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2005; 7(4) : 273

INDIAN JOURNAL OFPRACTICAL PEDIATRICS

••••• IJPP is a quarterly subscription journal of the Indian Academy of Pediatrics committed to presenting practical pediatric issues and management updates in a simple and clear manner••••• Indexed in Excerpta Medica from January 2003

Vol.7 No.4 OCT-DEC 2005

Dr. A. Balachandran Dr. K.NedunchelianEditor-in-Chief Executive Editor

CONTENTS

FROM THE EDITOR'S DESK 275

TOPIC OF INTEREST - NEONATOLOGYNeonatal hyperbilirubinemia - A continuing saga 278

- Diwakar KK

Ventilation strategies in neonates with respiratory distress 287

- Karthik Nagesh NFeeding low birth weight babies 304

- Sheila Samanta Mathai

Fetal origins of adult disease - Implications for the 21st century 310

- Venkatesh SampathNeonatal sepsis - Newer perspectives 317

- Ranjan Kumar PejavarX-ray abdomen in the neonate 326

- Muralinath SFollow-up of the high risk neonates 335

- Lakshmi V, Shanmughasundharam R

IJPP

Journal Office: Indian Journal of Practical Pediatrics, IAP-TNSC Flat, ‘F’ Block, Ground Floor, Halls Towers,56, Halls Road, Egmore, Chennai - 600 008. INDIA. Tel.No. : 044-28190032 E.mail : ijpp_iap@rediff mail.comAddress for ordinary letters: The Editor-in-Chief, Indian Journal of Practical Pediatrics, Post Bag No.524,Chennai 600 008.Address for registered/insured/speed post/courier letters/parcels and communication by various authors:Dr. A. Balachandran, Editor-in-chief, Indian Journal of Practical Pediatrics, “F” Block, No. 177, Plot No. 235,4th Street, Anna Nagar East, Chennai - 600 102. Tamil Nadu, INDIA.

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Indian Journal of Practical Pediatrics 2005; 7(4) : 274

Fetal diagnosis and therapy 341

- Karthikeyan GFrequently asked questions in neonatal office practice 349

GENERAL PEDIATRICSSystemic lupus erythematosus in children - Clinical spectrum andmanagement 352- Uma Shankari Ali

RADIOLOGIST TALKS TO YOUAcute abdomen in the child - I 359

- Vijayalakshmi G, Natarajan B, Ramalingam A

CASE STUDYAmniotic band syndrome - A case report 361

- Thiraviam Mohan M, Gopal Subramoniam

AUTHOR INDEX 363

SUBJECT INDEX 364

BOOK REVIEW 351

NEWS AND NOTES 303,316,325,334,348,362

Published and owned by Dr. A. Balachandran, from Halls Towers, 56, Halls Road, Egmore,Chennai - 600 008 and printed by Mr. D. Ramanathan, at Alamu Printing Works,9, Iyyah Mudali Street, Royapettah, Chennai - 600 014. Editor : Dr. A. Balacnadran.

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* The views expressed by the authors do not necessarily reflect those of the sponsor orpublisher. Although every care has been taken to ensure technical accuracy, no responsibility isaccepted for errors or omissions.

* The claims of the manufacturers and efficacy of the products advertised in the journal are theresponsibility of the advertiser. The journal does not own any responsibility for the guarantee of theproducts advertised.

* Part or whole of the material published in this issue may be reproduced withthe note "Acknowledgement" to "Indian Journal of Practical Pediatrics" without prior permission.

- Editorial Board

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2005; 7(4) : 275

EDITOR’S DESK

Greetings from the Journal Committee ofIJPP. This issue will bring out some moreinteresting articles on Neonatology. The topicswill be useful for practicing pediatricians andpostgraduates both at tertiary care centers andprimary heath care level. The Journal Committeeis taking utmost care in keeping the academicstandards.

The article on ‘Neonatal hyperbiliru-binemia’ is discussed in detail by Dr.Diwakar.The respiratory distress is one of the mostcommon causes of morbidity and mortality inneonatal period. The article on ‘Ventilationstrategies in neonates with respiratory distress’written by Dr.Karthik Nagesh will be an eyeopener for younger colleagues in the NICUdealing neonates with respiratory distress. Hehas given a vivid picture about the variousmodalities of the management of neonates withrespiratory distress. Feeding the low birth weightbabies often pose problems among practitionersand is still a nutritional challenge.

Dr.Sheila Samanta Mathai has discussed thecommon problems encountered in the “Feedinglow birth weight babies”. She concluded thatLBW babies need to be put on breast milk assoon as possible after birth and monitoring ofthe growth of these children during follow-up.The article on ‘Fetal origins on adult disease –Implications for the 21st century’ byDr.Venkatesh Sampath, USA is quite interestingand will throw more light on this subject. The‘Neonatal sepsis’ is the commonest cause of

morbidity and mortality in NICU. Dr.RanjanKumar Pejavar has given a detailed summary onthe newer perspectives.

The practical value of plain x-ray in theevaluation of neonates’ abdomen is welldiscussed by Dr.Muralinath. He has written thebasic approach to the reading of an x-rayabdomen of a neonate with gastrointestinaldisorders. We hope the postgraduates willappreciate the value of a plain x-ray abdomen atthe bedside. The ‘Follow-up of the high riskneonate’ is an essential component in the tertiaryneonatal care.

Dr.Shanmughasundharam, et al hashighlighted the goals and the need for follow-upof high risk neonates. The recent advances inmedical technology made the fetal diagnosis andtherapy possible in this decade. Dr.Karthikeyanhas reviewed the current status of the screeningand diagnostic technologies that are available infetal medicine as well as therapeuticinterventions.

The Editorial Board of IJPP has discussedthe FAQs in neonatal office practice. The articleon ‘Systemic lupus erythematosus in children’is well written by Dr.Uma Sankari Ali. She hasdiscussed the clinical spectrum, management,outcome and follow-up with review of currentliterature.

Dr.Vijayalakshmi, et al has dealt about theimportant role of ultrasonogram while evaluatingchildren with acute abdominal pain.

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INSTRUCTIONS TO AUTHORS

GeneralPrint the manuscript on one side of standard size A4, white bond paper, with margins of at least 2.5 cm (1”)in double space typescript on each side. Use American English using Times New Roman font 12 size.Submit four complete sets of the manuscript.They are considered for publication on the understanding that they are contributed to this journal solely.All pages are numbered at the top of the right corner, beginning with the title page.All manuscripts should be sent to: The Editor-in-Chief, Indian Journal of Practical Pediatrics

Manuscript1st Page –

TitleName of the author and affiliationInstitutionAddress for correspondence (Email, Phone, Fax if any)Word countNo. of figures (colour / black and white)No. of referencesAuthors contribution

2nd Page –Abstract (unstructured, not exceeding 100 words) with key words (not exceeding 4)

3rd Page -AcknowledgementPoints to remember (not more than 5 points)TextReferencesTablesLegendsFigures – should be good quality, 4 copies black & white / colour,*(4 x 6 inches – Maxi size) Glossy print* Each colour image will be charged Rs. 1,000./- separately, with effect from January 2006 (Except forinvited articles).

TextOnly generic names should be usedMeasurements must be in metric units with System International (SI) Equivalents given in parentheses.

ReferencesRecent and relevant references onlyStrictly adhere to Vancouver styleShould be identified in the text by Arabic numerals in parentheses.Type double-space on separate sheets and number consecutively as they appear in the text.Articles without references / defective references will entail rejection of article.

TablesNumbered with Roman numerals and typed on separate sheets.Title should be centered above the table and explanatory notes below the table.

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Figures and legendsUnmounted and with figure number, first author’s name and top location indicated on the back of eachfigure.Legends typed double-space on separate sheet. No title on figure.All manuscripts, which are rejected will not be returned to author. Those submitting articles should thereforeensure that they retain at least one copy and the illustration, if any.

Article CategoriesReview article

Article should be informative covering the recent and practical aspects in that field. Main articles can be in1500 – 2000 words with 12 – 15 recent references and abstract not exceeding 100 words.

Case report (covering practical importance)250 – 600 words, 8 – 10 recent references

Clinical spotters section150 – 200 words write upWith 1 or 2 images of clinically recognizable condition(of which one could be in the form of clinical photograph / specimen photograph / investigation)

Letters to the Editor200 – 250 words pertaining to the articles published in the journal or practical viewpoints with scientificbacking and appropriate references in Vancouver style.

Selection proceduresAll articles including invited articles will be peer reviewed by two masked reviewers. The decision of theEditorial Board based on the reviewers’ comments is final.

Check ListCovering letter by corresponding authorDeclaration (as enclosed) signed by all authors **Manuscript (4 copies)Accompanied by a copy in CD / or submit as an email attachment in addition to hard copy.

Failing to comply with the requirement at the time of submission would lead to the rejection of the article.Author’s contribution / Authorship CriteriaAll persons designated as authors should qualify for the authorship. Authorship credit should be based onsubstantial contributions to i) concept and design, or collection of data, or analysis and interpretation of data; ii)drafting the article or revising it critically for important intellectual content; and iii) final approval of the versionto be published. All conditions 1, 2 and 3 must be met. Participation solely in the collection of data does notjustify authorship and can be mentioned in the acknowledgement if wanted.

