Volume 2 No. 4, December 2006

Journal of Paediatric Journal of Paediatric Respirology and Critical Care (JPRCC) is the official peer-reviewed Respirology and Critical Care publication of the Hong Kong Society of Paediatric Respirology, and is published quarterly by Medcom Limited. ISSN 1814-4527. Website: www.hkspr.org. Printed in Hong Kong.

An official Publication of The opinions expressed in the JPRCC are those of the authors and do not necessarily reflect the Hong Kong Society of Paediatric official policies of the Hong Kong Society of Paediatric Respirology, the institutions to which the Respirology authors are affiliated, or those of the publisher. Copyright @2006 by the Hong Kong Society of Paediatric Respirology. All rights reserved. No part Editor of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written Dr. Daniel NG permission of the editor or the publisher.

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1 Editorial Journal of Paediatric Respirology and Critical Care Entering the 10th year Daniel Kwok-Keung NG Department of Paediatrics, Kwong Wah Hospital, Hong Kong

This is the second Christmas issue of our Journal, Your Society has established two prizes for the I would like to wish all members a peaceful Christmas best paediatric respiratory medicine essay for the and a rewarding 2007. Our society was founded in medical undergraduates from the two universities. 1997 and next year will be our tenth year of existence. This year, Mr. John Li is the winner from the University We will celebrate this with an enhanced education of Hong Kong and his essay “Neonatal respiratory program. In the November CME meeting, the topic distress syndrome: a review of current understanding was "Childhood pneumonia" and it attracted a large and new concept" is published in the current issue. audience. The success of this particular meeting Dr. Tak-wai Wong shared with us his collection suggests that the way forward for the monthly CME of unusual neck masses. This case report would meetings is to target a larger audience in a bigger certainly help decrease the unnecessary venue when the topic is believed to be of a more investigations often associated with these masses. general interest. We could probably host this Our statisticians, Mr. Wilfred Wong et al, have enhanced CME meeting every three to four months. prepared some raw data, available in the society's For the 2007 calendar, the interesting topics would website, for the readers to analyze after reading probably include the new guideline for childhood their article on regression. I believe this hands-on snoring led by the Sleep Focus Group under Dr. PY experience is important for the clinicians to learn Chow and the new asthma guideline led by the more about statistics. Asthma Focus Group under Dr. Gary Wong. For the 10th ASM, it will be held from October 6th through We will also have a new session on X-ray quiz 7th in the Hong Kong Convention and Exhibition and you are encouraged to tackle it before checking Centre. It will cover pulmonology, allergy, sleep- the answers. Do enjoy the current issue in your disordered breathing and critical care. Please mark favourite sofa, helped by a cup of tea. See you all in your diary and your support would ensure success of 2007. the event.

2 Volume 2 No. 4, December 2006 Review Article Neonatal respiratory distress syndrome: review on current understanding and the new concept John Wing LI Year V Medical Student, The University of Hong Kong

(Recipient for 2006 HKSPR Paediatric Respirology Award)

Introduction a genetic or racial reason that accounted for the difference. Interestingly, in recent decades, there is an Neonates presenting with respiratory distress can be due upsurge of RDS in Hong Kong (Figure 1)8,9 and other to various underlying problems. One of the commonest developed Chinese communities. However, due to the and most important aetiology, yet the least understood, advancement in obstetrical care (prevention of is respiratory distress syndrome, also known as hyaline prematurity and prophylactic antenatal steroid injection) membrane disease. This article summarises the current and neonatal intensive care, the incidence of RDS in understanding of this syndrome, focusing especially on Hong Kong at present has dropped and approached a the management- treatment and prevention (surfactant comparable rate compared with the Caucasians', which therapy and antenatal steroid), and the latest scientific is approximately 2% of all newborn infants or 20% of advancement in understanding the mechanism of this infants weighing less than 2500 g.3 Nevertheless, the clinical problem. incidence of RDS is dependent on the gestational age, the use of antenatal steroid, and many other factors. Therefore, the overall figure is merely a reference. Background Boys are twice more commonly affected than girls at Parber and Wilson first introduced the term 'hyaline comparable gestational age.10 RDS frequently occurs in membrane' after observing premature infants who died infants born to mothers with diabetes mellitus, in infants from respiratory distress. As the clinical signs were similar born prematurely, born by Caesarean delivery, born with and consistent, it was later grouped as a distinct entity, intrauterine growth retardation, in the second twin, and know as respiratory distress syndrome (RDS).1 in infants with family history of RDS.3

RDS of the newborn is a disease seen especially in premature infants (predominantly occurs in infants Pathophysiology younger than 32 weeks gestational age and in those weighing less than 1200 g), characterised clinically by Traditionally, the underlying reason for the clinical dyspnoea with diaphragmatic breathing pattern, presentation of RDS is hypothesised to be a lack or respiratory rate more than 60 breaths per minute, and a characteristic expiratory grunt which are all present within 4 to 6 hours after delivery. The postmortem findings show patchy lung atelectasis, alveoloar ducts lined by an eosinophilic membrane and pulmonary congestion.2,3

Incidence

In the past, RDS was relatively infrequent in Chinese comparing with the West.4-9 It was then considered to be

8,9 Email: [email protected] Figure 1. Incidence of RDS in Chinese preterm infants.

