Clinical review

Recent advances Paediatric surgery Paul D Losty

Department of Introduction Paediatric Surgery, Institute of Child Paediatric surgery—the surgical care of children from Summary points Health, Alder Hey Children’s Hospital, the to adolescent—is a comparatively new surgical Liverpool L12 2AP specialty, which began shortly after the second world Exploring mechanisms to modulate abnormal Paul D Losty, war.12 Pioneering work during the formative years of fetal development pharmacologically may provide senior lecturer the specialty has enabled many lethal congenital alternatives to and invasive fetal Paul.Losty@rlchtr. malformations to be corrected. The surgical treatment interventions nwest.nhs.uk of childhood disease has also progressed enormously. Progress in neonatal surgery has resulted in the BMJ 1999;318:1668–72 This review focuses on recent advances in paediatric surgery and its relation with scientific research, which is survival of children with many types of congenital rapidly translating state of the art care from research to lethal malformations the patient. Advances in paediatric gastroenterology include a greater understanding of biological mechanisms Methods regulating normal and abnormal gut motility This article is based on a personal awareness of devel- New treatments are needed to induce biological opments in paediatric surgery and relevant contribu- regression of tumours and tumour maturation tions from major paediatric surgical journals, review articles, and the proceedings from meetings of various Several laparoscopic techniques are now feasible, international associations. safe, and effective

Fetal surgery and interventions Future developments include tissue engineering, antiangiogenic agents, scarless healing, in utero The close liaison between paediatric surgeons and col- gene replacement, and treatments with growth leagues in fetomaternal medicine enabled fetal defects factors to be diagnosed with ultrasonography and the clinical course and pathophysiology of many of these disorders to be observed (box). surgery immediately after birth can be effectively The antenatal detection of a fetal structural abnor- planned and a good outcome anticipated (fig 1). Some mality often entails referral to a paediatric surgeon, abnormalities, however, may result in the death of the who can counsel parents and discuss the likely fetus or neonate. In such cases fetal surgery or outcomes for the fetus. For some structural abnormali- intervention may be required.3 This has led to the ties, such as the abdominal wall defect, gastroschisis, emergence of fetal surgery programmes, with a few centres mainly concentrated in North America.3 Abnormalities considered amenable to surgery in Fetal malformations detected by antenatal utero include benign forms of cystic lesions, ultrasonography which may lead to hydrops. Fetal lung resection is Spina bifida and hydrocephalus technically feasible, with reasonable outcome for high 3 Gastroschisis risk cases treated at specialist centres. Oesophageal atresia In affected by moderate to severe maternal Exomphalos oligohydramnios associated with reduced amniotic Cystic lung lesions fluid volume and obstruction of the urinary tract in Renal tract disease males, intervention can protect renal function and Congenital diaphragmatic hernia 3 Bladder exstrophy maintain lung growth. In such cases, usually Cardiac defects secondary to posterior urethral valves, lung hypoplasia Cloacal exstrophy can be avoided by bladder decompression using ultra- Duodenal atresia sound guided percutaneous catheters to divert urine from the fetal bladder to the amniotic cavity