Declaration by authors **I/We certify that the manuscript titled ‘……………………………….’ represents valid work and that neitherthis manuscript nor one with substantially similar content under my/our authorship has been published or isbeing considered for publication elsewhere. The author(s) undersigned hereby transfer(s), assign(s), or otherwiseconvey(s) all copyright ownership, including any and all rights incidental thereto, exclusively to the IndianJournal of Practical Pediatrics, in the event that such work is published in Indian Journal of Practical Pediatrics.I / we assume full responsibility for any infringement of copyright or plagiarism.

Authors’ name(s) in order of appearance in the manuscript Signatures (date)

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NEONATALHYPERBILIRUBINEMIA -A CONTINUING SAGA

* Diwakar KK

Abstract: Neonatal hyperbilirubinemia hasalways been a subject of significant clinicalinterest. Occurrence of bilirubin associatedencephalopathy, lends an urgency to thediagnosis and management of neonatal jaundice.As therapy is primarily aimed at preventingbilirubin encephalopathy, it would be suitable toapproach neonatal jaundice in a three-prongedmanner. 1. Evaluation based on ‘risk-for-encephalopathy’, 2. Evaluation for etiology and3. Management.

Key words: Hyperbilirubinemia, Neonataljaundice, Phototherapy, Exchange transfusion

Neonatal hyperbilirubinemia or jaundice inthe newborn is still one of the most discussedtopics in neonatology. The sheer prevalence ofneonatal jaundice and periodic occurrence ofbilirubin associated encephalopathy ensuressustained interest on this subject. While theetiology of hyperbilirubinemia may be varied, theprinciples of therapy have remained fairlyconstant over the decades. Better understandingof the genetic and biochemical variablescontributing to bilirubin elevation has made ‘theat-risk’ approach and early intervention easier.Though a small percentage of neonatal jaundice

belong to the ‘direct hyperbilirubinemia’ group,most of the discussion in neonatal jaundice isfocused on the travails of ‘indirecthyperbilirubinemia. The subject has beendiscussed under the following three headings;

1. Evaluation based on ‘risk-for-encephalopathy’.

2. Evaluation for etiology.

3. Management.

Needless to say all the steps have to be donesimultaneously.

At risk for encephalopathy

a. Level of unconjugated bilirubin

Quantifying the level of jaundice has been thefoundation for satisfactory management ofhyperbilirubinemia. The observer variability andthe influence of the skin color in clinicallyevaluating hyperbilirubinemia by ‘Kramer index’has been the Achilles’ heel of this method(Table 1). On the other hand despite its reliability,the pain of repeated blood sampling makesevaluation of serum bilirubin a distasteful taskfor the baby and health care personnel. Theadvent of transcutaneous bilirubinometry hassignificantly simplified the task of monitoring thejaundice level in infants. The reliability of theinstruments for bilirubin estimation [Minolta ®and Bilicheck ®] have shown reasonabledependability for both, with clinical assessmentbeing considered least reliable1.

The fear for the level of 20 mg/dL has givenanxious moments to doctors and the relatives ofthe ‘jaundiced’ infant. Researchers havesuggested that serum bilirubin level is preferably

NEONATOLOGY

* Professor & Head, Department of Neonatology,Professor, Department of Pediatrics,Malankara Orthodox Syrian Church MedicalCollege, Kochi, Kerala

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maintained below 335 micromols/L (appr.1 mg/dL = 18 micromol/L)2. However, what isoften missed is that there is nothing sacrosanctabout this level of bilirubin. At many an occasionlevels lower than this value have also knownto be associated with encephalopathy. Nocontroversy exists about the mandatoryrequirement for monitoring the bilirubin levelsof all infants, specially the at-risk neonates. Therise of bilirubin at a rate exceeding 1 mg/dL/houris still considered an indicator for exchange trans-fusion in the ‘at-risk’ patient (0.25 mg/dL/hr forphototherapy as per American Academy ofPediatrics).

The gold standard for deciding therapy to preventencephalopathy continues to be serum bilirubinlevels for want of better parameters. After 48hours of life, serum bilirubin is evaluated 8-12hourly if levels are above 14 mg/dL, 6th hourlyif above 16 mg/dL, 4th hourly if above 18 mg/dL and more frequently at higher values. It cannever be over emphasized that at risk patients,and jaundice occurring before 48 hours of agemust be monitored more frequently and morediligently.

It should be remembered that bilirubin risesby the ‘hours’ of life and hence the time ofsampling must be as ‘hours of life’ and not ‘dayof life.’ It must be recognized that 25 hours and47 hours would both be 2nd day, but the risk for

encephalopathy for same levels of serumbilirubin would be much higher for the earlierhours. This significance would be missed if the‘day of life’ were to be the criterion.

b. Patient factors

The multifactorial etiology of bilirubin associatedencepahalopathy is significantly influenced bythe altered physiologic integrity of the blood brainbarrier 3, sudden surge in free bilirubin levels,variable affinity of bilirubin to various neuronalsites and a multitude of hitherto known andunknown factors. This makes predictingencephalopathy a challenging task.

The concept of free bilirubin having a ‘cytotoxic’effect on the neuronal cells has led to varioustheories interpreting the possible facilitators forbilirubin induced neuronal injury. The relativeselectivity of injury being confined to areas likethe basal ganglia implies an association of thehigher metabolic rate, oxygen consumption andhighly vascular characteristics of these areas andtheir vulnerability to bilirubin associated neuronalinjury. MRI evaluation of bilirubinencephalopathy has shown a greater involvementof globus pallidus and putamen and the thalamusto be affected to a lesser extent4.

The following host factors, play determiningroles in promoting encephalopathy,

i. Gestation: A less developed hemopoetic andhepatic functions would result in the lessmature infant having more prolonged andhigher levels of serum bilirubin. As thegestational age increases, the permeabilityof the blood brain barrier to bilirubin andbilirubin – albumin complex decreases.Other systems like the gastro intestinal tractalso become more functionally mature.

ii. Albumin levels: The albumin: bilirubin ratioseems to be a plausible predictor forencephalopathy. It seems logical that in

Table 1. Criteria to estimate clinicaljaundice (Kramer Index)

Area of body Range of bilirubin(mg/100 ml)

Face 4–8Upper trunk 5–12Lower trunk and thighs 8–16Arms and lower legs 11–18Palms and soles >15

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infants with lower albumin levels, the freebilirubin content would be more, therebyenhancing the risk of encephalopathy5.

iii. Systemic compromise in the infant couldresult in various alterations – each being anadditional deleterious contributor tobilirubin encephalopathy. Factors reducingthe albumin levels would contribute toreduced albumin binding and a larger loadof free bilirubin in the serum. The integrityof the blood brain barrier is affected byacidosis and hypoxic ischemic damages,facilitating greater permeability to thebilirubin complexes. A large surge ofbilirubin or enhanced contact time of thebilirubin to the neurons is found to beessential to precipitate an encephalopathy.The factors increasing the circulation timewould ensure greater period of contact ofthe bilirubin moieties to the neurons –facilitating neuronal damage, thus explainingthe higher risk of encephalopathy inasphyxiated or septic neonates in shock. Thecompounding factors of metabolic acidosiswould damage the blood brain barrier.

iv. Increasing post natal age, tends to decreasethe risk of hyperbilirubinemia and theassociated encephalopathy. Whilematuration of the blood brain barrier andgreater vasomotor stability would be theexplanation for preventing encephalopathy,multiple factors of gastro intestinal maturityare useful protectors. Increasing gut motility,passage of meconium with its additionalbilirubin load, maturation of the GIThormones, resulting in the antegrade flowof bile, bacterial colonization of the gut withthe resultant reduction in the efficacy ofintestinal glucoronidase all result in reducingenterohepatic circulation and total bodybilirubin load. Structural anomalies of theGIT would influence the gut motility and

reduce propagation of the intestinal contents,resulting in an increased amount ofenterohepatic circulation.

Evaluation for etiology

Recognizing the etiology is essential for thecomprehensive management of any disease.While therapy of neonatal jaundice with theubiquitous phototherapy and exchangetransfusion has effectively reduced its morbidity,identifying the exact cause for thehyperbilirubinemia could often be daunting.

As in all aspects of clinical medicine, historyprovides many clues. The hour of occurrence ofjaundice, and the rapidity of rise must always besought for.

Clinical jaundice noticed beyond 36 hoursof life, increasing by 72 to 96 hours, with atendency to reduce, and disappear by the 7th -10th day has become the accepted pattern of theso called physiologic jaundice in a term infant.In preterm infant, the jaundice tends to peak bythe 7th day and disappear by the 14th day. It hasbeen the custom to state that serum bilirubin interm infants having ‘physiologic jaundice’ rarelyrises above 12 mg/dL. There is a significantregional and ethnic variation in this levels. Levelsas high as 14-15 mg/dL are not uncommonly seenin many term infants with physiologic jaundice.However, it must be reiterated that all causes forelevation in serum bilirubin must be ruled outbefore labeling an infant as having ‘exaggeratedphysiologic’ jaundice. Similarly persistence ofjaundice beyond the accepted periods viz. 7 daysin term infants and 14 days in preterm infants, inthe absence of any other discernable cause isoften termed as ‘prolonged physiologic jaundice’.

