Paediatrics and Child Health April2012

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Paediatrics

and Child Health

Paediatrics and Child Health is the continuously updated review of paediatrics and child health (formerly Current Paediatrics) Paediatrics and Child Health is an authoritative and comprehensive resource that provides all paediatricians and child health care specialists with up-to-date reviews on all aspects of hospital/community paediatrics and neonatology, including investigations and technical procedures in a 4-year cycle of 48 issues. The emphasis of the journal is on the clear, concise presentation of information of direct clinical relevance to both hospital and community-based paediatricians. Contributors are chosen for their recognized knowledge of the subject. The journal is abstracted and indexed in Current Awareness in Biological Sciences. The layout of the journal, including the design and colour, enables fast assimilation of key information. For ease of reference, Paediatrics and Child Health is available in print and online formats.

Editor-in-Chief Patrick Cartlidge

DM FRCP FRCPCH

Senior Lecturer in Child Health and Honorary Consultant Neonatologist, Wales College of Medicine, Cardiff University, Cardiff, UK

Founding Editor Richard Wilson

MB FRCP FRCPCH DCH

Associate Editors Allan Colver MA MD FRCPCH Professor of Community Child Health, Sir James Spence Institute, Newcastle University, Newcastle, UK Harish Vyas DM FRCP FRCPCH Professor in PICU and Respiratory Medicine, Queen’s Medical Centre, Nottingham University Hospital, UK Doug Simkiss BMedSci MBChB DCH DTMH MSc FRCP (Ed) FRCPCH FHEA Associate Professor in Child Health, Warwick Medical School, Warwick, UK Honorary Consultant Paediatrician, Birmingham Community HealthCare NHS Trust and Sandwell and West Birmingham NHS Trust, Birmingham, UK

Nicholas Mann MD FRCP FRCPCH DCH Consultant Paediatrician, Department of Paediatrics, Royal Berkshire Hospital, Reading, UK Alistair Thomson MA MD BChir FRCPCH FRCP DCH DRCOG Consultant Paediatrician, Leighton Hospital, Crewe, UK Colin Powell MBChB DCH MRCP FRACP FRCPCH MD Consultant Paediatrician, University Hospital of Wales, Cardiff, UK Peter Heinz MD State Exam Med FRCPCH Consultant Paediatrician, Addenbrooke’s Hospital, Cambridge, UK

International Advisory Board R Adelman (Phoenix, USA) Z Bhutta (Karachi, Pakistan) MC Chiu (Kowloon, Hong Kong) P Malleson (Vancouver, Canada)

A Bagga (New Delhi, India) H Buller (Rotterdam, The Netherlands) M Hassan (Islamabad, Pakistan) A Martini (Genova, Italy)

A Moosa (Saffat, Kuwait)

C Morley (Carlton, Australia)

BJC Perera (Colombo, Sri Lanka)

J Pettifor (Johannesburg, South Africa)

M Uchiyama (Niigata, Japan)

M van de Bor (Nijmegen, The Netherlands)

Paediatrics and Child Health has an eminent editorial board and a wide array of authors, all of whom are recognized experts in their field.

Visit our website at: www.paediatricsandchildhealthjournal.co.uk for previous issues, subscription information and further details.

SYMPOSIUM: NEONATOLOGY

Temperature monitoring and control in the newborn baby

convection and evaporation. Children and adults are homeothermic, 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 temperature, 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 thermogenesis). The term baby can alter body posture and skin blood flow reduces as the superficial capillaries constrict. As environmental temperature falls further outside the NTR, heat production 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, particularly 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.

Yvonne Freer Andrew Lyon

Abstract The 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 intermittent 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 outcome will be more 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 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 temperature settings, based on the concept of the neutral thermal environment, 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).

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.

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Recent evidence has shown that poor management of temperature 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 encephalopathy, 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.

Electronic thermometers have temperature sensors inside the tip and are covered with a sheath. They are used in monitoring or predictive mode. In the monitor mode the temperature is displayed once a steady state has been achieved, usually about 3e5 min.

With predictive mode the temperature is ‘predicted’ by a calculation 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 exception 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 nonshivering 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 indication 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 temperature 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.

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/night when measured. The temperature within the tissues of the body varies with metabolic rate and there is no such thing as a single central body temperature. Normal temperature 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 born at term. Despite an apparent normal temperature the infant may well be thermally stressed and at increased risk of adverse outcome.

How, where and frequency of temperature measurement The primary purpose of measuring 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.

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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.

Variation due to device and measurement method

decision-making, the degree of variability suggests that interventions may 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.

Accuracy of thermometers has been reviewed and according to manufacturing standards, devices should be within 0.2 C across 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 or method of recording a physiological parameter, as this measures strength of a relationship rather than agreement. Bland and Altman propose that by comparing the individual differences between two measurements, 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 thermometer and an electronic axillary thermometer against an indwelling rectal probe and an electronic and an infrared axillary skin thermometer against a glass mercury thermometer using this technique 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 between methods and this is of concern in clinical practice. Although the mean difference is small, and of no consequence to clinical

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How best to maintain temperature Simple methods for preventing heat loss are well known e a warm 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 can be minimized, as described above, but many preterm babies are cold on arrival in the neonatal unit. Heat from radiant heaters is often insufficient to compensate for the large losses due to evaporation. To overcome this, babies are wrapped in polyethylene occlusive skin wraps or placed into plastic bags to reduce TEWL. One systematic review of five studies utilizing plastic wraps/bags and stockinet hats showed that infants less than 28 weeks gestation who were 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

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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 warming mattresses, 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 association 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 literature. 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 semipermeable/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.

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 and not 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 birthweight infants. Adv Neonatal Care 2009; 9: 34e9.

Crawford DC, Hicks B, Thompson MJ. Which thermometer? Factors influencing best choice for intermittent clinical temperature assessment.

J Med Eng Technol 2006; 30: 199e211.

Flenady VJ, Woodgate PG. Radiant warmers versus incubators for regulating 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.