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(vesicoamnioticshunting) or at open fetal surgery to create a vesicostomy.3 Attention has also focused recently on the potential role of fetal surgery in spina bifida (1 in 2000 live births), a disability causing lower limb paralysis, skeletal deformity, incontinence, hydrocephalus, and mental impairment.4 Exposure of fetal neural tissue to the effects of chemicals in the amniotic fluid, and mechani- cal injury during birth and , may cause deterioration in neurological function. In an effort to ameliorate ongoing neurological damage, experimen- tal work in fetal sheep has confirmed that repair of the spina bifida defect in utero stops spinal cord destruction and restores normal neurological function at birth. This work has led to the first successful repair of an extensive thoracolumbar open spina bifida lesion in utero associated with hydrocephalus in a human 4 fetus. Although fetal surgery for spina bifida is at an Fig 1 Gastroschisis defect in neonate experimental stage, such pioneering advances merit careful consideration. Neonatal surgery Other fetal structural abnormalities have proved more difficult to treat—for example, congenital Neonatal surgery has undergone many major develop- diaphragmatic hernia, which occurs in 1 in 2500 live ments.213Oesophageal atresia (1 in 5000 live births) is births (fig 2). Despite diagnosis by antenatal ultra- most commonly characterised by the presence of a sonography, innovations in intensive care, and the sim- blind ending upper oesophagus and a fistula between ple nature of the defect, 40%-50% of cases die.5 This the lower oesophagus and airway. Such babies are high mortality is due to a primary abnormality in lung unable to swallow and classically present with excessive development and the prolapse of abdominal organs salivation, and choking episodes or respiratory distress into the chest, which severely further compromises on feeding due to pulmonary aspiration (fig 3) Survival fetal lung growth and development. Fetal surgery has from this condition remained poor until the early been restricted to fetuses with a poor outcome. 1960s, and neonates weighing as little as 1500 g Selection criteria now include early antenatal diagnosis currently have a predicted survival of 97% in specialist (less than 25 weeks of gestation), isolated congenital centres.14 diaphragmatic hernia defect with liver herniated into Hirschsprung’s disease (1 in 5000 live births) is the the chest, and fetuses without chromosomal abnor- commonest cause of intestinal obstruction in neonates malities.6 Two decades of experimental work have now (fig 4). Infants typically present with bile stained vomi- refined the surgical procedure to exploit mechanisms tus after initiation of feeds, abdominal distension, and that promote normal lung growth.78 The seminal delayed passage of meconium stool beyond 24 hours observation that congenital laryngeal obstruction in an after delivery. Fewer babies are now presenting beyond infant with an absence of both kidneys and Fraser’s the neonatal period owing to an increased awareness syndrome resulted in large stimulated research of this disorder: the gold standard for diagnosis is a into “plugging” the trachea to encourage lung rectal biopsy that shows an absence of ganglion cells. growth.910 This procedure—now termed PLUG (plug Traditionally, a “levelling” colostomy was performed in the lung until it grows)—is performed in some centres by open fetal surgery.10 Advances in minimally invasive surgery with a laparoscope, coupled with attempts to override the problem of preterm labour, have further led to tracheal plugging using video fetoscopic technology () to visualise, access, and occlude the fetal airway.6 Six of eight (75%) fetuses with congenital diaphragmatic hernia have survived after surgery using video fetoscopic technology. Less invasive strategies are being explored to stimu- late fetal lung development pharmacologically com- bined with postnatal repair of the diaphragmatic hernia defect.11 This is based on the observation that the lungs of babies with severe congenital diaphragmatic hernia resemble the immature lungs of premature newborn babies with respiratory distress syndrome.11 In experi- mental models of congenital diaphragmatic hernia, antenatal steroid treatment, widely used to stimulate lung maturation in premature babies, has been shown to reverse immature lung growth at the biochemical, mor- 11 12 phological, functional, and molecular level. An inter- Fig 2 Chest x ray film of neonate with congenital diaphragmatic national collaborative is currently evaluating hernia. Note presence of air filled intestinal loops in thoracic cavity its efficacy in humans. and shift of mediastinum and heart

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to appreciate the significance of normal and abnormal anorectal anatomy,17 and PSARP (posterior sagittal anorectoplasty) has significantly improved the quality of life, continence, and functional outcome for affected children. This operation comprises an initial colostomy then a major anorectal reconstruction in the first year of life. Although Goon previously studied the posterior sagittal anorectoplasty procedure as a primary operation in neonates with imperforate anus, few surgeons considered it of practical advantage to the infant.18 Albanese and colleagues have recently evaluated the operation as a single stage procedure, thereby avoiding colostomy in the newborn period, and outcome data are encouraging in the short term (CT Albanese et al, report of a meeting on one stage correction of high imperforate anus in the male neonate, Surgical Section of the American Academy of Pediatrics, San Francisco, 1998).