It must be appreciated that the onset ofjaundice within 24 hours should always beconsidered ‘unphysiologic’ and must beevaluated in detail. Hemolytic disease of the

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newborn – Rh isoimmunization or ABOincompatibility could present as early onsetjaundice. It must be recognized that other causesof hemolysis like congenital spherocytosis, G6PDdeficiency etc. could also present as neonatalhyperbilirubinemia. The history of jaundice inthe previous sibling should always be sought for,as this could provide an insight to the etiologyand possible cause of the jaundice. Beware of anelder sibling with bilirubin encephalopathy. Theapproach to management in such cases must bewith utmost caution and aggressive strategies forreducing bilirubin levels must be initiated at theearliest. An often forgotten event, is asking forthe color of urine and stools of neonatespresenting with jaundice. Obtaining the historyof high colored urine or pale stools wouldhighlight the chances of conjugatedhyperbilirubinemia or cholestatic jaundice.

The approach based on serum bilirubin isoften helpful (Table 2). The presence ofunconjugated hyperbilirubinemia must always becomplemented with the examination of theperipheral blood smear. The evidence ofhemolysis in the peripheral smear has sinisterimplications to the course of jaundice and theneonate requires more aggressive management

like exchange transfusion. The absence ofhemolysis would direct us to the other lesscommon causes (Table 2) for neonatalhyperbilirubinemia or could finally result in thenonspecific diagnosis of ‘exaggeratedphysiologic jaundice’. Hypothyroidism mustalways be ruled out, in all cases of unexplainedjaundice. This becomes even more important asregular neonatal screening for hypothyroidism isnot undertaken in our country. This incidentaljaundice could therefore be the first clue toalleviate a treatable cause of mental retardation.Glucoronyl transferase hypofunction has beenattributed to many an unexplained neonatalhyperbilirubinemia. Specific enzyme assayscould confirm these abnormalities.

Prolonged jaundice has many times been apresentation of neonatal hepatitis and other causesof conjugated hyperbilirubinemia. It musttherefore be realized that evaluation of jaundiceis always incomplete, without assessing the directbilirubin.

Of late, significant interest has beengenerated on the role of bilirubin as anantioxidant. The association of free radicals withelevated unconjugated bilirubin levels have beenassessed by many workers. The diminished

Table 2. Etiology of hyperbilirubinemia

Serum BilirubinUnconjugated Conjugated

Increased Bilirubin Others: Cholestasis Infectionproduction:Hemolytic disease, Rh, Exaggerated physiologic Non surgical Congenital /ABO, minor blood group jaundice (eg drugs) Acquiredincompatibility etc.

Extravasated blood, Conjugation disorders; Surgicaleg. Cephalhematoma Hypothyroidism;Subgaleal bleeds, cutaneous Breast milk jaundicebruising, hematoma

Polycythemia

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antioxidant associated oxidative stress of thepremature infants has also been considered as acause for hyperbilirubinemia.6

Management

The functional maturity of the liver wouldbe the final determinant of the levels ofunconjugated bilirubin in the blood. Therapy istherefore aimed at tiding over the interim periodof rising bilirubin load until the hepatic systemis functionally effective in reducing theunconjugated bilirubin. Therapy is aimed atensuring that serum bilirubin remain well belowthe ‘encephalopathic levels’. It is perhaps for thisreason that radical therapy like exchangetransfusion is rarely encountered in infantsbeyond the first week of life as presumably theliver would have ‘matured’ by that time. In thepresence of additional risk factors forencephalopathy, therapy is initiated at lowerserum bilirubin levels. Eg. Treatment would beinitiated at lower levels of serum bilirubin in aninfant who is premature, while the same level ofserum bilirubin in a term infant would not warrantany therapy. Investigations and treatmentcontinue to be the twin pillars of management.

Investigations

All investigations are for ascertaining theetiology and the risk for encephalopathy in the

infant (Table 3). Serial evaluation of bilirubinmust be done in all infants considered to havejaundice level higher than normal for the age andgestation. This could be by transcutaneousbilirubinometry or by serum bilirubin estimation.The frequency of assessment increases as thebilirubin values approach ‘encephalopathic’levels. It is our practice to evaluate serumbilirubin every 8 hours if the bilirubin levels areabout 14 mg/dL beyond 48 hours of life in terminfants. Bilirubin is assessed every sixth hourlyif values are above 16 mg/dL and fourth hourlyfor values over 18 mg/dL. Any value above 18mg/dL is considered as ‘high risk forencephalopathy’ and two hourly monitoring tobe done along with the assessment of serumalbumin level.

Relevant investigations have to beundertaken depending on the presence or absenceof hemolysis. Congenital hemolytic anemias mustbe considered if peripheral smear examination issuggestive of hemolysis, in the absence offetomaternal blood group incompatibility.Similarly unconjugated hyperbilirubinemia in theabsence of hemolysis would warrant evaluationfor sepsis, hypothyroidism and hypo functioninghepatic enzyme system. A missedcephalhematoma or borderline prematurity havebeen responsible for many an unexpectedhyperbilirubinemia. Conjugated bilirubin values

Table 3. Investigations

Tests ImplicationBiochemicala) Serum Bilirubin, Direct and Total Type of hyperbilirubinemia

Unconjugated / Conjugatedb) Serum albumin Bilirubin: Albumin Ratio – Risk for

encephalopathy if ratio highHematologica) Blood group and Rh typing of infant and mother Isoimmunizationb) Peripheral smear For evidence of hemolysis

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greater than 1.5-2.0 mg/dL must also be takenseriously and evaluated for infections andcholestasis7.

Some interest has been generated inconsidering end-tidal carbon monoxide levels asa predictor for significant hyperbilirubinemia ininfants with hemolysis8.

Treatment

The mechanisms and nuances of each formof therapy is beyond the purview of this article.It should suffice to say that the aim of treatmentshould be to reduce, if possible the bilirubinproduction, reduce serum bilirubin by directremoval or making it water soluble, increaseenterohepatic circulation and reduce factorsfacilitating encephalopathy.

Phototherapy

The recognition that phototherapy with lightof 425-475 nm wave length can convertunconjugated biliubin of the skin to water solubleisomers-geometric and structural (Lumirubin)has radically changed the prognosis ofhyperbilirubinemia in the newborn. A spectralirradiance of 6-15 micro watts/nm/cm2, is foundto be effective, with higher irradiance resultingin a greater degree of isomerization.

Phototherapy is usually started in terminfants when the serum bilirubin levels are over12mg /dL at 25-48 hrs of life or over 15mg/dL at48-72 hrs9 (Table 4). It is prudent to commencephototherapy as soon as serum bilirubin valuereaches 5-6 mg/dL below the indicated value forexchange transfusion for that infant. It wouldtherefore be obvious why phototherapy isinitiated in premature and at- risk infants, atlower levels of serum bilirubin as compared tonormal term infants.

Intensive phototherapy is commenced as therequirement for exchange transfusion becomesmore plausible – the aim being to reduce theserum bilirubin by 1-2 mg/dL every 6 hours.

Exchange transfusion

The indications and timing for exchangetransfusion has always been a matter of debate.Serum bilirubin values above 20 mg /dl has beentraditionally accepted as a strong enoughindication for exchange transfusion. However,the increasing awareness of transfusion relateddiseases and normal outcome observed in terminfants with bilirubin values well above20 mg/dL has resulted in a rethink about thesanctity of the number ‘20’. In the absence ofrisk factors, exchange transfusion has been

Table 4. Phototherapy: Birth weight is plotted against infant’s age in days.If the serum indirect bilurubin (mg/dL) is greater than the plotted number,consider phototherapy14.

Days 1 2 3 4 5 6 7

Birth wt. (gms)<1000 3 3 3 5 5 7 71000-1249 5 5 5 7-8 8 10 121250-1499 8 8 8 10 12 12 121500-1749 10 10 10 12 12 13 131750-1999 10 10 12 13 13 13 132000-2499 10 12 12 15 15 15 15>2500 10 12 13 15 17 17 17

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delayed to values as high as 25-29 mg/dL10.Recommendations for exchange are oftensubjective and could at times be even termed asvague. We have in our center utilized theobservation of Ahflors and modified it, thus usingthe product of albumin and bilirubin levels asguideline to decide the timing for exchangetransfusion (Table 5) 11.

Exchange transfusion continues to be theultimate weapon in the armamentarium againsthyperbilirubinemia and prevention of bilirubinassociated encephalopathy. Well conducteddouble volume exchange transfusion using theappropriate group and Rh typed blood reducesthe serum bilirubin by 50-60 % in most instances.‘O positive’ blood would be required forexchange transfusion in cases of ABOincompatibility. Infants with Rh isoimmunizationwill ideally require Rh negative blood of thebaby’s group, in the absence of which ‘Onegative’ blood should suffice. The importanceof a good blood bank with all protocols for safeblood banking can never be over emphasizedunder these circumstances. ‘Rh negative’ donorsmust also be evaluated for ‘Du’ antigen, andshould be accepted for donation only if they are‘Du’ negative in addition to being ‘Rh-negative’by standard reagents.