Leslie A, Wardle SP, Budge H, Marlow N, Brocklehurst P. Randomised controlled trial of gel warming mattresses to prevent hypothermia during the resuscitation 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.

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 interpreted and acted upon. There are, as yet, no good data to guide us in deciding on the optimum management of the baby’s external environment. What is clear is that this important area of care can no

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Practice points C

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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.

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SYMPOSIUM: NEONATOLOGY

Investigation, prevention and management of neonatal hypoglycaemia (impaired postnatal metabolic adaptation)

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 with milk 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 production 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.

Jane M Hawdon

Abstract Blood glucose levels fall in the hours after birth in all babies but for most babies the normal process of neonatal metabolic adaptation mobilizes alternative 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

Clinical significance of impaired metabolic adaptation In some circumstances (see below), such as following preterm delivery, intrauterine growth restriction, perinatal hypoxiaischaemia 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 longterm 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.

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 physiological 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 unnecessary administration of formula or intravenous glucose which in turn impair metabolic adaptation to postnatal life.

Metabolic changes at birth

Causes of impaired neonatal metabolic adaptation

During pregnancy, the human fetus receives from its mother via the placental circulation a supply of substrates necessary for

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 addition, hormonal and enzyme adaptive responses may by immature or the baby may have systemic conditions which affect hepatic function and glucose production, eg severe infection.

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.

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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 carbohydrate 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.

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 pregnancy which has not been well controlled, the postnatal fall in blood glucose concentration is more prolonged or becomes clinically significant and this is the most common cause of neonatal hyperinsulinaemic hypoglycaemia. Fetal and neonatal hyperinsulinism may occur after maternal type 1 or type 2 diabetes or diabetes whose 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.

Perinatal hypoxia-ischaemia: the high metabolic requirement for anaerobic metabolism will reduce endogenous 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.

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).

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 impaired metabolic adaptation.

If hypoglycaemia is diagnosed, there must be urgent investigation for underlying conditions and appropriate management of these.

BeckwitheWiedemann syndrome: this condition is characterized 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.

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 hypoglycaemia are defects in cortisol production.

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 thiazide diuretic use may cause neonatal hyperinsulinism.

Maternal medication: maternal beta blocker therapy has been associated with impaired neonatal metabolic adaptation, although passage across the placenta and in breast milk is variable. This is not a contraindication to breast feeding. Often, the baby of the mother with hypertension also has IUGR, thus increasing the risk.

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.

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.

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

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

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urgent investigation for underlying cause (Table 2) and institution 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.

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 allow prompt and accurate blood glucose measurement.

Detection and management of neonatal hypoglycaemia Clinical scenario

Action

Sick baby or very preterm in NNU

Aim to maintain BG > 2.5 mmol/l If hyperinsulinism suspected aim to maintain glucose >3 mmol/l

Any baby with neurological signs - Abnormal tone - Decreased activity - Lethargic/reduced level of consciousness - Abnormal cry - Seizures

Admit to NNU Full investigations including BG Aim to maintain glucose >2.5 mmol/l If hyperinsulinism suspected aim to maintain glucose >3 mmol/l

Babies “at risk”:

Encourage breastfeeding as soon as possible after birth (if appropriate) Regular BG measurements e approximately 3e4 hourly pre-feed, commencing before the second feed after birth

- 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: C No abnormal signs and feeding well, BG > 2.0 mmol/l

Encourage breast feeding and observe No formula supplements if breast fed. Check pre-feed BG 3e4 h later pre-feed or sooner if abnormal signs (as above)

What to do if “at risk” and:

Continue breast feeding.

Add EBM and/or formula supplement (initially 10 ml/kg/feed) Check pre-feed 3e4 h later or sooner if abnormal signs

C No abnormal signs and feeding well, BG 1.0e2.0 mmol/l on 2 consecutive pre-feed measurements

Titrate volume of supplements against 3e4 hourly pre-feed BG What to do if “at risk” and: C

Admit to NNU for investigations and IV glucose, continue feeds if tolerated

BG < 1.0 mmol/l

Healthy term infants Includes LGA babies who are not: - Macrosomic appearance or

No glucose monitoring Encourage and support breast feeding If concerns around feeding assess for abnormal signs and clinical wellbeing. Investigate (including infection screen and BG) only if clinical concerns

- Infants of diabetic mothers NNU, neonatal unit; EBM, expressed breast milk; BG, blood glucose; LGA, large for gestational age; IV, intravenous; SGA small for gestational age.

Table 1

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Prevention and management of neonatal hypoglycaemia

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 hypoglycaemia 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 hypoglycaemia) 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.

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 hypoglycaemia, 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 monitoring (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 metabolic 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

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 monitoring 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): recognition 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 concentrated 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 subcutaneously at a dose of 10 mg/kg/day also suppresses insulin release.

These additional treatments should only be given after

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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 thresholds. 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: WileyBlackwell, 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.

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 unexpected neonatal 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

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 hypoglycaemia may create or add to anxiety for the parents. Treatment 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 supplementation 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

Practice points C

C

C

C

135

Blood glucose levels fall after birth in all babies, and most compensate for this by mobilizing alternative fuels Identification of babies at risk of impaired neonatal metabolic adaptation and prevention of hypoglycaemia is important to avoid brain injury Unnecessary separation of mother and baby or formula feeding of the baby should be avoided Investigations for underlying cause of hypoglycaemia should be carried out if hypoglycaemia is persistent, resistant or unexpected

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SYMPOSIUM: NEONATOLOGY

Resuscitation of the term and preterm infant

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 transition from the fetal to adult circulation with the closure of the ductus arteriosus, foramen ovale and ductus venosus.

Angela E Hayward

Abstract The vast majority of newborn infants make the transition from intrauterine 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 assistance 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 pharmacological support only needed in rare cases.

Physiology of newborn asphyxia

In 2010 the European Resuscitation Council (ERC) guidelines for Cardiopulmonary resuscitation (CPR) were updated and published. 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. Approximately 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.