Surgical gastroenterology Paediatric surgical gastroenterology is evolving rapidly, with an improved understanding of Hirschsprung’s dis- ease, intestinal motility disorders, constipation, short gut syndrome, and the role of the interstitial cells of Cajal as the gut pacemaker.19 20 Similar progress has occurred in intestinal and liver transplantation,21 22 where new approaches and operations may improve the quality of Fig 3 Chest x ray film of neonate with oesophageal atresia and life and functional outcome for affected infants. tracheo-oesophageal fistula. Note nasogastric tube coiled in blind Faecal incontinence with constipation causes ending upper oesophagus—air outlining stomach below diaphragm severe symptoms in children with congenital or confirms coexistence of distal tracheo-oesophageal fistula acquired bowel disorders (spina bifida, allied spinal neuropathies, anorectal malformations, sphincter the normally innervated ganglionic large intestine, and trauma, or problems with functional motility). Histori- the infant was discharged home to await a definitive cally, faecal incontinence was managed by diet, operation (“pull through”) to remove the aganglionic laxatives, or enemas. A significant number of patients bowel, with or without closure of the colostomy, within remained incontinent, and until recently there were the first year of life. This entailed two or three major few options for these children. A major advance has operations. Paediatric surgeons now tend towards per- been the introduction of the antegrade continence 23 forming a single stage procedure in the newborn enema procedure (ACE). This entails constructing a period without the need for a colostomy.15 16 catheterisable stoma from the appendix, which permits 24 Imperforate anus occurs in 1 in 4000 live births. irrigation of the colon with a cleansing enema. The absence of an anal orifice is easily diagnosed dur- The causes of intestinal failure and the short gut ing a routine examination of the neonate. In the past, syndrome are varied and can result from ischaemic neo- several operations treated this malformation. The pio- natal volvulus, necrotising enterocolitis, intestinal atresia, neering contributions of Peña led paediatric surgeons or prolonged gut dysfunction. Researchers are explor- ing growth factors as exogenous trophic agents for the failing gut.25 26 Whereas this treatment is at a promising experimental stage, intestinal transplantation has entered the clinical arena. The Pittsburgh group has reported the survival of 55% of patients undergoing intestinal transplantation, with most living at home and off parenteral nutritional support.21 Liver transplanta- tion in children continues to achieve excellent results22; 80% survival has been recently reported by the Birmingham group in the United Kingdom.22 The use of split liver transplantation (whole liver divided into two grafts) has led to a further increase in the donor pool.27

Surgical oncology Cancer is the second leading cause of death after accidents in those aged between 1 and 14 years. Progress has, however, been made in the management of several solid malignant tumours including Wilms’ tumour, Fig 4 Typical appearance of Hirschsprung’s disease at operation hepatoblastoma, and rhabdomyosarcoma.28–31 Children