3 Journal of Paediatric Respirology and Critical Care dysfunction of surfactant in the lung.11 Surfactant is a Apnoea, cyanosis and are grave prognostic complex lipoprotein comprises 6 phospholipids and 4 indicators.15 A mixed respiratory and metabolic acidosis apoproteins, produced by type II alveolar cells.12 usually develops. Arterial blood gas studies show Functionally speaking, lecithin, or dipalmitoyl hypoxaemia, hypercapnia, and respiratory acidosis. phosphatidylcholine (DPPC), and phosphatidylglycerol Hypoglycaemia, hyperkalaemia, and hypocalcaemia are (PG) are the major phospholipids. DPPC and PG along also common. with apoproteins SP-A, B, C, D, with the addition of other neural lipids, such as , triacylglycerol and free Pulmonary vascular resistance increases (pulmonary fatty acids, rapidly adsorb, spread, and reform into a ) as the lung is noncompliant and the stable monolayer dynamically in each respiratory cycle. presence of hypoxia and acidosis. Sequentially, this These special characteristics of surfactant lower the increases the right-to-left shunt of blood through the surface tension at the alveolar air fluid interface.3,13 patent ductus arteriosus (PDA), predisposing to heart failure. Death often directly results from pulmonary It has been shown that patients with RDS have low levels disease. However, it may also result from complications of DPPC and absent PG.14 With an inadequate supply of related to hypoxaemia (e.g. intracranial haemorrhage, surfactant, there will be a decrease in lung compliance, disseminated intravascular coagulation, pulmonary tidal volume, and functional residual capacity, with an haemorrhage and congestive heart failure) or from increase in dead space, resulting in a large ventilation- complications of assisted ventilation and other treatments perfusion mismatch. This results in alveolar (e.g., pulmonary interstitial emphysema, pneumothorax, hypoventilation and carbon dioxide retention, clinically pneumomediastinum, gas and renal failure). presenting as respiratory distress. As a result, the lungs The overall mortality is between 5-10%. Long term of these premature infants require a much higher critical respiratory and neurological sequelae should be noted, opening pressure in order to inflate. With progressive but it is difficult to distinguish whether these are the atelectasis together with barotrauma and oxygen toxicity, results of RDS or from prematurity itself. 3 endothelial and epithelial cells lining these distal airways are damaged, which ultimately results in exudation of fibrinous matrix derived from blood, forming the hyaline Investigations membrane.3 Blood gas analysis is obtained from an indwelling arterial Thus, the postmortem findings of these neonates are (umbilical) catheter or an arterial puncture, which elicits clearly comprehensible. Macroscopically, the lungs respiratory and metabolic acidosis together with appear "liver like" and airless. Microscopically, hypoxaemia.3 Chest X-ray of an infant with RDS eosinophilic hyaline membranes lining the alveolus can classically demonstrates poor lung expansion, bilateral be seen. Diffuse atelectasis of distal airspaces with diffuse reticulogranular (ground glass) appearance in the distension of distal airways and perilymphatic areas can early phase and air bronchogram in the late phase. be observed. 3 Nonetheless, the lung appearance can be very variable throughout the clinical course.3 Cardiomegaly can be seen, resulting from PDA, associated congenital cardiac Clinical Features and Course anomaly, poor lung expansion or prenatal asphyxia.

Within the first 4 hours of life, infants with RDS present with all the clinical signs of respiratory distress, which Treatment persist beyond 24 hours of age if no exogenous surfactant is given. The signs include tachypnoea Besides transferring the patient to neonatal intensive care (respiratory rate >60/min), cyanosis, nasal flaring, unit and adequate monitoring, there are currently expiratory grunting, subcostal and intercostal retractions. numerous ways to manage RDS, including ventilatory On auscultation, air entry is diminished despite vigorous support, positioning the infant into a prone position, respiratory effort.3 increasing the by dopamine and saline,

4 Volume 2 No. 4, December 2006 Review Article and postnatal steroid injection. This, in other words, at, or soon after birth for infants judged to be at high risk means there is no good single treatment. However, most of developing RDS.17 Exogenous surfactants can be paediatricians agree that rescue surfactant therapy is broadly categorised into 2 groups, namely the synthetic an effective way to minimise the damage of RDS. The type and the natural type. Multiple randomised control following discussion will focus mainly on surfactant trials and meta-analysis have been published to show replacement therapy. which one is more beneficial.

In a Cochrane review by Soll and Blanco in 2001,18 Surfactant Replacement Therapy comparison of the efficacy of these 2 types of surfactant was performed. It demonstrated that both natural As the pathology of RDS is believed to be a lack of surfactant extracts and synthetic surfactant extracts are surfactant, it is rational to replace the surfactant in the effective in the treatment and prevention of RDS in neonates' lungs. The first attempt of surfactant therapy neonates. Comparative trials show with the use of natural was in the 1960s, when the investigators gave surfactant extract treatment, there is a greater early aerosolised DPPC to infants with established RDS.13 improvement in the requirement for ventilator support, Their attempts failed chiefly because of the lack of fewer pneumothoraces, and fewer deaths. Natural understanding of the constituents of surfactant. surfactant may be associated with an increased intraventricular haemorrhage, though the more serious With improvement in basic science and more clinical haemorrhages (Grade 3 and 4) are not significantly trials done throughout the years, surfactant rescue is increased (Table 1). The author concluded that natural widely accepted as the treatment for RDS. In fact, surfactant extracts seemed to be the more desirable surfactant replacement therapy for RDS of premature choice when compared to currently available synthetic infants has been the standard treatment for more than surfactants and they should be used if available. 15 years, approved by the Food and Drug Association of USA. It has been proven that with the administration Furthermore, Lam et al19 in 2005 carried out a of surfactant, there is a decrease in the severity of randomised control trial to compare the efficacy between respiratory distress, the frequency of pneumothorax, and 2 types of natural surfactant, namely Survanta and bLES increased survival rate without chronic lung disease, and (bovine Lipid Extract Surfactant, bLES Biochemicals, reduced mortality.16 Inc.). They are both pulmonary surfactant preparations of bovine origin, but they differ in their concentration of Current guideline in the Royal College of Paediatricians phospholipid and basic manufacturing process. Survanta recommends the administration of exogenous surfactant was less capable of reducing surface tension and hence