In the 1960s an animal model for neonatal hypoxia was developed 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.

Normal newborn physiology

Resuscitation at birth

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

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.

Keywords guidelines; neonatal; newborn; premature; resuscitation

Background

Angela E Hayward MBBS MRCPCH is Consultant Neonatologist at the University Hospital of Wales, Heath Park, Cardiff, UK. Conflict of interest: none.

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Resuscitation Council (UK)

Guidelines 2010 Resuscitation

Newborn Life Support Dry the baby Remove any wet towels and cover Start the clock or note the time Assess (tone), breathing and heart rate

Birth

30 s

If gasping or not breathing: Open the airway Give 5 inflation breaths

AT

ALL

STAGES 60 s

Consider SpO2 monitoring

ASK:

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 Reassess heart rate every 30 s If heart rate is not detectable or slow (< 60 min-1 ) consider venous access and drugs

Acceptable pre-ductal SpO2

2 min 3 min 4 min 5 min 10 min

60% 70% 80% 85% 90%

DO

YOU

NEED

HELP?

Figure 1 Newborn Life Support Algorithm 2010. With kind permission of the Resuscitation Council (UK).

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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 babyâ&#x20AC;&#x2122;s relatively large occiput. A rolled towel or padding of not more than 2 cm may be placed under the babyâ&#x20AC;&#x2122;s shoulders to assist with neutral positioning 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.

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 environment 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.

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 ineffective 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.

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 metabolic 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 temperature. 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 temperature. Resuscitation and stabilization can occur with the plastic cover in place. The baby should then be kept wrapped in polyethylene until admission to the neonatal unit and the temperature checked.

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. Occasionally, 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

Assessment: APGAR scores are not calculated to guide resuscitation 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 improved with 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.

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a

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 movement 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 significant reduction in death or bronchopulmonary dysplasia in infants treated with either early CPAP or intubation and surfactant in the delivery room. They also reported preterm infants exposed to CPAP following delivery had fewer days of ventilation and oxygen requirement.

100 90

Oxygen saturation (%)

80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

7

8

9

10

7

8

9

10

Air versus oxygen: in term newborn infants who require positive 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 antioxidants. 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 resuscitating 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.

Minutes after birth b

100 90

Oxygen saturation (%)

80 70 60 50 40 30 20 10 0 0

1

2

3

4

5

6

Minutes after birth c

100 90

Oxygen saturation (%)

80 70 60

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

50 40 30 20 10

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 no medical 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, Vento M et al. Defining the reference range for oxygen saturation for infants after birth. Pediatrics 2010; 125(6): e1340ee1347 with kind permission of the American Academy of Pediatrics.

0 0

1

2

3

4

5

6

7

8

9

10

Minutes after birth 3rd

10th 75th

25th 90th

50th 97th

Figure 2 Oxygen saturation percentiles for newborn infants with no medical intervention after birth. (a) Third, 10th, 25th, 50th, 75th, 90th and 97th Spo2

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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 endotracheal 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 documented in colorimetric devices when they have been contaminated 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.

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 ventilations. 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 medication 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 resuscitation 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.

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 endotracheal 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 recommended 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 6.0 6.5 7.0 7.5 8.0 8.5 9.0

23e24 25e26 27e29 30e23 33e34 35e37 38e40 41e43

0.5e0.6 0.7e0.8 1.9e1.0 1.1e1.4 1.5e1.8 1.9e2.4 2.5e3.1 3.2e4.2

Kempley ST, Moreiras JW, Petrone FL. Endotracheal tube length for neonatal intubation. Resuscitation 2008; 77: 369e373.

Ongoing care following resuscitation Newborns who have responded to resuscitation efforts remain at risk for further deterioration. It is essential for them to have

Table 1

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SYMPOSIUM: NEONATOLOGY

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 metaanalysis 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. Resuscitation 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 multicenter, 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 recommendations. Resuscitation 2010; 81S: e260e87.

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 transport 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 decision 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, Oâ&#x20AC;&#x2122;Donnell CP, Schulze A. Resuscitation of newborn infants with 100% oxygen or air: a systematic review and meta-analysis. 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 intubations in very low birth weight infants during neonatal resuscitation at birth. J Perinat Med 2009; 37: 79e84.

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Practice points C C C

C

C

141

The need for resuscitation is not always predictable.

Effective airway management is vital.

Pulse oximetry readings should guide the need for supplementary oxygen.

Where there is evidence of hypoxiceischaemic encephalopathy, cooling should be considered.

Ongoing clinical research is required to further our knowledge.

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SYMPOSIUM: NEONATOLOGY

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.

Understanding blood gases/ acidebase balance Nitin Goel

HA4Hþ þ A

Jennifer Calvert

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.

Abstract Acidebase 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 intervention provided.

Normal acidebase regulation The process of maintaining pH balance during normal metabolism 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 conjugate base.

Keywords acidebase balance; acidosis; alkalosis; anion gap; base deficit; blood gas analysis; pH

pH ¼ pK þ log½A =½HA

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 respiratory 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.

Extracellular buffers: the bicarbonate system is the principal buffer in the extracellular fluid (ECF) and is based on the relationship 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 þ HCO 3 4H2 CO3 4CO2 þ H2 O The pK for this buffer is 6.1. For bicarbonate buffer, the HendersoneHasselbalch equation is: pH ¼ 6:1 þ log½HCO 3 =½CO2

pH a 1=Hþ

Mathematical manipulation of the above equation produces the following relationship, ½Hþ ¼ 24 pCO2 =½HCO 3

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.

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

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.

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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.

(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 nephrotoxins 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 predisposed to metabolic acidosis.

(2) Excretion of Hþ ions which takes place at the distal tubules and the collecting duct, thus acidifying the urine. The principal 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 intraluminal 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 concentration 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 nephrocalcinosis, vitamin D intoxication or Amphotericin B administration, which produce secondary distal RTA. Patients with distal RTA cannot acidify their urine and have a urine pH more than 5.5, despite acidosis.