While the ‘pull –push method’ through theumbilical vein continues to be the most commonmethod for exchange transfusion, dual portalroutes for exchange transfusion are becomingequally popular. Peripheral or umbilical arteryhave been used by many workers to withdrawblood with the peripheral or umbilical vein beingused for transfusing the blood. It has been ourpractice to use the umbilical vein to withdrawthe ‘jaundiced blood’ and use the peripheral veinto infuse the compatible blood by syringe infusionpump at a synchronized predetermined rate.

While ‘fresh blood’ has for long been thechoice, it has become increasingly difficult toobtain, especially since the mandatory screeningrequirements of standard blood banks. The sheernon-availability of a compatible donor could alsomake obtaining ‘fresh blood’ difficult.

In the present days of component bloodbanking saline washed compatible packed cellscould be reconstituted with the compatible plasmato the acceptable packed cell volume (PCV), andused for exchange transfusion. The salinewashing reduces the risk of hyperkalemia of thestored packed cell, and the plasma reconstitutionto appropriate PCV reduces the chances of post-exchange transfusion hyperkalemia.

Table 5.Total bilirubin (mg/dL) and bilirubin/albumin ratio (mg/g) as criteriafor exchange transfusion11

Birth weight (gram) <1250 1250-1499 1500-1999 2000-2499 >2500

Standard risk 13.0 15.0 17.0 18.0 25-29Or bilirubin/albumin ratio* 5.2 6.0 6.8 7.2 8.0High risk# 10.0 13.0 15.0 17.0 18.0Or bilirubin/albumin ratio* 4.0 5.2 6.0 6.8 7.2* Exchange transfusion at whichever criterion comes first# Risk factors: Apgar <3 at 5 minutes, PaO2 <40 mm at > 2 hour, pH< 7.15 at >1 hour, body weight

<1000 g, Hemolysis, clinical CNS deterioration, total protein <4 g/dL or albumin <2.5 g/dL

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Newer therapies

Intravenous gama globulin in immunehemolytic jaundice, Tin-mesoporphyrin andBilirubin-oxidase are some of the modalities usedin experimental or limited clinical trials byvarious workers. Antenatal phenobarbitone givento the mother in doses of 30 mg three times a dayhave been shown to reduce exchange transfusionin neonates with hemolytic disease 12.

Supportive care

The treatment of neonatalhyperbilirubinemia would never be completewithout mentioning the concomitant supportivecare. Satisfactory oral feeds ensures adequatehydration and nutrition. The ensuing bowelmovements are very useful in reducing theenterohepatic circulation. Trans-epidermal lossof water in low birth weight infants undergoingphototherapy can be reduced by coating the skinwith clear ointment 13.

Breast feeding, in addition to the nutritionalbenefits, would serve as a good indicator tomonitor encephalopathy. Any reduction in thejaundiced infant’s interest to suck at the breastshould be considered sinister and an indicator forimmediate exchange transfusion.

Follow-up

All infants with significant jaundice —hyperbilirubinemia to an extent where exchangetransfusion was undertaken or seriouslycontemplated — must be meticulously followedup for auditory assessment and developmentalevaluation.

In the absence of an identifiable cause forthe jaundice, the search for an etiology shouldbe continued at follow up. In addition to providingan insight to the current problem, the informationobtained could be invaluable for subsequentpregnancies.

Management of hyperbilirubinemia shouldfollow the basic tenets of

1. At Risk Approach: Greater caution forinfants with higher risk for encephalopathy.

2. Low threshold for initiating phototherapy inthese patients.

3. A regular hospital policy for evaluation ofbilirubin levels in all infants andmanagement of hyperbilrubinemia.

4. Exchange transfusion when indicated.

5. Specific recommendations for follow-upbilirubin assessment in infants dischargedbefore 72 hours of age.

Neonatal hyperbilirubinemia will continueto be a much debated topic. Research hascontributed to a better understanding about theetiopathogenesis of bilirubin encephalopathy. Itis however interesting to realize that despite thelarge amount of scientific evaluation, the basictenets of managing hyperbilirubinemia during theearly neonatal period have remained relativelyunchanged.

Points to remember

1. Neonatal hyperbilirubinemia could resultin bilirubin associated encephalopathy.

2. Serum bilirubin levels have to be regularlymonitored in the newborns especially theat risk infants.

3. Prematurity, low serum albumin levels,asphyxia, sepsis and other factors thatcould interrupt the integrity of the bloodbrain barrier, increase the risk ofencephalopathy even at lower levels ofserum bilirubin.

4. Phototherapy must be initiated appro-priately in infants with hyperbilirubinemia.

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5. Exchange transfusion would have to beundertaken if bilirubin levels andassociated risk factors predict a high riskfor encephalopathy.

References

1. Szabo P, Wolf M, Bucher HU, Haensse D,Fauchere JC, Arlettaz R. Assessment ofjaundice in preterm neonates: comparisonbetween clinical assessment, twotranscutaneous bilirubinometers and serumbilirubin values. Acta Paediatr 2004;93(11):1491-1495.

2. Soorani-Lunsing I. Total serum bilirubin levels335 micromol/L should be avoided. Pediatr Res2001; 50(6):701-705.

3. Wennberg RP. The blood-brain barrier andbilirubin encephalopathy. Cell Mol Neurobiol2000 ;20(1):97-109.

4. Shah Z, Chawla A, Patkar D, Pungaokar S. MRIin kernicterus. Australas Radiol 2003 ;47(1):55-57.

5. Ahlfors CE, Wennberg RP. Bilirubin-albuminbinding and neonatal jaundice. Semin Perinatol2004;28(5):334-339.

6. Turgut M, Basaran O, Cekmen M, Karatas F,Kurt A, Aygun AD. Oxidant and antioxidantlevels in preterm newborns with idiopathichyperbilirubinaemia. J Paediatr Child Health2004; 40(11):633-637.

7. Camilia RM, John PC. NeonatalHyperbilirubinemia In: Manual of NeonatalCare 5th Edn, Eds, John P Clocherty, EriceEichencoald, Ann R Stark, Lippin CottWilliams and Wilkins, Philadelphia,2004;pp185-221.

8. Herschel M, Karrison T, Wen M, Caldarelli L,Baron B. Evaluation of the direct antiglobulin(Coombs’) test for identifying newborns at riskfor hemolysis as determined by end-tidal carbonmonoxide concentration (ETCOc); andcomparison of the Coombs’ test with ETCOcfor detecting significant jaundice. J Perinatol2002 ;22(5):341-347.

9. Engmann C, Schumacher RE. Phptotherapy. In:Michigan Manual of Neonatal Intensive Care,3rd Edn, Ed. Donn SM, Hanley and Belfus 2003;pp 351-354.

10. Newman TB, Maisels MJ. Evalauation andtreatment of jundice in the term newborn: akinder, gentler approach. Pediatrics 1992;89:809-818.

11. Ahlfors CE. Criteria for exchange transfusionin jaundiced newborn. Pediatrics 1994; 93(3):488-494.

12. Trevett TN Jr, Dorman K, Lamvu G, Moise KJJr. Antenatal maternal administration ofphenobarbital for the prevention of exchangetransfusion in neonates with hemolytic diseaseof the fetus and newborn. Am J Obstet Gynecol.2005; 192(2):478-482.

13. Wananukul S, Praisuwanna P, Kesorncam K.Effects of clear topical ointment ontransepidermal water loss in jaundiced preterminfants receiving phototherapy. J Med AssocThai 2001; 84(6):837-841

14. Pejavar RK. Jaundice. In: NNF Manual ofNeonate Care, 1st Edn, Jayshree Mondkar, RKPejavar, Prism Books Pvt. Ltd., Bangalore2004; pp 110-120.

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NEONATOLOGY

VENTILATION STRATEGIES INNEONATES WITH RESPIRATORYDISTRESS

Karthik Nagesh N

Abstract: Mechanical ventilation continues to beone of the most common therapies in neonateswith respiratory failure. The aim in ventilatingthese babies with respiratory failure is to achieveadequate gas exchange without injuring thelungs. We now have the opportunity to apply anumber of advanced ventilatory modes whichwere not previously available for treatingnewborns.These offer multiple mode selectionand improved pneumatics.Ventilatory strategyshould take into account the pathophysiology,nature and course of the disease.Newerventilation strategies are more ‘kinder andgentler’ on the newborn lungs in order to reduceventilator induced lung damage.Key words: Neonatal ventilation,Strategies

Respiratory distress constitutes the largestcause of morbidity and mortality in the neonatalperiod due to minimal respiratory reserve andtransition from intrauterine to extrauterine life.It is estimated that 10-15 percent of babies withrespiratory problems die in the neonatal period.