1670 BMJ VOLUME 318 19 JUNE 1999 www.bmj.com Clinical review with advanced staged neuroblastoma continue to have a haemangiomatous malformations near the eye, limbs, or poor prognosis.32 airway. Folkmann and colleagues are exploring the use More than 80% of patients with Wilms’ tumour of antiangiogenesis treatments to control this process in survive in the long term.29 In patients presenting with benign haemangiomas and malignant tumours that are bilateral disease (5%-10% of cases) initial biopsy, dependent on angiogenesis.37 chemotherapy, and delayed renal sparing surgery (par- Unlike adults, fetal tissue heals without scarring. The tial nephrectomy) can also achieve good survival.33 fetus mounts little inflammatory response, regenerates Bilateral nephrectomy and renal transplantation is epithelial and mesenchymal tissues, and restores near now rarely necessary.28 perfect tissue architecture.38 Adzick and colleagues The management of hepatoblastoma, the most observed these findings during studies on fetal surgery.38 common malignant liver tumour of childhood, has Various biological modifiers are involved in this process. improved.30 Overall survival is 65%-70%, and surgical Exploiting such mechanisms may unravel new treat- mortality has been reduced to 0%-3%. Liver transplan- ments to prevent the crippling scar formation seen after tation has a role in selected cases.30 New treatment pro- severe burns in children. Advances in gene transfer tocols for children with a poor prognosis are needed. technology may soon also make it possible to consider Treatment of rhabdomyosarcoma has changed signifi- in utero gene therapy for certain fatal genetic diseases.39 cantly.31 To achieve survival surgeons performed Fundamental to many lethal congenital and radical extirpative surgery with mutilating results.31 acquired diseases in children is growth failure or growth Refinements in treatments have improved outcome, arrest resulting in organ dysfunction. Understanding and surgery, integral to survival, is now less mechanisms regulating normal and abnormal develop- aggressive.31 Neuroblastoma presents a major chal- ment in conditions such as congenital diaphragmatic lenge, and resection of the primary tumour offers the hernia and intestinal, liver, and renal failure may help best chance of survival.32 The role of surgery in solve these problems. Wilmore has predicted a “growth children with advanced disease remains controversial. factor revolution.”40 The search for elusive target specific The unique behaviour of this tumour in some patients growth factors as future treatments to ameliorate these invites new treatments to mimic its spontaneous disorders is now underway. regression.34 The benefits of screening programmes are, at present, unproved.32 1 Spitz L. So you want to train in paediatric surgery. Br J Hosp Med 1996;56:281-3. 2 Arul GS, Spicer RD. Where should paediatric surgery be practiced? Arch Laparoscopy Dis Child 1998;79:65-72. 3 Adzick NS, Harrison MR. Fetal surgical therapy. Lancet 1994;343:897- Paediatric surgeons only recently have embraced the 902. 4 Adzick NS, Sutton LN, Crombleholme TM, Flake AW. Successful fetal potential of laparoscopic surgery in their clinical prac- surgery for spina bifida. Lancet 1998;352:1675-6. tice. Paramount to its success are training, patient 5 Clark RH, Hardin WDJ, Hirschl RB, Jaksic T, Lally KP, Langham Jr MR, et al. Current surgical management of congenital diaphragmatic hernia: a safety, correct clinical application, and good outcome. report from The Congenital Diaphragmatic Hernia Study Group. Several procedures are feasible, safe, and effective J Pediatr Surg 1998;33:1004-9. 6 Harrison MR, Mychaliska GB, Albanese CT, Jennings RW, Farrell JA, including fundoplication for gastro-oesophageal Hawgood S, et al. Correction of congenital diaphragmatic hernia in utero reflux, cholecystectomy, splenectomy, nephrectomy, IX: fetuses with poor prognosis (liver herniation and low lung-head ratio) orchidopexy for the impalpable testis, and endoscopic can be saved by fetoscopic temporary tracheal occlusion. J Pediatr Surg 1998;33:1017-23. 35 testicular vein ligation for varicocele. Thoracoscopic 7 Wilson JM, DiFiore JW, Peters CA. Experimental fetal tracheal ligation surgery for palmar hyperhidrosis, empyema, lung prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia. J Pediatr Surg biopsy, and resection of foregut duplications have been 1993;28:1433-40. reported. Evolving procedures include laparoscopic 8 DiFiore JW, Wilson JM. Lung liquid, fetal lung growth and congenital 35 diaphragmatic hernia. Pediatr Surg Int 1995;10:2-9. one stage “pull through” for Hirschsprung’s disease. 9 Wigglesworth JS, Desai R, Hislop AA. Fetal lung growth in congenital laryngeal atresia. Pediatr Pathol 1987;7:515-25. 10 Harrison MR, Adzick NS, Flake AW, Vanderwall KJ, Bealer JF, Howell LJ, et al. Correction of congenital diaphragmatic hernia in utero VIII: The future response of the hypoplastic lung to tracheal occlusion. J Pediatr Surg 1996;31:1339-48. The loss or failure of an organ or tissue in a child 11 Losty PD, Donahoe PK, Schnitzer JJ. Prenatal hormonal therapy for lung through disease or aberrations in development is hypoplasia associated with congenital diaphragmatic hernia. Semin Neonatol 1996;1:193-202. costly and may involve transplantation, plastic surgery, 12 Schnitzer JJ, Hedrick HL, Pacheco BA, Losty PD, Ryan DP, Doody DP, et artificial prostheses, biosupport technologies, and al. Prenatal glucocorticoid therapy reverses pulmonary immaturity in congenital diaphragmatic hernia in fetal sheep. Ann Surg intensive medical treatments. Donor shortage, imper- 1996;224:430-9. fect tissue substitutes, and the chronic nature of specific 13 Rickham PP. Thoughts about the past and future of neonatal surgery. diseases dictate that new solutions are required. Tissue J Pediatr Surg 1992;27:1-6. 14 Spitz L. Esophageal atresia: past, present and future. 36 J Pediatr Surg engineering is a promising development. Vacanti and 1996;31:19-25. colleagues have successfully created several tissues and 15 Teitelbaum DH, Coran AG. Primary pull through in the newborn. Semin Paediatr Surg 1998;7:103-7. organs—cartilage, heart valves, liver, and intestine— 16 Huddart SN. Hirschsprung’s disease: present UK practice. Ann R Coll from isolated cells maintained in culture, grown on Surg Engl 1998;80:46-8. 17 Peña A. Advances in anorectal malformations. Semin Pediatr Surg biodegradable polymer scaffolds, which may be utilised 1997;6:165-9. as future treatments.36 18 Goon HK. Repair of anorectal anomalies in the neonatal period. Pediatr Surg Int 1990;5:246-9. Haemangiomas are among the most common 19 Martucciello G, Holschneider AM. Update on basic research on Hirschs- lesions in children. Some of these involute naturally as a prung’s disease. Eur J Pediatr Surg 1998;8:131-2. 20 Thomsen L, Robinson TL, Lee JCF, Farraway LA, Hughes MJG, Andrews child gets older and require no active treatment; others DW, et al. Interstitial cells of Cajal generate a rhythmic pacemaker may behave unpredictably. Angiogenesis is fundamental current. Nature Med 1998;4:848-51. 21 Reyes J, Bueno J, Kocoshis S, Green M, Abu-Elmagd K, Furukawa H, et al. to this growth process. Loss of function, tissue damage, Current status of intestinal transplantation in children. J Pediatr Surg or life threatening complications may accompany 1998;33:243-54.