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. þ 2 H2 PO1 4 4H þ HPO4

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 physiological changes by the renal and respiratory systems are employed. In a primary metabolic disorder, the respiratory system provides the compensation, whereas in a primary respiratory 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, hypoventilation causes CO2 retention and thus an increase in pCO2.

The resulting increase in Hþ ions directly stimulates chemoreceptors 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 generating new bicarbonate. They can thus respond to acidebase imbalance by acidifying or alkalinizing the urine. This is accomplished by:

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Disturbances of acidebase balance

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 excretion, accompanied by bicarbonate reabsorption. In renal insufficiency, 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.

þ

Abnormalities in blood pH, due to an increase in H 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.

Anion gap: an important tool in evaluating the cause of metabolic acidosis is the ‘anion gap’, the difference in the measurement of the most abundant serum cation (Naþ) and the sum of two most abundant serum anions (HCO3 and chloride, Cl ).

Metabolic acidosis This results from an alteration in the balance between production and excretion of acid; by increased exogenous intake or endogenous 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.

↑PCO

½Naþ ð½Cl þ ½HCO 3 Þ This gap also represents the difference between unmeasured anions (phosphate, sulphate, proteins, acids e.g. lactate, ketoacids) 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.

pH < 7.35

↓HCO

Respiratory acidosis

–

Metabolic acidosis

↑Bicarbonate reabsorption ↑HCO –

Hyperventilation ↓PCO

CO + H O ↔ H CO ↔ H+ + HCO

↓Bicarbonate reabsorption ↓HCO –

Hypoventilation ↑PCO

Metabolic alkalosis

Respiratory alkalosis

↓PCO

–

pH > 7.45

Respiratory compensation

↑HCO

–

Metabolic compensation

Figure 1 Acidebase regulation: interplay of bicarbonate buffer, respiratory and renal systems.

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Acidebase disorders, blood gas findings and common causes in neonates Disorder

Blood gas analysis (normal range) Causes HCO3L BE pH pCO2 (7.30e7.45) (4.5e6 kPa) (19e24 mmol/l) (L3 to D3)

Metabolic acidosis Uncompensated Y Compensated Low Normal

Normal Y

Y Y

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)

145

Metabolic alkalosis Uncompensated [ Compensated High Normal

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

Ă&#x201C; 2011 Elsevier Ltd. All rights reserved.

Respiratory acidosis Uncompensated Y Compensated Low Normal

[ [

Normal [

Normal [

Respiratory abnormalities: respiratory distress syndrome, chronic lung disease, pneumothorax, meconium aspiration, transient tachypnoea of newborn, pneumonia, pulmonary hypoplasia, congenital lung malformations Central nervous system depression: hypoxic ischaemic encephalopathy, excess opioids, raised intracranial pressure, 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

Respiratory alkalosis Uncompensated [ Compensated High Normal

Y Y

Normal Y

Normal Y

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

Table 1

SYMPOSIUM: NEONATOLOGY

Prematurity: hyperchloraemic acidosis Renal tubular acidosis: proximal/distal Gastrointestinal bicarbonate losses: ileostomy, diarrhoea

SYMPOSIUM: NEONATOLOGY

Normal plasma

Acidosis (no gap) UC

UC UA

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.

Acidosis (increased gap) UC

UA UA HCO

Respiratory alkalosis This occurs with excessive pulmonary losses of CO2 and resulting 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.

HCO Na

Na

Cl

Na

HCO

Cl Cl

The anion gap UC, unmeasured cations; UA, unmeasured anions.

Figure 2 Anion gap.

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 bicarbonate, 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 bicarbonate & pCO2 and little change in pH.

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 bicarbonate 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.

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 dependent 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

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

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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

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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 bicarbonate 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 reliable for babies with hypotension, poor perfusion or cold peripheries. Capillary blood samples also cannot reliably monitor oxygenation status or predict the degree of hypoxaemia. 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 monitoring are useful adjuncts to blood gas measurements. Pulse oximeters work on the principle that oxygenated and deoxygenated 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 vasodilated 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.

Guide for blood gas values in neonates Normal reference ranges (arterial sample)

pH PaCO2 (kPa) PaO2 (kPa) HCO3 (mmol/l) BE (mmol/l)

7.30e7.45 4.5e6.0 6.0e8.0 19e24 3 to þ3

Table 2

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 textbook 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.

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 bicarbonate 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 ‘standardized’ HCO3 and BE. Normal ranges vary slightly with gestation & postnatal age and the desired values of these parameters for

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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 newbornâ&#x20AC;&#x2122;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.

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A stable pH is essential for optimal cellular metabolism and can be challenging in the newborn period Acidebase balance is regulated by buffers, the respiratory & renal systems When the compensatory response falls outside the expected value, a mixed acidebase disorder is likely Blood gases can be used to monitor acidebase balance Blood gases should always be interpreted in conjunction with information from the clinical history & examination and noninvasive monitoring

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SYMPOSIUM: NEONATOLOGY

Recognition and management of neonatal seizures

electrical discharge is due to depolarization of neurons, resulting from an influx of sodium ions. Negative potential across neuronal cells is maintained by an ATP (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 hypoglycaemia 2 Excessive release of the excitatory neurotransmitter glutamate 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 neurotransmitter 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.

Vaishali Patel Amit Kandhari Shobha Cherian

Abstract Seizures 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 Neurodevelopmental basis for neonatal seizures Anatomical: neonates rarely develop easily recognizable tonicclonic 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.

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 may be as high as 57e132 per 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.

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-isoxazolepropionic 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 inhibition 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

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.

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neonatal period, GABA agonists e.g. barbiturates and benzodiazepines, are relatively ineffective. With maturation, NKCC1 expression diminishes and KCC2 expression increases. GABA activation then causes chloride to flow into the cell and hyperpolarize 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.

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.

Clinical features There are four major types of neonatal seizures. Their incidence, clinical manifestations and EEG (electroencephalograph) correlates 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 eliminated by gentle passive flexion of the affected limb. Jitteriness may occur with hypoglycaemia, hypocalcaemia, drug withdrawal and hypoxic-ischaemic encephalopathy.

