is an acute
phase protein). An abdominal ultrasound is useful in identifying
choledochal cysts, gall stones, sludge in the biliary tree or gall-
bladder. A small or absent gallbladder is suggestive but not
diagnostic of biliary atresia and the triangular cord sign (echo-
genic area at porta hepatis) is thought to be specific for biliary
� 2012 Elsevier Ltd. All rights reserved.
Causes of neonatal conjugated hyperbilirubinaemia
Extra hepatic
Hepatic bile duct
anomalies
Biliary atresia, choledochal cyst, cholelithiasis, inspissated bile secretion, spontaneous perforation of the
bile duct, neonatal sclerosing cholangitis
Intrahepatic
Intrahepatic bile
duct anomalies
Intrahepatic biliary hypoplasia (Alagille’s syndrome), caroli’s disease (dilated intrahepatic bile ducts),
congenital hepatic fibrosis
Idiopathic neonatal hepatitis
Infections Viral (TORCH, HIV, echovirus, adenovirus, coxsackie virus, human herpes virus-6, hepatitis B & C,
parvovirus B19, varicella zoster), Bacterial (sepsis, urinary tract infection, syphilis, tuberculosis, listeriosis)
Parasitic (toxoplasmosis, malaria)
Metabolic disorders Alpha1-antitrypsin deficiency, galactosaemia, glycogen storage disorder type IV, cystic fibrosis, neonatal
haemochromatosis, tyrosinaemia, inborn errors of bile acid metabolism, dubin-johnson and rotor syndrome,
hereditary fructosaemia, niemann-pick type C, gaucher’s disease, progressive familial intrahepatic cholestasis,
aagenaes syndrome, wolman’s disease, peroxisomal disorders (zellweger’s syndrome), carbohydrate deficient
glycoprotein syndrome
Chromosomal disorders Down’s syndrome, trisomy 13 and 18, turner’s syndrome
Endocrinopathies Hypothyroidism, hypopituitarism,
Toxic Parenteral nutrition, foetal alcohol syndrome, drugs
Vascular Budd-chiari syndrome, neonatal asphyxia, congestive heart failure, multiple haemangiomata
Neoplastic Neonatal leukaemia, histiocytosis X, neuroblastoma, Hepatoblastoma, erythrophagocytic lymphohistiocytosis
Other Neonatal lupus erythematosus
Table 1
PERSONAL PRACTICE
atresia. A normal gallbladder makes biliary atresia unlikely but
does not exclude it.
Subsequent investigations
Further investigation to establish the cause of conjugated
hyperbilirubinaemia should be tailored according to history,
examination, and initial laboratory results. Second/third
line investigations should ideally be performed in a tertiary
institution under close guidance and supervision of paediatric
hepatologist. Hepatobiliary scintigraphy, endoscopic retrograde
cholangiopancreatography, magnetic resonance cholangio-
Initial investigations for neonates with conjugated hyperbiliru
First line inve
Immediate investigations Total and conjugated bilirubin, blood group
blood glucose, sodium, potassium, urea, cre
for reducing substances.
If acutely unwell add Plasma ammonia, lactate, pyruvate, acid-bas
samples of plasma and urine for future anal
Liver function AST, ALT, alkaline phosphatase, gamma GT,
Infection Blood cultures, c-reactive protein, urine cult
hepatitis A, B, and C serology
Metabolic/storage Cystic fibrosis genetics or sweat test, galact
phenotype, plasma and urine amino acids, u
iron and ferritin
Endocrine Thyroid function tests, cortisol (preferably a
Miscellaneous Ultrasound scan of abdomen after 4 h fast l
Table 2
PAEDIATRICS AND CHILD HEALTH 22:4 171
pancreatography and liver biopsy may be required in selected
cases. In biliary atresia, typical liver biopsy findings include bile
duct proliferation, bile plugs in small bile ducts, portal tract
oedema and fibrosis. Liver biopsy is also useful for other specific
conditions such as alpha 1 antitrypsin deficiency and some
storage disorders. White cell enzyme analysis for glycogen and
lysosomal storage disorder, muscle biopsy for mitochondrial
cytopathy, bone marrow aspiration for storage disorders,
karyotype, ferritin and transferrin saturation, cerebrospinal fluid
examination for protein & lactate, MRI head and skin biopsy for
fibroblast culture are rarely required.
binaemia
stigations
and coomb’s test, full blood count, blood film and reticulocyte count,
atinine, bicarbonate, calcium, phosphate, coagulation screen, urine
e (blood gas), urinary pH, protein and ketones, chest X-ray, freeze
ysis.
albumin, cholesterol, triglycerides
ure and CMV, serology (IgM to Toxoplasma, Rubella, CMV, Herpes),
ose-1-phosphate uridyl transferase, alpha 1 antitrypsin level and
rine organic acids (succinyl acetone), carnitine and acyl carnitine,
fter 4 h fast)
ooking for gallbladder and choledochal cyst
� 2012 Elsevier Ltd. All rights reserved.