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22 Talbot D, Achilleos OA, Gunson BK, McKiernan P, Beath S, Kelly DA, et 33 Kumar R, Fitzgerald R, Breatnach F. Conservative surgical management al. Progress in paediatric liver transplantation—the Birmingham of bilateral Wilms tumor: results of the United Kingdom Children’s experience. J Pediatr Surg 1997;32:710-3. Cancer Study Group. J Urol 1998;160:1450-3. 23 Malone PS, Ransley PG, Kiely EM. Preliminary report; the antegrade 34 Rudin CM, Thompson CB. Apoptosis and disease: regulation and clinical continence enema. Lancet 1990;336:1217-8. significance of programmed cell death. Annu Rev Med 1997;48:267-81. 24 Shankar KR, Losty PD, Kenny SE, Booth JM, Turnock RR, Lamont GL, et 35 Georgeson KE. Minimally invasive pediatric surgery: current status. Semin al. Functional results following the antegrade continence enema Paediatr Surg 1998;7:193-239. procedure. Br J Surg 1998;85:980-2. 36 Pollok JM, Vacanti JP. Tissue engineering. Semin Pediatr Surg 25 Swaniker F, Guo W, Diamond J, Fonkalsrud EW. Delayed effects of 1996;5:191-6. epidermal growth factor after small bowel resection. J Pediatr Surg 1996;31:56-60. 37 Folkman J. Clinical applications of research on angiogenesis. N Engl J Med 26 Kato Y, Yu D, Schwartz MZ. Enhancement of intestinal adaptation by 1995;333:1757-63. hepatocyte growth factor. J Pediatr Surg 1998;33:235-9. 38 Cass DL, Meuli M, Adzick NS. Scar wars: implications of fetal wound 27 Rela M, Heaton ND. Split liver transplantation. Br J Surg 1998;85:881-3. healing for the pediatric burn patient. Pediatr Surg Int 1997;12:484-9. 28 Wiener JS, Coppes MJ, Ritchey ML. Current concepts in the biology and 39 Sylvester KG, Yang EY, Cass DL, Crombleholme TM, Adzick NS. management of Wilms tumor. J Urol 1998;159:1316-25. Fetoscopic gene therapy for congenital lung disease. J Pediatr Surg 29 Haase GM. Current surgical management of Wilms’ tumor. Curr Opinion 1997;32:964-9. Pediatr 1996;8:268-75. 40 Wilmore DW. Will organ growth replace transplantation? Lessons from 30 Geiger JD. Surgery for hepatoblastoma in children. Curr Opinion Pediatr patients with short bowel syndrome. The Robert E Gross lecture. 28th 1996;8:276-82. annual meeting of the American Pediatric Surgical Association, Naples, 31 Andrassy RJ. Rhabdomyosarcoma. Semin Paediatr Surg 1997;6:17-23. FL, 1997. 32 Grosfeld JL. Neuroblastoma. In: O’Neill JA, Rowe MI, Grosfeld JL, Fonkalsrud EW, Coran AG, eds. Pediatric surgery, 5th ed. Chicago: Mosby, 1998:405-19. (Accepted 8 January 1999)