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 developmental 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

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 period. Presynaptic release of glutamate results in excitation of post synaptic neuron (left panel) by activating NMDA and AMPA receptors. GABA release (right panel) results in hyperpolarization in the mature CNS and depolarization in the immature CNS. NKCC1: sodium-chloride co-transporter, KCC2: potassium-chloride co-transporter, NMDA: N-methyl-D-aspartate, AMPA: alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid, Naþ: sodium, Ca2þ: calcium, Cl : chloride.

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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

þ/

Clonic

25e30%

Tonic

5%

Myoclonic

15e20%

- Orobuccal: sucking, chewing, lip smacking, hiccups - Ocular: blinking, staring, horizontal deviation of eyes - Limbs: cycling, rowing - Autonomic: alteration in heart rate, blood pressure, apnoea, colour change - Repetitive jerking - Focal, multifocal or generalized (rare) - Sustained posturing of limbs/trunk - Deviation of head/eyes - Focal, generalized - Generalized may mimic decerebrate or decorticate posturing - Rapid isolated jerks - Common in flexor group of muscles - Focal, multifocal, generalized, axial

þ Focal: þ Generalized:

Focal and multifocal: Generalized:þ

Table 1

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?

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 observable seizures, full channel EEGs are essential for diagnosis and for assessing efficacy of treatment. Video-EEG monitoring, where continuous EEG monitoring is accompanied by contemporaneous video recording documenting suspicious clinical behaviours, 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 view of 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.

Recognition of seizures Neonatal seizures are difficult to recognize, as there are often no clinical manifestations of electrographic seizures; a phenomenon

Why treat?

The impact of convulsions on the immature brain has long been debated. Although the immature brain is more prone to seizures,

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 progresses 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 hyperglycinemia 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 encephalopathy. 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

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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, independent of the severity of hypoxia-ischaemia. Also, post-hoc analysis of data from the Cool-Cap hypothermia trial revealed that the absence 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 anticonvulsants 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.

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)

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 definition 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 clinical, 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 hypoglycaemia 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.

Table 2

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

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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 long half-life (2e4 days) and enters the CSF rapidly. It is given as a loading dose of 20 mg/kg (which may be repeated if the initial dose is ineffective) and achieves therapeutic levels (20e40 mg/ litre) in the serum within a short time.

Phenytoin e acts by reducing electrical conductance in neurons by stabilizing sodium channels. Both phenytoin and

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Prolonged/ repeated seizures affects

Respiratory system

Po2

Pco2

Cardiovascular system

BP

Energy metabolism

Glycolysis

Neuro-transmitters

ATP/ ADP

Re-uptake of EAA

Release of EAA

Lactate+ H+ CBF

CBF

Brain glucose

EAA

Haemorrhage

Brain injury

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.

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 phenobarbitone 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 arrhythmias and hypotension, it should not be given with phenytoin and must be administered under continuous cardiac monitoring.

Levetiracetam (Keppra) e is a commonly prescribed anticonvulsant medication in older children and adults. Its anticonvulsant action is not well understood but is believed to impede

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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: Paraldehyde e was 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

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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 electroencephalography in neonates. Pediatr Neurol 2009; 41: 315e26.

11 Jensen FE. Neonatal seizures: an update on mechanisms and management. Clin Perinatol 2009; 36: 881e900.

mg of pyridoxine should be administered intravenously under EEG monitoring. Seizure activity stops within minutes and the EEG normalizes.

How long to treat?

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 demonstrated that systemic therapy with phenobarbitone, benzodiazepines, 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 background 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 background 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

Practice points

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.

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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 Electrical seizures may occur without any clinical manifestation, a phenomenon known as electro clinical dissociation The need to treat electrical seizures is controversial Phenobarbitone remains the mainstay of therapy despite being ineffective in a significant proportion Levetiracetam, topiramate and bumetanide may have a role in the future

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SYMPOSIUM: NEONATOLOGY

The role of brain MRI scanning in the newborn

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.

Pia Wintermark

The newborn brain Abstract

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 differentiation 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 developmental processes with a significant cell loss, leading to disruption of normal developmental processes. This can cause dramatic deterioration of subsequent brain development and brain functions. 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.

Very sick newborns are at high risk for brain injuries and adverse neurodevelopmental 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 standard 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 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

Introduction Very sick newborns are at high risk for brain injuries and adverse neurodevelopmental outcomes. A major issue confronting caregivers 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 accurate anatomical details that cannot be obtained by any other imaging modality. Furthermore, more and more studies are

Diseases leading to brain injuries in newborns Hypoxic-ischaemic encephalopathy Stroke Cerebral sinovenous thrombosis Prematurity Congenital cardiopathy Infection: Cytomegalovirus, Enterovirus, Parechovirus, Herpes Simplex Virus, .

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

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 Childrenâ&#x20AC;&#x2122;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.

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Table 1

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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 haemorrhage, intraventricular haemorrhage and periventricular haemorrhagic 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 cardiovascular 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

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 perinatal 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 conventional 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

Figure 1 Stroke in a term newborn. MRI performed at 42 4/7 weeks of corrected age (5 days of life). (a) Axial T1-weighted image, (b) Axial T2-weighted image, (c) Axial apparent diffusion coefficient (ADC) map, and (d) Axial diffusion-weighted image showed the infarction within the left cerebral artery territory.

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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.