Assisted ventilation can be defined as themovement of gas in and out of the lungs by anexternal source connected directly to the patient1.In the neonate, it is usually a temporary measureto support pulmonary function till the baby can

* Consultant Neonatologist andDirector-Pediatric Research Manipal Hospi-tals and Manipal Acunova, Bangalore.

breathe adequately without help. Ventilatorysupport may be required in neonates withimpaired ventilation and gas exchange. The goalis to optimise gas exchange, improve pulmonarymechanics and to reverse the underlying causeof respiratory failure. Recent advances inneonatal ventilatory care have led to an increasedsurvival of smaller and critically ill babies.

Respiratory distress - Evaluation

To evaluate the respiratory distress, at leastthree aspects should be considered: (1) clinicalsigns of respiratory distress, (2) blood chemistryand (3) chest radiography. Table 1 provides a listof clinical entities that can lead to respiratorydistress in neonates.

Infants who have some respiratory difficultyin the delivery room may have elevation ofrespiratory rate and retractions for a few hours.This may subside in many neonates while someof them continue to manifest these symptoms.Careful recording of respiratory rate andretractions are to be kept from birth. Variousclinical scores have been developed to evaluaterespiratory distress. The consistent features ofthese scores were respiratory rate, retractions,grunting, cyanosis and auscultatory findings ofbreath sounds.

Clinically one should look for the followingsigns:

• Increase in respiratory rate

• Increasing retractions / effort

• Prolonged apnea with cyanosis / bradycardiaor both.

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• Cyanosis unrelieved by oxygen

• Hypotension / pallor or decreased peripheralperfusion.

• Periodic breathing with prolonged pauses

• Gasping with the use of accessoryrespiratory muscles.

Downes’ and Vidyasagar’s score describesa clinical scoring system which wassimultaneously compared with sequential arterialpH and blood gas measurements. The scoringsystem (Table 2) consisted of 0-2 numericalsgiven to 5 major clinical features, to provide thepediatricians who lack access to blood gasanalysis. It is a simple clinical scoring systemthat also provides a guide to treatment as well asprognosis. The score can also be used to predictthe inspired O2 concentration requirements.

A point to remember is that such clinicalscoring systems only provide an objective methodof assessment of respiratory distress and not afinal diagnosis.

Laboratory studies

Blood gases usually are obtained from eitheran indwelling arterial (umbilical) catheter or anarterial puncture.Blood gases can exhibitrespiratory and metabolic acidosis along withhypoxia.

- Respiratory acidosis occurs because ofalveolar atelectasis and / or overdistensionof terminal airways.

- Metabolic acidosis is primarily lacticacidosis, which results from poor tissueperfusion and anerobic metabolism.

- Hypoxia occurs from right-to-left shuntingof blood through the pulmonary vessels,PDA and / or foramen ovale. ‘Pulseoximetry’ is used as a noninvasive tool tomonitor oxygen saturation, which should bemaintained at 90-95%.

Table 1. Clinical entities leading torespiratory distress syndromeI. Obstructive airway disease

Congenital anomalies:1. Choanal atresia2. Laryngeal webs3. Laryngomalacia4. Tracheal aplasia / stenosis5. Tracheoesophageal fistula and esophageal atresiaExternal compression of the upper airway:1. Vascular ring2. Tumors and cystsTrauma:1. Post extubation laryngeal edema and subglottic stenosis2. Vocal cord paralysis3. Laryngeal fracture4. Tracheal perforation

II. Lung parenchymal diseasesCongenital anomalies:1. Lung cysts2. Congenital cystic adenomatoid malformation3. Congenital lobar emphysema4. Hypoplasia and agenesis of the lungs5. Chylothorax6. Congenital pulmonary lymphangiectasis7. Congenital stridorAcquired disorders:1. Transient tachypnea of newborn2. Hyaline membrance disease3. Meconium aspiration4. Pneumonia5. Bronchopulmonary dysplasia6. Pulmonary hemorrhage7. Wilson Mikity syndrome8. Pneumothorax and pneumomediastinum

III. Non-pulmonary causes1. Heart failure2. Intracranial causes3. Metabolic acidosis4. Shock5. Severe asphyxia6. Diaphragmatic hernia (congenital)7. Phrenic nerve paralysis8. Muscular disorders and weakness9. Chest wall deformity

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X-ray Chest

Radiology plays an important role in theevaluation of a sick neonate. The use ofimmobilisation techniques and fast exposuretime, has enabled efficient roentgenographicexaminations of the newborn.

Respiratory distress in a newborn can be dueto a variety of causes. ‘Hyaline membranedisease’ (HMD) is characterized byhypoventilated lungs. The lungs may appearhomogeneously dense to granular with airbronchograms, or almost normal. ‘Pulmonary airleaks’ may present as pulmonary interstitialemphysema, pneumothorax, pneumomedia-stinum and pneumoperitoneum. The “spinnakersail” sign of elevated thymus along with air inthe subcutaneous tissues of the neck is a classicradiologic feature of pneumomediastinum.Meconium aspiration causes typical changes inthe chest, i.e., hyperventilated lungs with coarsepatchy densities from meconium plugs or distalatelectasis. Air trapping by the lungs is thepredominant feature of ‘meconium aspiration’.Pneumonia may vary and lungs may show lobarconsolidation, small diffuse nodularity, coarsepatchy infiltrates, diffuse haziness or perihilarstreaks. Complications of pneumonia, such asabscess, empyema and pneumatoceles are amanifestation of staphylococcal, streptococcal or

Escherichia coli pneumonias. Multiple cysticlesions in the chest may be seen with congenitallung anomalies such as cystic adenomatoidmalformation and diaphragmatic hernia. Amediastinal shift may be seen in these conditions.Congenital lobar emphysema is often associatedwith adjacent lobar atelectasis and can bediagnosed by chest X-ray.

Indications for ventilatory supportin the neonate

The most common cause for beginningassisted ventilation in newborn is ‘respiratoryfailure’. This could take two forms; one is apneawhen ventilation is mandatory, as the patient isnot breathing. The other is when the mechanismof pulmonary gas exchange is impaired.

Types of respiratory support currentlyavailable for respiratory distress in neonatesinclude a) Continuous positive airway pressureand b) Mechanical ventilation

A. Continuous positive airwaypressure (CPAP)

When infants continue to exhibit respiratorydifficulty with increasing respiratory rate,retractions and grunting and require inspiredoxygen concentrations greater than 40%, theinfant should be supported with constant positiveairway pressure (CPAP) – Table 3.

Table 2. Clinical respiratory distress scoring system* (Downe’s andVidyasagar’s)

Score 0 1 2Respirations (rate/min) <60 60-80 >80 or apneaCyanosis None in room air In 40% O2 More than 40%O2

Retractions None Mild Moderate to severeGrunting None Audible with stethoscope Audible without

stethoscopeAir entry (N) Delayed or decreased Barely audible

*Score in normal infant=0. Score in infants with severe respiratory distress=10

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Indications for CPAP

• FiO2 > 0.4 to 0.5 (by O2 hood)*

• Frequent apnea with documentedhypoxemia**

• Clinically significant chest retractions afterrecent extubation from mechanicalventilation for RDS.

*Especially, in a preterm with RespiratoryDistress Syndrome (RDS)

** In practice, any baby with distress scoringmore than 3/10 on the Downe’s or SilvermanRespiratory distress score or requiring morethan 2-3 litres per minute of oxygen flow tomaintain SaO2 qualifies for CPAP therapy2,3.

CPAP aims to maintain a continuousdistending pressure to the alveoli duringexpiration to prevent them from collapsing.Thisis especially useful in treating babies with RDS,who have low functional residual capacity (FRC)and lung compliance(c).This helps in betterventilation perfusion matching (V/Q), anddecreases the frequency of apneic spells2. It alsoproduces a more regular breathing pattern inpreterms,helps splint the airway and diaphragm, reduces obstructive apnea and enhancessurfactant release in RDS.

Technique:CPAP through a ventilator or otherdevice e.g a CPAP driver is administered througha continuous flow of heated, humidified gas (air/oxygen mixture) at a set pressure of 3-8 cm H2Owhile the baby breathes spontaneously. It can bedelivered through nasal prongs, nasopharyngealtube or the endotracheal tube. The equipment issimple to use, is less invasive, causes lessbarotrauma than mechanical ventilation, has agreater cost benefit, and has a more universalapplication. Essentially, any CPAP deliverysystem consists of three components: A). Circuit

for continuous flow of inspired gases,which areoxygen and compressed air.B).Oxygen-airblender enables to deliver the appropriate FiO2.The rate of the continuous flow of inspired gas iscontrolled by a flow meter. The minimal flowrate required should be sufficient to preventrebreathing of carbon dioxide, i.e. atleast two andhalf times the infant’s minute ventilation, andshould also compensate for leaks aroundconnectors and CPAP prongs. Usually flow ratesof 5-10 (LPM) is sufficient in neonates.The gasesare warmed and humidified by an incorporatedheated humidifier prior to delivery to the infant.C).CPAP –Patient airway interface device: Nasalmasks, nasal cannula, single and binasal tubes/prongs of varying lengths ending at either nasalor nasopharyngeal level have been used asinterfaces.