PERSONAL PRACTICE
Initial steps in the treatment of conjugated hyperbilirubinaemia
This involves diagnosing conditions amenable to specific medical
therapy (sepsis, galactosaemia, hypothyroidism, and hypopitu-
itarism) or early surgical intervention (biliary atresia, chol-
edochal cyst). In the majority of the other conditions, medical
management is mainly supportive; optimizing growth and
nutrition, and treating complications such as pruritis, portal
hypertension and liver failure.
Nutritional management
Practice points
In neonatal cholestasis, long chain fatty acids are not well
absorbed leading to malnutrition and fat-soluble vitamin defi-
ciency. Medium chain triglycerides (MCT) have better absorption
as they are relatively water soluble. Infants who are formula fed
should immediately be changed to a MCT based hydrolyzed
formula. Similarly, breast fed infants should also be temporarily
switched to lactose free (e.g. MCT based hydrolyzed) formula till
the investigation results exclude galactosaemia. In the mean
time, mother should be advised to continue to express breast
milk to prevent subsequent lactation failure. Caloric content
should be increased to 120e150% of the recommended intake.
Occasionally, parenteral nutrition may be required.
C Neonatal cholestasis is an uncommon serious disorder whichrequires urgent diagnostic workup
MedicationC Neonates with prolonged jaundice should have total and direct
serum bilirubin measurement and if found to have conjugated
hyperbilirubinaemia, should be promptly referred for further
investigation
C First line investigations look for immediately treatable condi-
tions and complications
C Biliary atresia is the most common cause of conjugated
hyperbilirubinaemia and early detection/referral for surgery
before 60 days significantly improves its prognosis
C Supportive management for cholestasis includes optimizing
nutrition and replacing fat soluble vitamins
Fat soluble vitamin supplements should be added in doses 2e4
times the recommended daily allowance and should continue for
at least 3 months after resolution of jaundice as there is delay
before normal bile flow is re-established. Either multivitamin
preparation or individual vitamins (Vitamin K 1e2 mg per day,
Vitamin E 100 mg per day, alphacalcidol 30e50 nanogram/kg
per day and vitamin A 5000 international units per day) should
be prescribed.
Ursodeoxycholic acid is a hydrophilic bile acid which replaces
hydrophobic bile acids in the bile pool and stimulates bile flow. It
has been shown to improve biochemical measures of cholestasis
and pruritis. Initial dose is 20 mg/kg per day in divided doses.
It should be discontinued when cholestasis has resolved.
PAEDIATRICS AND CHILD HEALTH 22:4 172
Occasionally, other medication (such as rifampicin, Pheno-
barbital or cholestyramine) may be required to treat pruritis from
cholestasis. A
FURTHER READING
1 Venigalla S, Gourley RG. Neonatal cholestasis. Semin Perinatol 2004; 28:
348e55.
2 De Bruyne R, Van Biervliet S, Vande Velde S, Van Winckel M. Clinical
practice; neonatal cholestasis. Eur J Pediatr 2011; 170: 279e84.
3 McKiernan PJ. Neonatal cholestasis. Semin Neonatol 2002; 7: 153e65.
4 Roberts E. Neonatal hepatitis syndrome. Semin Neonatol 2003; 8:
357e74.
5 Kelly DA, Davenport M. Current management of biliary atresia. Arch Dis
Child 2007; 92: 1132e5.
6 Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation
of cholestatic jaundice in infants: recommendations of the North
American Society for Paediatric Gastroenterology, Hepatology and
Nutrition. JPGN 2004; 39: 115e28.
� 2012 Elsevier Ltd. All rights reserved.