(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 developing brain injuries, such as lactates (product of anaerobic glycolysis), N-acetyl-aspartate (NAA) (neuronal marker), glutamine/GABA (neurotransmitter), creatine (energy metabolism), choline (cell membrane marker) and myo-inositol (glial cell marker). Early elevation of lactate and later reduction of Nacetyl-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 suppressed. This imaging technique is more sensitive than T1- and T2-weighted imaging for detecting pathologies specifically located periventricular or subcortical within the brain parenchyma, 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 variations of the neonatal circle of Willis and to explore possible vascular-related abnormalities, such as arteriovenous malformations. 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 methaemoglobin 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 connectivity 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

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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 implications 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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Conclusions

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 evaluating 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

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 neurodevelopmental disability and who may benefit from early intervention 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

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 practitioners, NICU nurses and respiratory therapists who care exclusively for the newborn from NICU departure to return, as well as neuroradiologists and MRI technicians who know how to operate, 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 infantâ&#x20AC;&#x2122;s head and body and further reduce motion artifacts. If possible, feeding should be administered 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 treatments 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 administered in some of the MRI suites.

FURTHER READING 1 MRI step-by-step, interactive course on magnetic resonance imaging: http://www.imaios.com/en/e-Courses/e-MRI. 2 Ajayi-Obe M, Saeed N, Cowan FM, Rutherford MA, Edwards AD. Reduced development of cerebral cortex in extremely preterm infants.

Lancet 2000; 356: 1162e3.

3 Barkovich AJ. MR imaging of the neonatal brain. Neuroimaging Clin N Am 2006; 16: 117e35.

4 Barkovich AJ. An approach to MRI of metabolic disorders in children.

J Neuroradiol 2007; 34: 75e88.

5 Berfelo FJ, Kersbergen KJ, van Ommen CH, et al. Neonatal cerebral sinovenous thrombosis from symptom to outcome. Stroke 2010; 41: 1382e8.

6 Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic 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.

9 Govaert P, Ramenghi L, Taar R, De Vries L, DeVeber G. Diagnosis of perinatal stroke I: definitions, differential diagnosis and registration.

Acta Paediatr 2009; 98: 1556e67.

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.

Radiology 2009; 252: 209e17.

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: 286e94.

13 Kate R, Atkinson D, Brant-Zawadzki M. Fluid-attenuated inversion recovery (FLAIR): clinical prospectus of current and future applications. 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 followup. J Child Neurol 2011; 26: 1111e20.

15 Kirton A, DeVeber G. Advances in perinatal ischemic stroke. Pediatr Neurol 2009; 40: 205e14.

16 Lawrence RK, Inder TE. Anatomic changes and imaging in assessing brain injury in the term infant. Clin Perinatol 2008; 35: 679e93.

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17 Limperopoulos C. Extreme prematurity, cerebellar injury, and autism.

Semin Pediatr Neurol 2010; 17: 25e9. €ppi PS. Neuroimaging of 18 Lodygensky GA, Vasung L, Sizonenko SV, Hu 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 variations of the circle of Willis in preterm-at-term and term-born infants: an MR angiography study at 3T. AJNR Am J Neuroradiol 2009; 30: 1955e62.

20 Mathur AM, Neil JJ, McKinstry RC, Inder TE. Transport, monitoring, and successful brain MR imaging in unsedated neonates. Pediatr Radiol 2008; 38: 260e4.

21 Mathur AM, Neil JJ, Inder TE. Understanding brain injury and neurodevelopmental 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 development in newborns with congenital heart disease. N Engl J Med 2007; 357: 1928e38.

25 Mukherjee P, McKinstry RC. Diffusion tensor imaging and tractography 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. €ppi PS. The role of functional magnetic resonance 28 Seghier ML, Hu 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.

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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 Am J Neuroradiol in press.

37 Xu D, Vigneron D. Magnetic resonance spectroscopy imaging of the newborn brain e a technical review. Semin Perinatol 2010; 34: 20e7.

Practice points C

C

C

C

C

C

There have been tremendous advancements in the development of magnetic resonance imaging (MRI) technologies devoted to the newborn brain.

MRI is a noninvasive and nonionizing neuroimaging technique.

When available, it should be preferred over computed tomography scan in newborns, especially as it provides additional detailed imaging of the brain parenchyma.

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.

A dedicated imaging protocol should be developed for scanning 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 T1and 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.

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 neurodevelopmental disability and who may benefit from early intervention services.

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.

Acknowledgements The author thanks Aaron Johnstone and Therese Perreault for their thorough review of the manuscript.

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Cleft lip and palate: current management Tim Goodacre Marc C Swan

Abstract Cleft lip and palate are the most common presenting congenital conditions of the face and cranial bones. This article describes current understanding 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 multidisciplinary team including clinical psychology support for child and family is discussed.

Figure 1 Left complete unilateral cleft of lip, alveolus, hard and soft palate.

populations. The incidence of isolated CP is racially homogeneous 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.

Keywords alveolar bone graft; cleft lip; cleft palate; naso-alveolar moulding; orthognathic; pharyngoplasty; postoperative emergencies; submucous

Aetiology Over 300 syndromes are associated with orofacial clefting and most occur as an isolated abnormality e 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.

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

Genetics

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

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

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.

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Genetic associations with orofacial clefting CL P Chromosomal Single gene

CP

Trisomy 13 or 21 Van der Woude (Chromosome 1, AD) EEC (ectrodactyly, ectodermal hyperplasia and CL P) Syndrome (Chromosome 3, AD)

Sporadic

Treacher Collins Syndrome (Chromosome 5, AD) Stickler Syndrome (Chromosome 12, AD) Velocardiofacial Syndrome (Chromosome 22, AD) Opitz G/BBB Syndrome (AD) Pierre Robin Sequence

CL P, cleft lip and palate; CP, cleft palate; AD, autosomal dominant.

Table 1

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.

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.

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 diagnosed antenatally. The addition of three-dimensional (and now four-dimensional) ultrasound methods gives better quality

a

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

b

Figure 2 Intra-uterine magnetic resonance imaging scan (sagittal view) demonstrating normal (a) and cleft (b) palates. The absent palatal stripe (red arrow) in (b) is a pathognomic sign of cleft palate.

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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.

specialized speech and language therapists is an acceptable early management plan for these cases.

Diagnosis of SMCP is often delayed. Awareness of the presenting 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, therefore, successful) procedure.

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

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 conjunction with good nurse specialist support. The use of such splints is routine now across south east Asia.