The procedure is initiated by positioning theinfant in supine position with the head elevatedto about 30 degrees. Appropriate size nasal/nasopharyngeal cannula are chosen and aremoistened with sterile water or saline prior toinsertion and fixation.Nasal CPAP is preferred4,5.Endotracheal CPAP (ETCPAP) may increasedead space airway resistance thereby increasingthe work of breathing in small babies and henceis less preferred. Initial desired CPAP pressureis usually kept at 4- 5 cm H2O. The inspired gastemperature is kept at 36°C. After the CPAP isproperly applied, the infant should breathe moreeasily and the respiratory rate and retractionsshould decrease. The FiO2 should be adjusted tokeep the PaO2 between 50 and 70 mm Hg or SaO2at low 90’s. As the infant’s respiratory distressimproves, the FiO2 should be lowered graduallyin decrements of 2 to 5% while maintaining thePaO2 of 50 to 70 mm Hg. The CPAP pressure iskept at 5 cm H2O until the tachypnea andretractions become minimal or disappear. At thistime, the requirement of FiO2 should be in therange of 25% or even at the level of room air.

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The CPAP may then be discontinued. The CPAPcircuit should be changed at least once in 3 days.If the infant becomes tachypneic or is havingretractions, desaturations or frequent episodes ofapnea / bradycardia while off CPAP, the CPAPshould be reintroduced even though the infantmay be breathing room air and the signs ofrespiratory disease are minimal or no longerpresent. If CPAP of 6-7 cm H2O with FiO2 of0.5-0.6 is not sufficient to maintain SaO2, theinfant probably needs to be ventilatedmechanically.

Underwater “Bubble CPAP” has provided analternative to pressure derived from conventionalventilators. It is in use since first devised in the1970’s4. The bubble CPAP uses a column ofwater, in a bottle, to provide the positive airwaypressure rather than a variable resistor valve. Thelightweight corrugated expiratory limb tube,preferably with a heating wire inside, is insertedinto a bottle of 0.25% acetic acid solution orsterile saline with an antiseptic like povidoneiodine filled up to a height of 7 cm. The tubemust be immersed to a depth of 5 cm to create +5 cm H2O CPAP. In addition to providing positiveairway pressure, bubble CPAP results in smallvibrations in the infant’s chest at the frequencyof 15-30 Hz. Data in preterms ready forextubation suggest that in comparison withstandard CPAP, bubble CPAP reducesrespiratory rate and minute ventilationsignificantly without increasing PaCO2

3.Comparing underwater bubble ETCPAP withconventional ventilator derived ETCPAP inpreterms suggested that the bubbling alsocontributed to gas exchange3.

Prophylactic CPAP in absence of RDS: Thereis currently insufficient information to makerecommendations for the clinical practice ofprophylactic CPAP as in preterm infants it doesnot lead to a decreased incidence or severity of

RDS and does not reduce rate of complicationsor mortality6.

Early treatment of RDS with CPAP: Earlyrandomized trials evaluating the effect of CPAPversus no CPAP in the treatment of RDS7 showedthat it improved oxygenation, reduced the needfor subsequent mechanical ventilation andreduced the death rate. No effects on chronic lungdisease (CLD) was however demonstrated andCPAP was found to increase the incidence ofpulmonary air leak. Decreased cardiac output andshock can occur with prolonged CPAP due toincreased intrathoracic/intrapleural pressurecausing reduced systemic venous return3.

A recent multicenter controlled trial hasdemonstrated that early nasal CPAP incombination with early treatment with surfactant(Curosurf) significantly improved oxygenationand reduced the subsequent need for mechanicalventilation. Recent meta-analyses conclude thatCPAP is most beneficial early in established RDSand decreases the need for mechanical ventilationand may reduce mortality3,8.

CPAP following extubation: A recent meta-analysis of controlled trials9, concluded thatCPAP was effective in preventing failure ofextubation in preterms.

B. Mechanical ventilationAbsolute indications for mechanicalventilation

• Prolonged apnea• PaO2 < 50 mm Hg on an FiO2 > 0.8 (except

in cyanotic congenital heart disease)• PaCO2 >60mm Hg with persistent acidosis• Failure of CPAP at FiO2 > 0.6 to 0.7

Relative indications for mechanical ventilation• Frequent, intermittent apnea (unresponsive

to drugs)

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• To prevent deteriorating gas exchange withanticipatory early mechanical ventilation.

• To relieve the “work of breathing” in anewborn with signs of respiratory distress.

Ventilation modalities available -Intermittent Positive-Pressure Ventilation(IPPV)/Intermittent Mandatory Ventilation(IMV)

Positive pressure inflation of the lung duringa positive-pressure breath causes gas to flow intothe lung because airway pressure is greater thanalveolar pressure. The volume of gas enteringthe lung over timeperiod is a function of the Peakinspiratory pressure (PIP), inspiratory time (Ti),and respiratory system compliance andresistance. Most ventilators that are currently inuse in neonatal intensive care units are-timecycled and pressure limited in which PIP,Positive End-Expiratory Pressure (PEEP),inspiratory time (Ti) and expiratory time (Te) areadjusted independently. The rate [breaths perminute, (BPM)] is altered by changing Ti or Teor both. Continuous flow of fresh air-oxygenmixture enables babies to breath spontaneouslybetween ventilator derived breaths (IntermittentMandatory Ventilation, IMV).

Mean airway pressure (MAP) is ‘theaverage’ pressure at the proximal airway overtime,if the inspiratory pressure waveformresembles a square wave. An understanding ofthe basic pathophysiology of the underlyingrespiratory disorder is essential to optimize theventilatory strategy. For example, RespiratoryDistress Syndrome is characterized by lowcompliance and low FRC. The ‘time constant’of the respiratory system is proportional to thecompliance and the resistance and is a measureof the time necessary for the alveolar pressure toreach 63% of the change in airway pressure.Lungs with decreased compliance (eg, in RDS)have a shorter time constant and hence complete

inflation and deflation occurs faster than normallungs. Increasing the MAP increases PaO2 ininfants with lung disease. MAP is a function ofPIP, PEEP, and Ti. Hence, increasing MAP byincreasing PIP increases the driving pressure forgas flow into poorly ventilated lung units.Increasing MAP by increasing Ti allows moretime for gas to distribute to these units andincreasing MAP by increasing PEEP splints thesmall airways open, decreases airway resistance,decreases the time constant for inspiration, andallows more gas to enter the lung unit for anygiven PIP or Ti. All three techniques improveventilation to the poorly ventilated lung units andincrease their PaO2. However for a given increasein MAP, increasing PEEP or PIP results in agreater increase in PaO2 than increasing Ti.

Changes in PIP affect both PaO2 (by alteringMAP) and PaCO2 (by its effects on tidal volumeand alveolar ventilation). Therefore, an increasein PIP improves oxygenation and decreasesPaCO2. A high PIP may however increase therisk of barotrauma with resultant air leaks andchronic lung disease (CLD). A useful clinicalindicator of adequate PIP is a gentle chest risewith every breath, though presence of breathsounds is not very helpful in determining optimalPIP. Absent breath sounds however, indicateinadequate PIP (or a blocked and/or displacedETT or even ventilator malfunction). Theminimum possible effective PIP should be usedand frequent changes in PIP in the presence ofchange in pulmonary mechanics are oftennecessary.

Adequate PEEP helps to prevent alveolarcollapse, maintains lung volume at end-expiration, and improves V/Q matching.Increases in PEEP usually increase oxygenationassociated with increase in MAP. However, inneonates, a very elevated PEEP (>5-6 cm H2O)may not improve oxygenation any further and,in fact, may decrease venous return, cardiac

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output, and oxygen transport. High level of PEEPalso may decrease pulmonary perfusion byincreasing pulmonary vascular resistance. Whileboth PIP and PEEP increase MAP and mayimprove oxygenation, they have opposite effectson PaCO2. With RDS, an improvement incompliance occurs with low levels of PEEP,followed by a worsening of compliance at higherlevel PEEP (>5-6 cm H2O). A minimum PEEPof 2-3 cm H2O atleast is recommended duringIMV, since endotracheal intubation eliminates theattempt to maintain FRC by vocal cord adductionand closure of the glottis (grunting) in neonateswith RDS.

Changes in frequency (BPM) alter alveolarminute ventilation and, thus, PaCO2. Increasesin rate and, therefore in alveolar minuteventilation decrease PaCO2 proportionally, anddecreases in rate increase PaCO2. Frequencychanges alone usually do not alter MAP norsubstantially alter PaO2. Changes in inspiratorytime however that accompany frequencyadjustments may change the airway pressure

waveform and thus alter MAP and oxygenation.Generally, a high-rate, low-tidal volume strategyis preferred in RDS. A long inspiratory timeincreases the risk of pneumothorax as it resultsin alveolar overdistention. There is a higherincidence of pneumothorax in infants ventilatedwith a long Ti than in those ventilated with a shortTi. As the ventilator rate increases, the absolutetime allotted for expiration decreases. If Tedecreases to less than three time constants forexpiration, gas trapping and alveolaroverdistention may occur1,7,10,11.