SELF-ASSESSMENT
PAE
Self-assessment
Part A
An eight-year-old girl is referred to the paediatric unit with
(b) Codeine
(c) Ibuprofen
(d) Piroxicam
a 7-week history of persistent swelling and redness of herright knee. There is no history of trauma or recent foreign
travel; she has been feeling weak, but has not had a fever or
weight loss or other constitutional symptoms. On further
questioning she has had pain reoccurring every month for
the past 4 months and lasting about a week each time.
There is no family history of note. General examination is
unremarkable. She walks with an antalgic gait, and her
right knee is red and swollen with restricted movements
and a small joint effusion. There is no leg length discrep-
ancy. Initial investigations include:
Haemoglobin 13.6 g/dl (12.0e15.5) C3 Normal range
White cell count 8.4 � 109/L (4.5e13.0) C4 Normal range
Platelets 278 � 109/L (150e400)
C reactive protein 1.5 mg/L (<3.0) Smooth muscle abs Positive
Phosphate 1.51 mmol/L (1.00e2.00) Mitochondrial abs Negative
Alkaline phosphatase 771 U/L (130e900) Antinuclear factor Negative
Calcium 2.53 mmol/L (2.20e2.60) Parietal cell abs Negative
IgG 8.8 g/L (5.4e16.1) Urinary HMA/VMA Normal range
IgA 1.10 g/L (0.4e2.4)
IgM 0.7 g/L (0.5e1.8)
Questions
1. What is the most likely diagnosis? Select one answer
(a) Septic arthritis
(b) Juvenile idiopathic arthritis e oligoarticular
(c) Traumatic injury
(d) Haemophilia
(e) Juvenile idiopathic arthritis e polyarticular
(f) Tuberculous osteomyelitis
(g) Leukaemia
(h) Hypermobility
2. What medical management should be instigated first?
Select one answer
(a) Paracetamol
Rebecca Balfour MB BCh is a Speciality Trainee at the Child and
Adolescent Health Directorate, Hywel Dda Local Health Board,
Bronglais Hospital, Aberystwyth, Wales, UK. Conflict of interest: none.
Simon Fountain-Polley MB BCh, MRCPCH is a Consultant at the Child and
Adolescent Health Directorate, Hywel Dda Local Health Board,
Bronglais Hospital, Aberystwyth, Wales, UK. Conflict of
interest: none.
DIATRICS AND CHILD HEALTH 22:4 173
(e) Intra-articular corticosteroid
(f) Methotrexate
3. If initial management is unsuccessful select the next best
management option:
(a) Paracetamol
(b) Codeine
(c) Ibuprofen
(d) Piroxicam
(e) Intra-articular corticosteroid
(f) Methotrexate
Part B
Questions
For the following statements choose the most appropriate
answer from the list of conditions:
A. Juvenile idiopathic arthritis e oligoarticular
B. Juvenile idiopathic arthritis e extended oligoarticular
C. Juvenile idiopathic arthritis e polyarticular, RF negative
D. Juvenile idiopathic arthritis e polyarticular, RF positive
E. Juvenile idiopathic arthritis e psoriatic
F. Juvenile idiopathic arthritis e enthesitis related
G. Juvenile idiopathic arthritis e systemic
H. Juvenile idiopathic arthritis e undifferentiated
1. A 14-year-old boy attends for repeat joint injection of an
inflamed right knee. He has a raised red rash over his
knees, which his mother says has been present only
over the last 2 weeks.
2. A 5-year-old girl is examined prior to a planned repeat
joint injection for an arthritic right knee noted on
a recent follow-up clinic appointment. Her father
mentions she has had pain on eating, especially apples.
As well as a restricted swollen right knee she has
restriction of movement in her left knee and both ankles
associated with swelling.
� 2012 Elsevier Ltd. All rights reserved.
SELF-ASSESSMENT
3. A 15-year-old boy complains of pain in his ankles when
walking and in the mornings. He was initially seen by
the orthopaedic team who put him in plaster casts for
both legs which relieved his symptoms. There is
a family history of ulcerative colitis.
4. A 4-year-old girl with 8 weeks of painful restriction of
movement in a swollen left knee e the only positive
finding. No evidence for malignancy is found. The
family commutes between the UK and Gibraltar. Her
father has psoriasis.
Part A
Answers
1. b e JIA e oligoarticular
Juvenile Idiopathic arthritis is a diagnosis of exclusion
when no other cause can be found. It is diagnosed in chil-
dren under 16 years of age with arthritis in one or more
joint persisting for more than 6 weeks. They present with
joint swelling, tenderness and signs of inflammation. This
can be further divided depending upon the number of joints
involved at presentation and the presence of any other
features including psoriasis, HLA-B27 positivity, Rheuma-
toid factor positivity or systemic features. Oligoarthritis is
when there are four or less joints involved at presentation.