Figure 3 The midline zona pellucida of a submucous cleft palate.

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Figure 4 Pre-operative views of bilateral cleft lip and palate (a) and (b) with post-operative image (c).

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.

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.

Pierre Robin sequence The sequence of cleft palate associated with micrognathia, glossoptosis, 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

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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 nasopharyngeal airway requires placement on the ward postoperatively, 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 the first 12 h is expected, although the surgeon should be alerted if it is fresh or brisk. Later bleeding can be reactionary or secondary in nature. Either way, the child will require some sedation (usually morphine 0.1 mg/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 incisions 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 room and 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.

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Secondary surgery: Secondary procedures include pharyngoplasty, alveolar bone grafting and osteotomyeorthognathic surgery. Bleeding is the most common later emergency. It should be managed with all usual supportive measures (ABC, intravenous fluids and cross matching if appropriate) and early return to theatre. Airway obstruction can frequently follow the less physiological forms of pharyngoplasty.

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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 anterior 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.

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 nasopharyngeal airway and nasogastric feeding tube in situ.

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.

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The dilemma of the mutually opposing benefits of early and later hard palate repair on palatal growth versus speech development 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.

capability with lowest incidence of velopharyngeal incompetence. 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 velopharyngeal 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 10 years.

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 correction 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 minimize deep seated scar tissue and offer the potential to generate more bone from the under surface of the periosteum. Subtle corrections of the lip scar with the interposition of small flaps above the white 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).

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 animal models. 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 experimental with respect to orofacial clefting and there is little prospect of clinical trials commencing in the foreseeable future.

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 Sommerlad. The outcome of this procedure appears to have no adverse growth effect and produces the very best speech

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Figure 6 Pre-operative (a) and post-operative (b) appearances of a left unilateral cleft lip and palate.

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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).

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 hypernasality, nasal emission and nasal turbulence or resonance.

When young children have incompetent palatal musculature, some will develop very substantial compensatory misarticulations 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 intervention 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.

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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 pharyngeal 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 myomucosal flap from the posterior pharyngeal wall and attaching it to

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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 the most effective in the whole 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 indisputable (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 hypoplasia, and are destined to require significant secondary surgery regardless of their primary treatment protocol.

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’ pharyngoplasty 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 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.

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Alveolar bone grafting Primary cleft repair does not correct the bony deformity in the gum ridge, although recent work on primary gingivoperiosteoplasty is an attempt to address this. Since the 1970s, it has been understood that the bone defect is best filled with cancellous (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.

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Figure 8 Secondary bone grafting of the cleft alveolus: pre-operative (a) and immediate post-operative (b) views.

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Clinical psychology 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 management from prenatal diagnosis to adulthood is invaluable, and essential as a guide to achieve holistic care from all team members.

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 intervention in families at high risk of adverse psychological consequences 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 influencing subsequent cognitive ability becoming clear.

Rice DPC. Craniofacial anomalies: from development to molecular pathogenesis. 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 in orofacial clefts. Cleft Palate Craniofac J 2007; 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.

Practice points

CSAG 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.

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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, Wade A, Mars M, Sommerlad BC, 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 gingivoperiosteoplasty versus alveolar bone graft: an outcome analysis of costs in the treatment of unilateral cleft alveolus. Cleft Palate Craniofac J 2002; 39: 26e9.

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Cleft lip and palate are the most commonly encountered anomalies of the craniofacial region The genetic basis of non-syndromic clefting is complex and poorly understood. Environmental factors are involved in a proportion of cases Antenatal diagnosis of lip clefts can be expected in about twothirds 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 counselling and advice. Outcome following such support is very good 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 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 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 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 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 teams as early as possible 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 Comprehensive and ‘holistic’ cleft care involves mandatory clinical psychology support of children and their families.

Unnecessary surgical interventions can be reduced, and longterm global health outcomes are improved

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PERSONAL PRACTICE

Conjugated hyperbilirubinaemia

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.

Julie Brent Mansoor Ahmed

Causes of conjugated hyperbilirubinaemia What is 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.

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 hyperbilirubinaemia). 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 hyperbilirubinaemia. This personal practice review focuses on the initial diagnostic approach and management of conjugated hyperbilirubinaemia during the first few weeks after birth.

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 galactosaemia 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 admission and details of parenteral/enteral nutrition.

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.

Focussed physical examination Anthropometric assessment (including weight, length and head circumference measurement) should be undertaken. In intrauterine 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/galactosaemia) and cardiac evaluation may also be required.

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

Diagnostic workup

Julie Brent MBBS MRCPCH is an ST-5 Paediatrics, at Queen’s Hospital, Burton Upon Trent UK. Conflicts of interest: None.

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.

Mansoor Ahmed MBBS FRCP FRCPCH is Consultant Paediatrician at Queen’s Hospital, Burton Upon Trent, UK. Conflicts of interest: None.

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PERSONAL PRACTICE

Old red blood cells breakdown

Globin Haemoglobin Haem spleen Unconjugated Bilirubin

Albumin

Bilirubin-albumin complex (Water insoluble) Hepatocytes Uridine diphosphoglucuronic acid glucuronyl transferase Conjugated Bilirubin bilirubin diglucuronide (Water soluble) Bile salts Kidneyy Bile Reabsorbed Urobilin Colonic bacteria Urobilinogen

Stercobilinogen

Stercobilin

Figure 1 Schematic diagram of bilirubin pathway.

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 coagulopathy, neoplastic disorders, acute liver failure, hypoglycaemia, sepsis, metabolic disorders like galactosaemia and panhypopituitarism) requiring immediate treatment. Once these disorders have been excluded, the most important differential is to look for biliary atresia. A paediatric hepatologist should be consulted early as prompt referral for surgery to manage biliary atresia before 60 days improves prognosis.