Lesson of the week Importance of distinguishing between cellulitis and varicose eczema of the leg C M Quartey-Papafio

Differentiating Dermatologists often see patients with gravitational The rash was exudative, with papules, vesicles, and varicose (varicose) eczema that has been treated unsuccessfully as crusts. Acute gravitational (varicose) eczema was (gravitational) cellulitis of the leg on medical or surgical wards. It is diagnosed, and her antibiotics were stopped. The leg eczema and important to recognise the difference between these two was cleansed with 1:10 000 potassium permanganate cellulitis can conditions early. This should reduce morbidity and solution (an astringent to treat the exudation) followed help reduce costs, in terms of the length of stay in hospital and the by a potent topical steroid twice daily. The foot of the morbidity and use of expensive intravenous antibiotics for a condition bed was raised to reduce venous hypertension in the the costs of that is not life threatening and can be cleared with topi- leg. The rash cleared in five days and the woman was hospital stay cal steroids in a few days. I document two such cases. discharged home. She was told to apply the topical and antibiotics steroid if the eczema recurred.

Department of Case reports Case 2 Dermatology, Case 1 A 68 year old man was admitted to a surgical ward Pilgrim Hospital because his leg had been red and weeping for two days. NHS Trust, Boston An overweight 47 year old woman was admitted to a PE21 9QS medical ward. Her right leg had been swollen for four It was not, however, painful. He had also noticed a rash C M Quartey- days and was covered with tiny blisters. Her general on his abdomen on the day he was admitted to hospi- Papafio, tal. The patient had a history of myocardial infarction locum consultant in practitioner had noted that the leg did not look like a dermatology “simple cellulitis.” Physical examination showed that the and pulmonary embolism. He was taking prophylactic patient’s temperature was 37°C and that her right leg aspirin and was not allergic to any drugs. Physical examination was normal. Apart from his leg, he looked BMJ 1999;318:1672–3 was swollen and inflamed and covered in tiny blisters. Other findings were normal. A diagnosis of cellulitis of well and was not feverish. Cellulitis of the left leg was the right leg was made. Swabs from the leg and blood diagnosed. Skin swabs and blood were taken for cultures were taken and she was given co-amixiclav— culture, and he was prescribed intravenous benzyl- intravenously for two days, then orally. Routine blood tests, including the white cell count, were normal, and culture of the swabs and blood were negative. After seven days she had improved and was discharged home. Four weeks later she was readmitted to hospital with the same symptoms and signs. Her general practitioner noted that she had “cellulitis of the right leg failing to respond to antibiotics.” The woman’s temperature was normal and all the investigations were repeated, with normal or negative results. On this occasion she was treated with intravenous benzylpenicillin and flucloxacil- lin and analgesics. When she had not improved after five days she was referred to a dermatologist. At this time, the patient had a five week history of a swollen leg which was also affected by a pruritic rash. Varicose eczema (note the crusting)

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