Table 1. Comparing the results of using natural surfactant VS synthetic surfactant in neonatal RDS Natural surfactant Synthetic surfactant Pneumothorax Significant decreased risk Baseline Patent ductus arteriosus No statistical difference Sepsis No statistical difference

Intraventricular hemorrhage Marginally increased risk Baseline Severe Intraventricular hemorrhage(Grade 3 or 4) No statistical difference Retinopathy of prematurity (ROP) No statistical difference

Bronchopulmonary dysplasia No statistical difference Chronic lung disease No statistical difference Mortality Marginally decreased risk Baseline

Improvement in requirement of ventilatory support Earlier Baseline

5 Journal of Paediatric Respirology and Critical Care showed a slower response. bLes contains numerous rupture of membranes or any condition requiring elective phospholipids and has a higher concentration of preterm delivery. For mothers of advancing gestation hydrophobic protein SP-B and SP-C, and was shown to (>34 weeks), the potential benefits of the use of steroid have a greater surface tension-reducing property and decrease, the number needed to treat and the risk of quicker response.20,21 bLes, being obtained from alveolar side effects both increase. Thus, it is the obstetricians' lavage fluid, also seems more resistant to inhibition by choice to commence this treatment in this group. plasma proteins.22 A Cochrane meta-analysis of 18 trials in 2002 showed a The authors concluded that infants with RDS responded significant reduction in incidence of RDS in neonates of well to both Survanta and bLES replacement. mothers with antenatal corticosteroid injection, especially Nonetheless, treatment with bLES was associated with in babies born before 34 weeks of gestation. The number a more prompt response, as indicated by the oxygen needed to treat is 94. The benefit holds in all preterm index within 8 hours after the surfactant administration. babies among different gender and races.25 However, in However, in Hong Kong, rescue therapy within the first cases of multiple pregnancy, a significant reduction in 30 minutes of life using Survanta is still the treatment of rates of RDS has not been demonstrated after employing choice as Survanta had a clinical role, while bLES had antenatal corticosteroid, though it is still recommended not been licensed yet.19 and is a common practiced in Hong Kong.

The effect of treatment is optimal if the baby is delivered Side Effects of Surfactants more than 24 hours and less than seven days after commencement of treatment.25 Long-term follow up of There are no data to show any immune responses to survivors from randomised trials of antenatal exogenous surfactant proteins instilled into the lung, corticosteroid therapy through childhood to adulthood though this is theoretically possible.23 Massive pulmonary (20 years old) shows no adverse neurological or cognitive haemorrhage has been reported but is rare. There is effects.26-28 no evidence of cerebral ischaemia and effect on intraventricular haemorrhage. Long term neurological Corticosteroid use antenatally does not appear to follow-up shows neither additional neurological deficits increase the risk of either foetal or maternal infection, in surfactant treated survivors, nor any increase in severe regardless of whether the membranes are ruptured or retinopathy of prematurity. not at the time of treatment. However, its use is contraindicated in pregnant women suffering from systemic infection (e.g. Tuberculosis) or showing Prevention symptoms and signs of chorioamnionitis as there is a potential risk of worsening the infection when steroid is Prevention is better than cure. It is recognised that used and do harm to both the mother and the foetus.29 prevention of prematurity and the use of antenatal steroid are effective ways to tackle RDS, which is a disease Betamethasone is the steroid of choice to enhance predominately in the premature infants. Antenatal steroid lung maturation as it is a steroid which crosses the use is discussed below. placenta and binds to 75% of the receptors in the foetal lung, maximising its ability for gene transcription which enhances lung maturity.30 Recommended Antenatal Steroid Injection therapy involves two doses of betamethasone 12 mg, given intramuscularly 24 hours apart. Higher or more In the Royal College of Obstetricians and Gynaecologists frequent doses do not increase the benefits of guideline,24 antenatal steroid is indicated in pregnant antenatal corticosteroid therapy and may increase the women of 24 to 34 weeks of gestation with threatened likelihood of adverse effects such as foetal growth preterm labour, antepartum haemorrhage, preterm retardation and brain damage, as shown in animal

6 Volume 2 No. 4, December 2006 Review Article studies.31,32 In a teaching hospital in Hong Kong major risk factors for RDS can be better controlled. In (Queen Mary Hospital), the use of antenatal steroid the future, the induction of human ENaC system, both is very well established, where over 80% of premature antenatally and postnatally, can be a possible alternative delivery are covered by it.19 solution to this fascinating, yet very challenging condition.