Initial investigations in neonates with conjugated hyperbilirubinaemia 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

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(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 antitrypsin 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 gallbladder. A small or absent gallbladder is suggestive but not diagnostic of biliary atresia and the triangular cord sign (echogenic area at porta hepatis) is thought to be specific for biliary

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Causes of neonatal conjugated hyperbilirubinaemia Extra hepatic Hepatic bile duct anomalies Intrahepatic Intrahepatic bile duct anomalies Idiopathic neonatal hepatitis Infections

Metabolic disorders

Chromosomal disorders Endocrinopathies Toxic Vascular Neoplastic Other

Biliary atresia, choledochal cyst, cholelithiasis, inspissated bile secretion, spontaneous perforation of the bile duct, neonatal sclerosing cholangitis Intrahepatic biliary hypoplasia (Alagille’s syndrome), caroli’s disease (dilated intrahepatic bile ducts), congenital hepatic fibrosis 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) 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 Down’s syndrome, trisomy 13 and 18, turner’s syndrome Hypothyroidism, hypopituitarism, Parenteral nutrition, foetal alcohol syndrome, drugs Budd-chiari syndrome, neonatal asphyxia, congestive heart failure, multiple haemangiomata Neonatal leukaemia, histiocytosis X, neuroblastoma, Hepatoblastoma, erythrophagocytic lymphohistiocytosis Neonatal lupus erythematosus

Table 1

atresia. A normal gallbladder makes biliary atresia unlikely but does not exclude it.

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.

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 hyperbilirubinaemia First line investigations Immediate investigations

If acutely unwell add Liver function Infection Metabolic/storage

Endocrine Miscellaneous

Total and conjugated bilirubin, blood group and coomb’s test, full blood count, blood film and reticulocyte count, blood glucose, sodium, potassium, urea, creatinine, bicarbonate, calcium, phosphate, coagulation screen, urine for reducing substances.

Plasma ammonia, lactate, pyruvate, acid-base (blood gas), urinary pH, protein and ketones, chest X-ray, freeze samples of plasma and urine for future analysis.

AST, ALT, alkaline phosphatase, gamma GT, albumin, cholesterol, triglycerides Blood cultures, c-reactive protein, urine culture and CMV, serology (IgM to Toxoplasma, Rubella, CMV, Herpes), hepatitis A, B, and C serology Cystic fibrosis genetics or sweat test, galactose-1-phosphate uridyl transferase, alpha 1 antitrypsin level and phenotype, plasma and urine amino acids, urine organic acids (succinyl acetone), carnitine and acyl carnitine, iron and ferritin Thyroid function tests, cortisol (preferably after 4 h fast) Ultrasound scan of abdomen after 4 h fast looking for gallbladder and choledochal cyst

Table 2

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PERSONAL PRACTICE

Initial steps in the treatment of conjugated hyperbilirubinaemia

Occasionally, other medication (such as rifampicin, Phenobarbital or cholestyramine) may be required to treat pruritis from cholestasis.

A

This involves diagnosing conditions amenable to specific medical therapy (sepsis, galactosaemia, hypothyroidism, and hypopituitarism) or early surgical intervention (biliary atresia, choledochal 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.

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.

Nutritional management In neonatal cholestasis, long chain fatty acids are not well absorbed leading to malnutrition and fat-soluble vitamin deficiency. 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.

Practice points C

Medication 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.

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C

C

C

C

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Neonatal cholestasis is an uncommon serious disorder which requires urgent diagnostic workup 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 First line investigations look for immediately treatable conditions and complications Biliary atresia is the most common cause of conjugated hyperbilirubinaemia and early detection/referral for surgery before 60 days significantly improves its prognosis Supportive management for cholestasis includes optimizing nutrition and replacing fat soluble vitamins

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SELF-ASSESSMENT

Self-assessment Part A

(b) Codeine (c) Ibuprofen (d) Piroxicam (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

An eight-year-old girl is referred to the paediatric unit with a 7-week history of persistent swelling and redness of her right 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 discrepancy. Initial investigations include:

Haemoglobin White cell count Platelets C reactive protein Phosphate Alkaline phosphatase Calcium IgG IgA IgM

13.6 g/dl 8.4 109/L 278 109/L 1.5 mg/L 1.51 mmol/L 771 U/L 2.53 mmol/L 8.8 g/L 1.10 g/L 0.7 g/L

(12.0e15.5) (4.5e13.0) (150e400) (<3.0) (1.00e2.00) (130e900) (2.20e2.60) (5.4e16.1) (0.4e2.4) (0.5e1.8)

Normal range Normal range

Smooth muscle abs Mitochondrial abs Antinuclear factor Parietal cell abs Urinary HMA/VMA

Positive Negative Negative Negative Normal range

Part B

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

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.

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.

PAEDIATRICS AND CHILD HEALTH 22:4

C3 C4

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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.

joints have not responded to adequate anti-inflammatory treatment. Repeat injections can be required. The procedure 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 hexacetonide (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 intraarticular steroid injections. Methotrexate is recommended because of the rapid onset of action and acceptable side effects. Initial treatment can be a once weekly oral medication, 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 antirheumatic 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, vomiting, 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-Hodgkinâ&#x20AC;&#x2122;s lymphoma has been reported.

Other medications that can be considered are systemic corticosteroids, sulfasalazine, or the increasing number of available biologic agents.

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 children 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, Rheumatoid 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, physiotherapists, 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 hypothetically increases the likelihood of concordance with treatment. With NSAIDs gastro-protective medication may need to be considered. Clinical response to these medications 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

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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 Idiopathic 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:

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SELF-ASSESSMENT

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 polyarthritis 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 a worse 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, lymphadenopathy, 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 interstitial disease. Around half of the children will recover almost completely with the other half having progressive involvement of more and more joints and subsequent disability.

Exclusions e a, b, c, d.

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: dactylitis, 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. B e Juvenile idiopathic arthritis e 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. Oligoarthritis tends to be more common than polyarthritis, affecting girls more than boys, with a peak in early childhood 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.

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FURTHER READING Brough R, Cleary G. When does a knee “need” a “joint” assessment? 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 Children and Adolescents Juvenile Idiopathic Arthritis. Oxford University Press, 2006.

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