The major effect of an increase in theinspiratory-to-expiratory (I/E) ratio is to increaseMAP and thus improve oxygenation. However,when corrected for MAP, changes in the I/E ratioare not as effective in increasing oxygenation asare changes in PIP or PEEP. A reversed I/E ratioas high as 4: 1 has been demonstrated to beeffective in increasing PaO2 which however maycause adverse effects of airleaks.

Changes in fraction of inspired oxygen(FiO2) alter alveolar oxygen pressure and thus

Table 3. Suggested Guidelines for Management of neonates with RespiratoryDistress

S.No. Condition of Infant Score(Downe’s) Management1 Severe retractions >6 Initiate

Apnea MechanicalRequires O2>60% Ventilation withChest X-ray (Extensive lesion) IMV

2 Spontaneous breathing >3-6 Initiate CPAPMild-moderate retractionsRequires 40%-60% O2

Chest X-ray mild to moderate changes3 No retractions 0-3 Initiate O2 by hood

Pink in 40% O2

R 40-60 / minX-ray normal to mild abnormality

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oxygenation. Because FiO2 and MAP determineoxygenation they can be adjusted alternatingly.During increasing support, FiO2 can be increasedtill about 0.6-0.7, when further additionalincreases in MAP are required. During weaninghowever, FiO2 needs to be decreased to about0.4 before reducing MAP. Oxygen-air flow ratesof 5-12 L/min are sufficient in most newborns,depending on the mechanical ventilator and ET-tube being used.

Hypercapnia usually is caused byhypoventilation or severe V/Q mismatch.Adequate ventilation is indicated by PaCO2 whichis equal to the rate of CO2 production divided bythe alveolar ventilation (VA).The latter isrepresented by the equation VA = (VT - VD) XRR, (VT- tidal volume, VD- dead space volume,and RR- respiratory rate). Elimination of carbondioxide from the alveoli is directly proportionalto alveolar minute ventilation which is affectedby tidal volume. PaCO2 decreases if either RR orVT is increased and PaCO2 increases if RR orVT is decreased. On a pressure-limited ventilatorat a constant Ti, the VT is determined by the lungcompliance and by PIP and PEEP. PaCO2 can bedecreased by increasing RR, by increasing PIP,or by decreasing PEEP.

Ventilation strategy in variousnewborn disease states

Respiratory failure can result fromnumerous illness due to varied patho-physiological mechanism. Hence the ventilatorystrategy should take into account thepathophysiology and nature/course of the disease.

1. Respiratory Distress Syndrome (HyalineMembrane Disease) (RDS):

In RDS there is severe decrease incompliance and stiff lungs. This causesdiffuse alveolar collapse and serious V/Qmismatching. Ventilation is needed in severe

RDS unresponsive to CPAP requiring highFiO2 and in babies who tire from theincreased work of breathing. The currentapproach is to use rapid ventilator rates (60-80 breaths/min) while reducing peakpressure (PIP) to a minimum with lowinspiratory times (Ti 0.3 to 0.4 secs). ThePEEP is kept about 4 to 5cm H2O. InitialPIP settings are based on auscultation ofgood breath sounds and observation of goodchest wall movements and are increased ifrequired. Usually, weaning is initiated afteratleast 48-72 hours by decreasing thepressure first and then rate and then FiO2.Extubation to head box O2 or CPAP is donewhen there is evidence of improvement inlung compliance and decrease in work ofbreathing with good blood gases achievedthrough spontaneous breathing. Highfrequency ventilation is resorted to in caseconventional ventilation fails to maintain gasexchange.

2. Meconium Aspiration syndrome: Aspiratedmeconium causes acute airway obstruction,increased airway resistance, patchyatelectasis with V/Q mismatching andhyperexpansion due to partial airwayobstruction with ‘ball valve effect’.Ventilatory strategy aims to keep pressuresmoderate, rates slow and PEEP low (4-5 cmH2 O) so as to prevent pneumothorax and tokeep open the partially obstructed airways.Rapid rates can be used if a secondaryinflammatory penumonitis develops later. A“hyperventilation” strategy is adopted forbabies developing Persistent PulmonaryHypertension (PPHN) associated with severeMAS. This entails using high rates upto 120breaths/min with low inspiratory times (0.25to 0.3 secs) to keep the PaCO2 in the rangeof 25 to 30mm Hg in order to promotepulmonary vasodilation. Big babies withsevere meconium aspiration may require

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sedation and paralysis to prevent them“fighting” the ventilator and thereby causingpneumothorax or other air-leaks.

3. Airleaks, Pneumothorax and PulmonaryInterstitial emphysema (PIE): Thesedisorders seriously reduce lung compliance.Hence the ventilatory goal is to reduceairway pressure by reducing peak inspiratorypressure, inspiratory time or PEEP and togive a high FiO2 to improve oxygenation.This prevents air from being driven into theinterstitium with each cycle. Very rapidrates. 80-120 breaths/min may be tried.High frequency ventilation (HFV) is a goodalternative to deal with this problem.

4. Apnea due to any cause: Apnea may requireventilatory support if recurrent or prolonged.The aim here is to provide a near physiologicrespiration using 30-40 breaths/min, lowPEEP (4-5 cm H2 O) and PIP (12-18 cmH2O). This strategy reduces risk ofbarotrauma.

5. Severe asphyxia, severe sepsis and shock:The aim in these conditions is to stabilizethe respiratory parameters of the neonatethrough appropriate ventilatory techniquesand to prevent hypoxia and acidosis. Ratesof 40-60 breaths/min with the least possiblepressures (PIP-18-20) are used to maintainadequacy of gas exchange till the neonate’sprimary problem stabilizes. Increase inpressures, PIP alongwith higher PEEP inthe range of 7-9 cm H2O may be warrantedsometimes when the baby’s lungs becomepoorly compliant with features of ARDS.

6. Pulmonary hemorrhage: In acute pulmonaryhemorrhage the strategy would be to keepthe PEEP as high as possible to the tune of8-10 cm Hg initially till the active bleedingstops and then gradually bring it down to6-7 cm H2O after a few hours. Endotrachealsuctioning is to be avoided.

7. Pneumonia: In severe respiratory infections,the decision to ventilate babies is based onthe same principles as outlined above.Ventilation strategy is to use the minimalpossible pressures to achieve adequateoxygenation as well as ventilation. Short Tiis preferred.

In many conditions other than RDS,e.g.Pneumonias, Meconium Aspiration,Pulmonary hemorrhage etc.,exogenoussurfactant replacement can be tried withgood results.

Respiratory care strategy inNeonates with Respiratory Distress

A plan, as is followed in our unit, forintervention using routinely availableconventional respiratory supports in neonateswith respiratory failure is outlined below. Onceintubated,initial settings for IMV could be aimedat keeping the ventilator rates about 60 BPM,PIPof about 18-20 cm H2O,PEEP of 4-5 cm H2O andTi of 0.3-0.5 with FiO2 about the same as whatwas required during CPAP or oxygen giventhrough hood.It is desirable to hand-ventilate thebaby initially to determine the minimal PIPnecessary to achieve good chest wall excursion ,good bilateral breath sounds and good SaO2. Afterrecovery from the initial stress of intubation ifthe infant still requires FiO2> 0.4 or A/a ratio< 0.22 and the chest x-ray is compatible with RDS(HMD), exogenous surfactant should be given.We would prefer to give exogenous surfactanteven in congenital pneumonias, pulmonaryhemorrhage and bad meconium aspirations.Because tiny preterm babies with weight <1250g., have structurally immature lungs and weakchest walls with poor respiratory drive, it ispreferred to routinely provide some form ofrespiratory support i.e., nasal CPAP or maybeeven IMV electively from birth in them. Forbabies who weigh between 1250 and 1500 g andhave RDS, mechanical ventilatory assistance

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may also be needed. An optimal conventionalventilation strategy suggested for any conditionis by using the lowest PIP possible ,modest PEEP(3-5 cm H2O), mild permissive hypercapnia(paCO2 45-60 mm Hg), judicious use of sedation/paralysis, and aggressive weaning. Blended air/oxygen mixture should be delivered warmed andhumidified to prevent excessive water loss fromthe respiratory tract and injury to the lung. Thetarget range for oxygen is SaO2 of approximately88% to 96%. Assuming modest permissivehypercapnia is not harmful, the PaCO2 should beapproximately 40 to 55 mm Hg in most patientswithout pulmonary interstitial emphysema, grossair leak, hyperinflation, or chronic changes onchest radiograph. Higher PaCO2 values may betolerated in patients with these complications. Inmost patients, arterial pH should be at least 7.25,although pH in the range of 7.20 to 7.25 may beacceptable.At lower pH, the PaO2 has to be higherto maintain adequate oxygen saturation. Trachealsuctioning and chest physiotherapy should beminimized in infants with RDS in the first fewdays after birth because secretions are scant, andthere is little evidence that suctioning and chestphysiotherapy are of benefit as theseinterventions also might increase the risk ofIVH1. Suctioning is often associated with acuteside effects of hypoxia, hypertension, andbradycardia1,7. Using optimal conventionalventilation strategy for neonates with variedproblems, and applying similar principles ofrespiratory care has shown good outcomes, asfrequently reported in the Indian literature as well.