Understanding the New Concept of RDS References RDS is identified as a result of insufficient or dysfunction of surfactant in a premature neonatal lung. In recent 1. Lee SS. Respiratory distress syndrome in the newborn infant. years, Helve et al33 demonstrated another mechanism The Bulletin of the Hong Kong Chinese Medical Association. which might contribute to the development of RDS, i.e. 1964;16. 2. Stedman's Medical Dictionary. 27th edition. Philadelphia, PA: the defective ENaC system. Lippincott Williams & Wilkins, 2000. 3. Rennie JM, Roberton NRC. Textbook of Neonatology. 3rd ENaC (amiloride sensitive epithelial sodium channel) is edition. New York: Churchill Livingstone, 1999;481-514. important for transepithelial lung liquid movement. It 4. Yeung CY. Traditional Asian practices and their influences on consists of 3 subunits (α, β and γ) of which α subunit is child health. J Paediatr Obstet Gynae 1991;17:5-12. 5. Yeung CY. Chinese neonates are different. Chapter in prerequisite for favourable ion channel function.34 Active Textbook of Neonatology. Hong Kong University Press, 1996; ion transport plays a critical role in liquid movements 877-83. across the foetal and perinatal lung epithelium.35-37 6. Yeung CY. Changing pattern of childhood diseases in Hong Throughout gestation, the foetal lung actively secretes Kong - a rapidly developing community. Current Paediatrics Cl− and fluid. The ability to actively reabsorb Na+ is 1999; 9:209-14. developed only during late gestation. At birth, the mature 7. Yeung CY. Changing pattern of neonatal diseases in Hong Kong. J Paediatr Obstet Gynae 2000;5-12. − lung switches from active Cl and fluid secretion to active 8. Yeung CY. Childhood respiratory diseases in Hong Kong. Na+ and fluid absorption, that is, to dry up the lungs, in Bronchus 1985;1:6-8. response to circulating catecholamines and changes in 9. Yeung CY. Changing pattern of lower respiratory tract oxygen tension.38-40 infections in Hong Kong children. Pediatr Pulmonol 2001; Suppl 23:161-4. 10. Farrell PM, Avery ME. Hyaline membrane disease. Am Rev Helve et al demonstrated a significantly lower expression Respir Dis 1975;111:657-88. of all 3 human ENaC subunits in the nasal epithelium in 11. Taussig LM, Landau LI. Pediatric Respiratory Medicine. St. preterm infants with RDS relative to healthy term infants, Louis: Mosby, 1999;464-87. suggesting that hENaC expression is regulated 12. Post M, van Golde LM. Metabolic and developmental aspects quantitatively during human foetal airway development. of the pulmonary surfactant system. Biochim Biophys Acta As a result, when there is a failure to switch from 1988; 947: 249-86. 13. Soll RF. Synthetic surfactant for respiratory distress syndrome secretion to absorption of fluid, respiratory distress might in preterm infants. The Cochrane Database of Systematic occur in the preterm infants, which means neonatal RDS Reviews 1998. Issue 3. Art. No.: CD001149. can possibly results from both a relative surfactant 14. Hallman M, Feldman B H, Kirkpatrick E, Gluck L. Absence of deficiency and excess lung liquid.41-44 phosphatidylglycerol (PG) in respiratory distress syndrome in the newborn. Study of the minor surfactant phospholipids in newborns. Pediatr Res 1977;11:714-20. 15. Neligan G A, Oxon DM, Smith C A. The blood pressure of Conclusion newborn infants in asphyxial states and hyaline membrane disease. Pediatrics 1960;26:735-44. The understanding and management of neonatal RDS 16. Soll RF, McQueen MC. Respiratory distress syndrome. In: have evolved over the years. Surfactant replacement Sinclair JC. Bracken MB editor(s). Effective Care of the therapy (natural type) is still the treatment of choice for Newborn Infant. Oxford: Oxford University Press, 1992:325-58. 17. Royal College of Paediatrics and Child Health. Guidelines for infants suffering from this syndrome. With the input and Good Practice. Management of Neonatal Respiratory Distress effort from multiple disciplines, prematurity and other Syndrome, 2000.