2. d e Piroxicam
Treatment of Juvenile Idiopathic Arthritis (JIA):
The treatment of JIA should be multi-disciplinary,
involving paediatricians, paediatric rheumatologists, phys-
iotherapists, occupational therapists, podiatrists, orthotists,
specialist nurses, psychologists, family support groups,
ophthalmologists and dentists. Fortunately there are many
children with chronic arthritis who have remission and this
should be the main aim of treatment. Further treatment
aims should be to control pain, preserving joint ranges of
movement and function, and to facilitate normal growth
and psychological development. It is important that the
child can continue to participate in school and physical
education activities to prevent adverse psychological
effects. Pharmacological treatment should start with the
safest measures and escalate depending upon disease
progression and the response to medications.
Non-steroidal anti-inflammatory medications (NSAIDs)
are recommended as the first line treatment because rapidly
controlling inflammation can reduce permanent sequelae.
There are several different options available and there is no
convincing evidence that one NSAID is superior to another.
Piroxicam is recommended because it is administered on
a once-daily basis, and is available as a melt, which hypo-
thetically increases the likelihood of concordance with
treatment. With NSAIDs gastro-protective medication may
need to be considered. Clinical response to these medica-
tions can be variable and can take as long as 4 weeks to see
any improvement in symptoms.
3. e e Intra-articular corticosteroid
Intra-articular glucocorticoid injections are indicated in
oligoarthritis or polyarticular arthritis when one or a few
PAEDIATRICS AND CHILD HEALTH 22:4 174
joints have not responded to adequate anti-inflammatory
treatment. Repeat injections can be required. The proce-
dure can be performed under local anesthetic in children
over 7 years, but general anaesthetic may be needed if the
hip joint is involved or several joints are being injected. Side
effects from injections include subcutaneous atrophy,
cutaneous depigmentation, and increased pain for 24e48 h
post-injection and theoretically septic arthritis. Avascular
necrosis after hip injections has been recognized. Systemic
side effects are rare with the use of triamcinolone hex-
acetonide (Lederspan).
Methotrexate is the second line therapy for children with
arthritis who show inadequate improvement with first line
medications. This can be used in conjunction with intra-
articular steroid injections. Methotrexate is recommended
because of the rapid onset of action and acceptable side
effects. Initial treatment can be a once weekly oral medica-
tion, with a starting dose of 10e15 mg/m2. Subcutaneous
injections may need to be given if the response is inadequate
or there is associated nausea and vomiting. Subcutaneous
injections have been shown to increase bioavailability by
10e12%. In most children a response would be expected
within the first 3 months although this can take up to 9e12
months. Current debate revolves around the use of SC
methotrexate from the start of disease modifying antirheu-
matic medication, as there is some evidence that it may lead
to quicker, more effective symptom resolution.
The best time to discontinue methotrexate is unclear, but
most Paediatric Rheumatologists will begin dose reduction
following 1e2 years of disease control, although up to half
of these children will have flare-ups and this is more
common if the age of onset of symptoms is less than 5
years. Side effects of methotrexate include nausea, vomit-
ing, mouth ulcers, reduced appetite, alopecia, transient rise
in liver enzymes and leucopenia. Folic acid has been shown
in adults to reduce side effects and debate continues as to
whether it should be given routinely to children while on
methotrexate. Malignancy is rare following methotrexate
but Non-Hodgkin’s lymphoma has been reported.
Other medications that can be considered are systemic
corticosteroids, sulfasalazine, or the increasing number of
available biologic agents.
Part B
Answers
1. E e Juvenile idiopathic arthritis e psoriatic
Classification of juvenile idiopathic arthritis:
The ILAR (International League of Associations for
Rheumatology) proposed a classification of Juvenile Idio-
pathic Arthritis with a subsequent revision. The children
included will be under 16 years of age and have had
arthritis in one or more joints persisting for more than 6
weeks, and for which no other cause is found. JIA is
a diagnosis of exclusion. The full classification has
a number of distinct inclusion and exclusion criteria but the
following summarises each group:
� 2012 Elsevier Ltd. All rights reserved.