7 Review Article Journal of Paediatric Respirology and Critical Care

18. Soll RF, Blanco F. Natural surfactant extract versus synthetic outcomes. JAMA 1995;273:413-18. surfactant for neonatal respiratory distress syndrome. The 32. Aghajafari F, Murphy K, Matthews S, Ohlsson A, Amankwah Cochrane Database of Systematic Reviews 2001, Issue 2. K, Hannah M. Repeated doses of antenatal corticosteroids in Art. No.: CD000144. animals: a systematic review. Am J Obstet Gynecol 2002; 19. Lam BCC, Ng YK, Wong KY. Randomized trial comparing 186:843-9. two natural surfactants (Survanta vs. bLES) for Treatment of 33. Helve O, Pitkanen OM, Andersson S, O'Brodovich H, Neonatal Respiratory Distress Syndrome. Pediatr Pulmonol Kirjavainen T, Otulakowski G. Low Expression of Human 2005;39:64-9. Epithelial Sodium Channel in Airway Epithelium of Preterm 20. Mizuno K, Ekegami M, Chan CM, et al. In vivo function of the Infants With Respiratory Distress. Pediatrics 2004;113:1267-72. modified natural surfactant. Pediatr Res 1994;2055:A345. 34. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, 21. Hall SB, Venkitaraman AR, Whitsett JA, Holm BA, Notter RH. Horisberger JD, et al. Amiloride-sensitive epithelial Na+ Importance of hydrophobic apoproteins as constituents of channel is made of three homologous subunits. Nature 1994; clinical exogenous surfactants. Am Rev Respir Dis 1992;145: 367:463-7. 24-30. 35. Strang LB. Fetal lung liquid: secretion and reabsorption. 22. Seeger W, Grube C, Gunther A, Schmidt R. Surfactant Physiol Rev 1991;71:991-1016. inhibition by plasma proteins: differential sensitivity of various 36. Pitkanen OM, O'Brodovich HM. Significance of ion transport surfactant preparation. Eur Respir J 1993;l6:971-77. during lung development and in respiratory disease of the 23. Bartmann P, Bamberger U, Pohlandt F, Gortner L. newborn. Ann Med 1998; 30:134-42. Immunogenicity and immunomodulatory activity of bovine 37. O'Brodovich H. Epithelial ion transport in the fetal and perinatal surfactant (SF -RI 1). Acta Paediatr 1992;81:383-8. lung. Am J Physiol 1991;261(4 Pt 1):C555-64. 24. Royal college of Obstetricians and Gynaecologist. Guideline 38. Brown MJ, Olver RE, Ramsden CA, Strang LB, Walters DV. No. 7. Antenatal corticosteroids to prevent respiratory distress Effects of adrenaline and of spontaneous labour on the syndrome, 2004. secretion and absorption of lung liquid in the fetal lamb. 25. Crowley P. Prophylactic corticosteroids for preterm birth. J Physiol. 1983;344:137-152 Cochrane Database Syst Rev 2002; (4): CD000065. 39. Pitkanen O, Transwell AK, Downey G, O'Brodovich H. 26. Smolders-de Haas H, Neuvel J, Schmand B, Treffers PE, Increased Po2 alters the bioelectric properties of fetal distal Koppe JG, Hoeks J. Physical development and medical history lung epithelium. Am J Physiol 1996;270(6 Pt 1):L1060-6. of children who were treated antenatally with corticosteroids 40. Bland RD, Nielson DW. Developmental changes in lung to prevent respiratory distress syndrome: a 10- to 12-year epithelial ion transport and liquid movement. Annu Rev Physiol follow-up. Pediatrics 1990;86:65-70. 1992;54:373-94. 27. Doyle LW, Ford GW, Rickards AL, Kelly EA, Davis NM, 41. Barker PM, Gowen CW, Lawson EE, Knowles MR. Decreased Callanan C, et al. Antenatal corticosteroids and outcome at sodium ion absorption across nasal epithelium of very 14 years of age in children with birth weight less than 1501 premature infants with respiratory distress syndrome. J Pediatr grams. Pediatrics 2000;106:E2. 1997;130:373-7. 28. Dessens AB, Haas HS, Koppe JG. Twenty-year follow-up of 42. Pitkanen OM, O'Brodovich HM. Significance of ion transport antenatal corticosteroid treatment. Pediatrics 2000;105:E77. during lung development and in respiratory disease of the 29. British Medical Association and Royal Pharmaceutical Society newborn. Ann Med 1998; 30:134-42. of Great Britain. British National Formulary 46. London: BMA 43. Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, and RPS; 2003. p.348. Schmidt A, et al. Early death due to defective neonatal lung 30. Ballard PL, Ballard RA. Scientific basis and therapeutic liquid clearance in alpha-ENaC-deficient mice. Nat Genet regimens for use of antenatal glucocorticoids. Am J Obstet 1996;12:325-8. Gynecol 1995;173:254-62. 44. O'Brodovich HM. Immature epithelial Na+ channel expression 31. NIH Consensus Development Panel on the Effect of is one of the pathogenetic mechanisms leading to human Corticosteroids for Fetal Maturation on Perinatal Outcomes. neonatal respiratory distress syndrome. Proc Assoc Am Effect of corticosteroids for fetal maturation on perinatal Physicians 1996;108:345-55.

8 Volume 2 No. 4, December 2006 Case Report Lesions one needs to yell out for diagnosis Tak-Wai WONG Department of Paediatrics & Adolescent Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong

Introduction anterior midline neck mass appeared when the boy yelled but immediately disappeared when returned to A neck mass protruding out on Valsalva manoeuvre is rest (Figure 1). Chest, cardiovascular, abdominal and an infrequently encountered clinical condition in children. neurological examinations were unremarkable. Three cases with such unusual neck masses were presented. In each of them the neck mass was shown Fibreoptic laryngoscopy showed screamer nodules over up nicely by asking the child to perform some sort of the vocal cords. Neck ultrasonography revealed a Valsalva manoeuvre, e.g. yelling, to help the doctor to normal thyroid gland but with the boy shouting a well study it and make the diagnosis. circumscribed echogenic mass was seen protruding from the infraclavicular to lower neck region. It descended back into the upper mediastinum afterwards Case 1 but the lower part was not well delineated. Magnetic resonance imaging (MRI) confirmed the herniating neck A 3-year-old boy was referred from his private doctor for mass corresponded to the superior aspect of thymus hoarseness of voice since infancy. He liked to scream (Figure 2). loudly, especially when agitated. His mother noticed an anterior neck swelling in the last 6 months whenever he cried, strained, yelled or screamed. At rest, the mass disappeared. There was no noisy breathing, choking, dysphagia or respiratory distress. Birth and perinatal course was uneventful with no history of neonatal resuscitation or intubation. Physical examination showed mild hoarseness of voice but no stridor, dyspnoea, or chest insucking. There was no goiter, cervical lymphadenopathy or neck mass visible at rest or upon At rest Yelling swallowing and the overlying neck skin was normal. An Figure 1. Anterior neck mass protruding when yelling.

(A) (B) (C)

(D) (E) (F) Figure 2. MRI neck and mediastinum during Valsalva manoeuvre - serial transverse images tracking the thymus (marked) from superior mediastinum (A) to lower neck level, with its left side slightly more superior than the right side (F).

Email: [email protected]

9 Journal of Paediatric Respirology and Critical Care

Case 2 bruit. There was no supraclavicular or cervical lymphadenopathy and chest, cardiovascular, abdominal A 11-year-old boy was referred from his private doctor and neurological examinations were unremarkable. for right-sided neck swelling for 3 months, suspected to be goiter. It was incidentally noted by his mother and he Blood tests showed normal thyroid function and negative had no thyrotoxic symptoms, dysphagia, dyspnoea, or anti-thyroid antibodies. Neck ultrasonography revealed hoarseness of voice. He enjoyed good past health and that the right-sided neck swelling during Valsalva there was no family history of thyroid problems. Physical manoeuvre was the abnormally dilated right internal examination showed a very small goiter with no nodules jugular . At rest the internal jugular were already or bruit. He was clinically euthyroid. A right-sided neck asymmetrical in caliber and the difference was amplified swelling arose from the lower neck only during Valsalva during Valvalsa manoeuvre (Figure 4). Right internal manoeuvre (Figure 3) and it completely subsided jugular phlebectasia was diagnosed. Conservative immediately afterwards. It did not transilluminate and was management was recommended. non-pulsatile. Auscultation showed no venous hum or

Case 3

A 2-year-and-8 month-old girl was referred from government outpatient clinic for neck swelling since age of 1 year. She was born with port-wine stain on the right side of her face, chin, neck and upper chest. Her parents noticed an anterior neck swelling since age 12 months during her vocalization and it was getting more prominent with age, easily noticeable when she shouted, laughed and strained. The mass disappeared at rest. There Figure 3. Right-sided neck swelling during Valsalva was no hoarseness of voice, respiratory distress or manoeuvre dysphagia. Her development was normal and there was

At rest : RIJV = 11.9 mm LIJV = 5.2 mm

Valsalva manoeuvre : RIJV = 18.8 mm LIJV = 8.1 mm Figure 4. Anteroposterior diameters of right and left internal jugular veins (RIJV and LIJV)

10 Volume 2 No. 4, December 2006 Case Report no history of visual problem or convulsion. Physical right side of jugular venous arch, which in turn examination showed extensive naevus flammeus (port- joined the right internal jugular vein (Figure 7). It wine stain) involving right temporal scalp, right side of was managed conservatively upon surgical advice face, chin, neck and right upper chest regions. There and laser therapy was arranged for the port-wine was no goiter, cervical lymphadenopathy or neck mass stain. visible at rest or upon swallowing. An anterior neck mass appeared above sternal notch when the girl yelled (Figure 5), which completely disappeared about 2 seconds after Discussion the girl stopped yelling. It did not transilluminate or pulsate. Auscultation showed no venous hum or bruit. Common differential diagnoses of midline anterior neck Chest, cardiovascular, abdominal and neurological mass in children includes goitre, thyroglossal duct cyst, examinations were unremarkable. dermoid-epidermoid cyst, cystic hygroma, branchial cleft cyst and arteriovenous malformation. The neck swellings Neck ultrasonography and doppler study showed in our three children appeared only during Valsalva a venous with turbulent blood flow over manoeuvre, therefore these were unlikely possibilities. the anterior midline lower neck region. Its axial cross-sectional diameter measured (transverse x The most common cause of a neck mass that becomes anteroposterior) 17 mm x 12 mm at rest and 22 mm x 17 visible or increases in size with Valsalva manoeuvre is mm when laughing. On magnetic resonance imaging laryngocele. Other lesions reported include saccular cyst, (MRI) and venography (MRV) the aneurysm (Figure 6) pharyngeal pouch, external laryngeal diverticulum, was noted to connect to left anterior jugular vein and jugular phlebectasia, cavernous haemangioma, jugular

Figure 5. Anterior neck mass protruding during yelling

Figure 7. MRV coronal Figure 6. MRI neck showing the venous aneurysm view showing the venous (marked) drainage