SELF-ASSESSMENT
To determine classification the following exclusion
criteria are assessed:
(a) Psoriasis in patient/first degree relative
(b) Arthritis in HLA B27 positive male with onset after 6
years of age
(c) Ankylosing spondylitis, enthesitis-related arthritis,
sacro-ilitiitis with inflammatory bowel disease, Reiter
syndrome, acute anterior uveitis in a first-degree relative
(d) Presence of IgM rheumatoid factor on at least two
occasions more than 3 months apart
(e) Presence of systemic arthritis
Psoriatic arthritis is classified in children with arthritis
and psoriasis or arthritis plus two of the following: dacty-
litis, nail pitting/onycholysis or psoriasis in a first-degree
relative. The most severe form is arthritis mutilans, which
is severely deforming. Prognosis is dependent on which
subtype is present.
Exclusions e b, c, d, e.
2. Be Juvenile idiopathic arthritise extended oligoarticular
Oligoarticular arthritis can be divided further into
persistent and extended. If persistent then four or less joints
are affected throughout the disease process. Extended
means that during the first 6 months four or less joints are
involved but with further joint involvement after 6 months.
These children are at high risk of associated uveitis and
ANA positivity may have prognostic significance. Oligoar-
thritis tends to be more common than polyarthritis,
affecting girls more than boys, with a peak in early child-
hood and a good prognosis; uveitis may affect up to a third
of children and requires regular ophthalmology reviews.
Exclusions e a, b, c, d, e.
3. F e Juvenile idiopathic arthritis e enthesitis related.
Children with enthesis related arthritis either have
enthesitis and arthritis or arthritis plus two of the following:
Sacro-iliac joint involvement, HLA-B27 antigen positivity,
onset at more than 6 years in a male, acute anterior uveitis
or a first degree relative with HLA-B27 related disease.
These children can have associated inflammatory bowel
disease, erythema nodosum and pyoderma gangrenosum.
There is usually a good prognosis for peripheral joint
involvement but permanent changes in the hips and spine
occur frequently.
Exclusions e a, d, e.
PAEDIATRICS AND CHILD HEALTH 22:4 175
4. H e Juvenile idiopathic arthritis e undifferentiated
The classification of undifferentiated arthritis is used for
any JIA, which doesn’t fit the criteria for any of the above
categories. It is also used if the arthritis fulfils the criteria for
two or more of the categories.
There are two further categories in JIA; these are poly-
arthritis and systemic disease. In polyarthritis there are five
or more joints involved during the first 6 months from the
onset of symptoms. This can then be further divided
depending on whether rheumatoid factor (RF) is positive
(exclusions e a, b, c, d, e) or negative (exclusions e a, b,
c, e). Those who are RF positive are more likely to be older at
the time of presentation, have rheumatoid nodules and
articular erosions. If they are RF positive they tend to have
aworse prognosis with symptoms continuing into adulthood
and have similar findings to adult rheumatoid arthritis.
Children with systemic disease can present at any age
with arthritis and fever for at least 3 days with one or more of
the following: evanescent erythematous rash, lymphade-
nopathy, hepatospelnomegaly and serositis. There is
a similar male to female ratio; antibodies and uveitis are
rarely present. The arthritis is usually oligoarticular at the
start but progresses to polyarticular. It most commonly
involves the knees, wrists and ankles. It can also involve the
cervical spine, hips, temporomandibular joint and the small
joints of hands. There can be extra-articular complications of
pericarditis, secondary amyloidosis and pulmonary intersti-
tial disease. Around half of the children will recover almost
completely with the other half having progressive involve-
ment of more and more joints and subsequent disability.
Exclusions e a, b, c, d.
FURTHER READING
Brough R, Cleary G. When does a knee “need” a “joint” assess-
ment? Arch Dis Child Educ Pract Ed 2007; 92: 44e49.
Cassidy JT, Petty RE, Laxer RM, Lindsley CB. Textbook of Paediatric
Rheumatology. Philadelphia Elsevier Saunders, 2005.
McCann LJ, Wedderburn LR, Hasson N. Juvenile Idiopathic Arthritis.
Arch Dis Child Educ Pract Ed 2006; 91: ep29eep36.
Szer S L, Kimura Y, Malleson PN, Southwood TR. Arthritis in Chil-
dren and Adolescents Juvenile Idiopathic Arthritis. Oxford
University Press, 2006.
� 2012 Elsevier Ltd. All rights reserved.