11 Journal of Paediatric Respirology and Critical Care venous aneurysm, cupula inflation, thymic herniation and even in children as young as our patient in Case 3. The superior mediastinal cyst. natural history of venous aneursyms depends on their anatomic location and those in the head and neck region, Although subclinical posterior buckling of the cervical including the internal jugular vein, appear to have a trachea due to thymic herniation has been previously benign course. Treatment strategies vary. Some reported in infants,1 clinically detectable thymic herniation recommended surgical excision while others adopt is rare in older children. With such a dramatic, clinically conservative management as serious complications visible and palpable thymic herniation in the neck, our have been rarely reported.15 patient in Case 1 is the youngest child reported in Hong Kong to date. Diagnosis can be confirmed by ultrasonography and MRI,2 and biopsy is unnecessary. References Little has been described in the literature regarding its natural history and it is believed to resolve with the 1. Mandell GA, Bellah RD, Boulden ME, Sherman NH, Harcke regression of the thymus but the age of resolution is HT, Padman RJ, McNicholas KW. Cervical trachea: dynamics unclear. It has been reported to persist into mid- in response to herniation of the normal thymus. Radiology 1993;186:383-6. childhood.2 Concerns, if any, would be cosmetic, 2. Wong KT, Lee DL, Chan MS, Tsang RK, Yuen EH, Ahuja AT. psychosocial disturbance or parental anxiety. Unusual anterior neck mass visible only during Valsalva's maneuver in a child. Am J Roent 2005;185:1355-7. Jugular phlebectasia is an entity that is being increasingly 3. Gerwig WJ. Internal jugular phlebectasia. Ann Surg 1952;135: recognized in recent years. Phlebectasia was the term 130-3. first used by Gerwig3 to describe an abnormal fusiform 4. Jasinski RW, Rubin JM. CT and ultrasonographic findings in dilatation of a vein. The internal jugular vein is the most jugular vein ectasia. J Ultrasound Med 1984;3:417-20. 5. Jeon CW, Choo MJ, Bae IH, Shin SO, Choi YS, Lee DW, et commonly affected and in most cases it is unilateral al. Diagnostic criteria of internal jugular phlebectasia in Korena right side involvement. Diagnosis is confirmed by children. Yonsei Med J 2002;43:329-34. ultrasonography at rest and during Valsalva manoeuvre 6. Ng DKK, Kwok KL, Lam HS. Unilateral internal jugular comparing both internal jugular veins.4,5 The cause is phlebectasia. HK Med J 2000;6:431. idiopathic. To date, locally reported cases were 7. Kwok KL, Lam HS, Ng DKK. Unilateral right-sided internal associated with childhood asthma6,7 but our patient in jugular phlebectasia in asthmatic children. J Paed Child Health Case 2 was a non-asthmatic. Surgical exploration and 2000;36:517-9. 8. Sander S, Elicevik M, Unal M, Vural O. Jugular phlebectasia resection was common in the past for diagnosis and in children: is it rare or ignored? J Ped Surg 1999;34:1829- 8,9 management but associated with potential 32. complications. Clinical course appears benign and 9. Gurpinar A, Kiristioglu I, Dogruyol H. Jugular phlebectasia. conservative management is recommended for Eur J Ped Surg 1999;9:182-3. asymptomatic patients.10-14 10. Al-Dousary S. Internal jugular phlebectasia. Int J Ped Otorhinolaryngol 1997;38:273-80. Venous malformations in general are rare in children. 11. Lubianca-Neto JF, Mauri M, Prati C. Internal jugular phlebectasia in children. Am J Otolaryngol 1999;20: 415-8. Opinions on their aetiology vary and classification is 12. Paleri V, Gopalakrishnan S. Jugular phlebectasia: theory of not universal. Most common lesions in the head and pathogenesis and review of literature. Int J Ped Otorhinolaryngol 15 neck region involve the internal jugular veins. 2001;57:155-9. Ultrasonography and Doppler study is diagnostic in the 13. Hopsu E, Pitkaranta A. Jugular vein aneurysm or phlebectasia. majority of patients, while computed tomography, Am J Surg 2004;188:622. angiography have also been used in the assessment of 14. Li J, Jiang X, Hu T. Surgical treatemnt of jugular vein these lesions. Recently developed fast sequences have phlebectasia in children. Am J Surg 2006;192:286-90. 15. Gillespie DL, Villavicencio JL, Gallagher C, Chang A, Hamelink enabled MRI and MR angiography to provide three- JK, Fiala LA, et al. Presentation and management of venous dimensional vascular imaging of the jugular venous . J Vasc Surg 1997:26:845-52. system as well as more central venous structures in the 16. Fitoz S, Atasoy C, Yagmurlu A, Erden I, Akyar S. Gadolinium- mediastinum.16 These non-invasive techniques without enhanced three-dimensional MR angiography in jugular ionising radiation have proven successful and reliable phlebectasia and aneurysm. Clin Imaging 2001;25:323-6.

12 Volume 2 No. 4, December 2006 Radiological Quiz Radiological Quiz Daniel Wai-Tai KO Department of Paediatrics, Queen Elizabeth Hospital, Hong Kong

Case History

Female / 5 yr. Known ALL on chemotherapy HKALL97 protocol. Developed neutropenic fever with sudden onset of shortness of breath. CXR showed pneumothorax and furthermore Serial CXRs and CT thorax were done.

What is the most probable diagnosis? A. Round pneumonia B. Pneumatocele C. Pneumocystic pneumonia D. Pulmonary aspergillosis E. Diffuse strongyloidosis

(Answer on page 17 )

13 Statistical Corner Journal of Paediatric Respirology and Critical Care Statistical Corner Wilfred Hing-Sang WONG ,1 Chun-Fan LEE ,2 Daniel Yee-Dak FONG 2 1Department of Paediatrics & Adolescent Medicine; 2Department of Nursing Studies, The University of Hong Kong, Hong Kong

Question 1: What is regression?

Answer : Regression is a statistical method to examine the use of one or more factors to explain or predict outcomes of interest. Therefore, regression analysis has a priori hypothesis of a causal relationship between factors and outcomes. However, it is important to note that a causal relationship cannot be established by just running a regression analysis. We also need to have an appropriate study design.

There can be many types of regression methods. The simplest type is the linear regression that exhibits itself by a regression equation:

Outcome = b0 + b1 Factor1 + b2 Factor2 + ...

For linear regression with more than one factor, we called it a multiple linear regression.

Question 2: How to perform linear regression in SPSS?

Answer: There can be two ways to perform linear regression in SPSS: 1. Analyze>Regression>Linear 2. Analyze>General Linear Model>Univariate The first method can only accommodate factors measured at least on an ordinal scale but is equipped with automated variable selection procedure. The second method may allow nominal factors but not automated variable selection.

The use of the two methods is illustrated in Figures 1 and 2, using a dataset available at http://www.hkspr.org/. In Figure 1, education level is treated as continuous and one level increase in education leads to 25.5 mg/dl increase in cholesterol, on average. In Figure 2, education level is treated as categorical and its effects are expressed as the differences of education levels 1 and 2 with level 3 (the reference level; the one with the highest value). For example, subjects at education level 1 are, on average 50.9 mg/dl lower in cholesterol than those at education level 3. Therefore, Figure 1 examines the linear trend of education level while Figure 2 examines the difference between different education levels, which in general results in smaller standard errors as more effects are being considered.

14 Volume 2 No. 4, December 2006 Statistical Corner

Question 3: How do we know a linear regression analysis is appropriate?

Answer: It is vitally important to check adequacy of a linear regression model. It can be done by examining residuals that are readily available in SPSS. There are at least two plots we need to obtain: Normal probability plot of residuals and scatter plot of residuals against predicted values (Figure 3). Model adequacy is demonstrated when points on the Normal probability plot are close to the diagonal line and points on the scatter plot appears to be randomly scattered.

Question 4: How should factors be selected in a linear regression model?

Answer: Selection of factors into a regression model is not a trivial task. Automated variable selection procedure is only appropriate as an exploratory tool or in prediction. Effects of factors are preferably examined by also accounting their inter-relationships. For example, the effect of a factor (say A) should be adjusted for factors that cause A but not factors that are caused by A. Therefore, selection of factors should incorporate both statistical and clinical expertise.

Figure 1. Using Regression>Linear in SPSS

15 Journal of Paediatric Respirology and Critical Care

Figure 2. Using General Linear Model>Univariate in SPSS

Figure 1. Forward arm stretching in pone kneeling.

Figure 3. Obtaining residuals plots using Regression>Linear in SPSS

16 Volume 2 No. 4, December 2006

Answers to Radiological Quiz on page 13

Answer: D

For neutropenic fever in immunocompromised patients, invasive aspergillosis (IA) is one of the important etiology and failure to treat it promptly will lead to high mortality, as high as ~80%. The most common manifestation of IA is invasive pulmonary aspergillosis (IPA).

The radiographic features of IPA include the halo-sign and the air-crescent sign (in our case). The presence of "halo" of low attenuation surrounding a nodular lesion is an early finding in IPA, representing the angioinvasive property of aspergillus. Later in the course of infection these nodular lesion may cavitate (usually in the temporal association with the recovery of neutrophils), forming an "air-crescent" sign. IPA may cause pneumothorax when the fungi damage the lung wall, as demonstrated in our CT film. Pneumoatocele is one of the differential diagnosis of the cystic lesion in the CXR together with pneumothorax. It is usually the sequalae of staphylococcus aureus pneumonia which usually shows extensive pneumonic change on the background of the cystic lesions.

Blood for galactomannin and 1,3-beta-glucan give the serological evidence of IA. However they are not sensitive. The definitive diagnosis of the IPA is based on the tissue biopsy and then the fungal culture. Empirical antifungal drug, mostly amphotericin B, should be commenced immediately in immunocompromised patients once IA is suspected in view of its high mortality. Aspergillus is resistant to fluconazole.

Acknowledgement

AstraZeneca Hong Kong Limited

GlaxoSmithKline

Merck Sharp & Dohme (Asia) Limited

17 Journal Watch/ Coming Activities Journal of Paediatric Respirology and Critical Care

Acute muscle weakness owing to severe hypokalaemia Bronchoscopic management of airway obstruction in resulting from dietary insufficiency: case report pediatric endobronchial tuberculosis Soo MT, Fung TH, Ng DKK, Chan S. Wong JS, Ng CS, Lee TW, Yim AP. Ann Trop Paediatr 2006;26:363-6 Can Respir J 2006;13:219-21

Application of artificial neural networks to establish a Cough frequency in children with mild asthma predictive mortality risk model in children admitted to correlates with sputum neutrophil count a paediatric intensive care unit Li AM, Tsang TW, Chan DF, Lam HS, So HK, Sung RY, et al. Chan CH, Chan EY, Ng DK, Chow PY, Kwok KL. Thorax 2006;61:747-50 Singapore Med J 2006;47:928-34 Exhaled nitric oxide levels are not correlated with The correlation among obesity, apnea-hypopnea index, eczema severity in Chinese children with atopic and tonsil size in children dermatitis Lam YY, Chan EY, Ng DK, Chan CH, Cheung JM, Leung SY, Hon KL, Leung TF, Kam WY, Lam MC, Wong KY, Yung E, et al. et al. J Asthma 2006;43:417-9 Chest 2006;130:1751-6 Twenty-four-hour ambulatory BP in snoring children Chylothorax in children after congenital heart surgery with obstructive sleep apnea syndrome Chan SY, Lau W, Wong WH, Cheng LC, Chau AK, Cheung YF. Leung LC, Ng DK, Lau MW, Chan CH, Kwok KL, Chow PY, et al. Ann Thorac Surg 2006;82:1650-6 Chest 2006;130:1009-17

Protecting sick children from exposure to passive The official website of Hong Kong Society of smoking through mothers' actions: a randomized controlled trial of a nursing intervention Paediatric Respirology is now online. Welcome Chan S, Lam TH. to our website: http://www.hkspr.org. J Adv Nurs 2006;54:440-9

Coming HKSPR Clinical Meetings

Date Venue Title(s) of Presentation Speaker(s) Chairperson

31 Jan 2007 1/F, Seminar Room Fulminant pseudomonal infection Dr Yuen Chi Lap Dr. Ellis Hon KWH

28 Feb 2007 1/F, Seminar Room A review of 10 paediatric patients with Dr. SC Sit Dr. Tony Lau KWH necrotizing pneumonitis

28 Mar 2007 Sheraton Hotel Wheezing Children - What is the Nikos Papadopoulos, Dr. KT So role of virus in wheezing & asthma University of Athens exacerbation?

First Announcement

10th Annual Scientiifc Meeting of HKSPR October 6th to 7th, 2007 Hong Kong Convention and Exhibition Centre

Main themes include asthma, allergies, sleep-disordered breathing, respiratory infections and vaccines, new diagnostic techniques in paediatric respiratory medicine, workshops for doctors and paramedical colleagues.

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