Adjuncts to ventilation: During ventilation,sedation can be used to reduce agitation ordistress or a tendency to “fight” the ventilator.This may help in better oxygenation9,10.Morphine, Lorazepam, Fentanyl and short actingbenzodiazepines like Midazolam in a continuousIV infusion have been tried. Muscular paralysiswith pancuronium bromide may be indicated insome babies who tend to breathe out of phase

with the ventilator and thus “fight” the ventilator.Gas exchange probably is facilitated with the useof muscle relaxation. But this may result indecreased dynamic lung compliance andincreased airway resistance and removes anycontribution of the infant’s own respiratory effortfrom tidal breathing, often necessitating increasein ventilator pressures.Venous return is alsoimpaired by lack of movement and decreasedmuscle tone therefore causing generalized edema.Pancuronium seems to have a favourable effecton IVH and airleaks in ventilated preterms withevidence of asynchronous respiratory efforts12.

Monitoring and supportive care duringventilation: Needless to say, proper ventilatorycare demands continuous monitoring of all vitalparameters-BP (intra-arterial preferred), arterialblood gases through indwelling arterial catheters,pulse oximetry (to determine SaO2 continuously),transcutaneous pO2/pCO2 and capnography inaddition to various biochemical, hematologicaland microbiological parameters. Supportivetherapy is required to minimize the work ofbreathing,heat losses,and to provide adequatefluids and calories.Good neonatal respiratoryand nursing care are the essential tools forimproved survival7,10,11. Supportive therapyincludes the following:

- Temperature regulation: Hypothermiaincreases oxygen consumption, therebyfurther compromising infants withrespiratory distress,especially who are bornprematurely. Therefore prevent hypothermiain infants during delivery, resuscitation, andtransport. Care for these infants in a thermo-neutral environment with the use ofincubators or radiant warmers.

- Fluids, electrolytes and nutrition: In infantswith respiratory distress, initially administer5% or 10% dextrose intravenously at60-80 ml/kg/day. Closely monitor bloodglucose, electrolytes, calcium, phosphorous,

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renal function and hydration (determined bybody weight and urine output to prevent anyimbalance). Add calcium at birth to the initialintravenous fluid. Start electrolytes as soonas the infant voids and as indicated byelectrolytes. Gradually increase the intakeof fluid to 120-140 mL/kg/day. Extremelypremature infants occasionally may requirefluid intake of as much as 180 ml/kg/day.Once the infant is stable, add intravenousnutrition with amino acids and lipid. Afterthe respiratory status is stable, initiate a smallvolume of gastric feeds (breast milk) via anasogastric tube to initially stimulate gutdevelopment and thereafter to providenutrition as intravenous nutritional supportis being decreased.

- Circulation and anemia: Assess the baby’scirculatory status by monitoring heart rate,peripheral perfusion, and blood pressure.Administer blood or volume expanders anduse vasopressors (eg. Dopamine) to supportcirculation. Monitor blood withdrawn forlaboratory tests closely in tiny infants andreplace the blood by packed cell transfusionwhen it has reached 10% of the infant’sestimated blood volume or if the hematocritlevel is less than 40 - 45%.

- Antibiotic administration: Start antibiotics inall infants who present with respiratorydistress at birth after obtaining blood culturesand discontinue antibiotics after 3-5 days ifblood cultures are negative.

- Support of parents and family: Often parentsundergo much emotional and / or financialstress with the birth of a critically ill infantand its associated complications. The parentsmay feel guilty, be unable to relate to theinfant in the intensive care setting, and beanxious about the prognosis for the infant.In addition, the infant may provideinadequate cues to arouse mothering. These

factors interact to prevent maternal-infantbonding. Hence, provide adequate supportfor these parents and other family membersto prevent or minimize these problems.

Weaning from ventilation

Weaning newborn infants from mechanicalventilation is an involved process which takesinto account a number of physiological,mechanical and pharmacological factors. Infantsmust exhibit a reliable respiratory drive, displayneuromuscular competence and be able toovercome the respiratory system load whilemaintaining oxygenation and minute ventilation.Close attention to spontaneous tidal volumes andrespiratory frequency helps.It is important toensure proper nutrition status and observe forconditions or complications like infection,neurologic dysfunction, neuromusculardisease,metabolic alkalosis, congestive heartfailure and anemia that might impede successfulweaning and extubation and may depressspontaneous breathing.

For larger infants, weaning down on ratesto 5-10 BPM or short period of ETCPAP maybegin when PIP has been stable at less than 16-18 cm H20 and FiO2 is less than 0.30 for at least24 hours and a good respiratory drive has beendemonstrated.Later, extubating/depronging to anoxygen hood when the infants require less than4 cm H2O of CPAP is done. For infants weighingless than 1750 g, when PIP requirement is lessthan 13-15 cm H2O and FiO2 is less than 0.30, itis possible to decrease the respiratory rate to 15-20 BPM gradually and then to wean directly tonasal CPAP .For this group of infants, theresistance of the endotracheal tube is such thatthe periods of ETCPAP or ventilatory rates lessthan 15 BPM cannot be tolerated for long. Itwould seem likely that nasal CPAP would bemost useful for extubation of infants <1750 g3.Randomized study has shown that there is noadvantage of either method in infants with acute

25


or chronic respiratory distress. Approximatelyone-third of its patients required re-intubationwithin 48 hours of extubation regardless of whichextubation method was used3. Physiotherapyprior to extubation has been shown in aretrospective and prospective controlled study3

to reduce postextubation atelectasis.There is noevidence either supporting or refuting the use ofinhaled nebulized racemic epinephrine inextubation13.

Complications of ventilatory therapy

Prolonged orotracheal intubation may causepalatal grooving which may interfere withdentition whereas nasotracheal. intubation mayresult in cosmetic deformities of the nose andeven nasal obstruction. Subglottic stenosis,although rare, can be a disastrous complicationof intubation. A too snugly fitting endotrachealtube, duration of intubation, and number ofreintubations all correlate with subsequentsubglottic stenosis. Necrotizing tracheo-bronchitis, a necrotic inflammatory processinvolving the trachea and mainstem bronchi hasbeen described in newborns requiring mechanicalventilation. Atelectasis occasionally occurs afterextubation from mechanical ventitation, with theright upper lobe most commonly affected1,7. Gastrapping during mechanical ventilation maymanifest as decreased tidal volume, carbondioxide retention, and/or lung hyperexpansion.A short expiratory time, a prolonged timeconstant, or an elevated tidal volume can resultin gas trapping. Although PaO2 may be adequateduring gas trapping, venous return to the heartand cardiac output may be impaired; thus, oxygendelivery can be decreased. Acute airleaks ofcourse may cause catastrophic deterioration,intraventricular hemorrhage (IVH) and even riskto life.

Ventilators used in newborn practice

Ventilation is achieved usually by the use

of intermittent positive pressure. Severalparameters are used to define and classify“positive pressure ventilators”. Most classifi-cations are based on the mechanism by whichthe machine enters its inspiratory phase.‘Negative pressure ventilators’ on the other handprovide assisted ventilation without endotrachealintubation, thus avoiding airway trauma andreducing the risk of infection, atelectasis andairleaks. However, the device entails enclosingthe baby from the neck down, in a close fittingair tight compartment which makes the patientinaccessible for routine procedures, x-rays, etc.and disallows proper observation.Hence thismodality is not in favour currently.

The positive pressure ventilators currentlyavailable include

1. Pressure limited time cycled continuousflow ventilators: These are used mostfrequently in neonatal practice. Examplesare Sechrist IV-I 00, Health Dyne 100,Infant Star, Bournes BP 200, Bear Cub,VIP Bird, and Baby bird ventilators. Acontinuous flow of heated and humidifiedgas is circulated past the infant’s airway. Therate and duration of inspiration(Ti) andexpiration(Te) are preselected. MaximumPeak Inspiratory pressure (PIP) and PositiveEnd-Expiratory Pressure (PEEP) can be setaccording to the babies need. The systemis simple to operate and can maintaingood control over respiratory pressures.Continuous flow enables successfulspontaneous respiratory efforts betweenventilator breaths (Intermittent MandatoryVentilation,IMV). However, there is verypoor control over the tidal volume delivered.Recent ventilators have an optional ‘patienttriggering device’ in order to giveSynchronised IMV(SIMV) to the baby inphase with the baby’s own respiratoryeffort.

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2. Volume Cycled Ventilators: Less frequentlyused in newborns, as the tidal volumes ininfants are small and most of the selectedtidal volume is lost in the ventilator circuitor from airleaks around the uncuffedendotracheal tubes. Also, high pressuresgenerated can cause airleaks as there is nocontrol .

3. High Frequency Ventilators: These are ofthree types: a). High Frequency Oscillators(HFO) b). High Frequency Jet Ventilators(HFJ). C). High Frequency Flow Interrupters(HFFI). These machines deliver extremelyrapid rates (300 to 1500 breaths/min, 50 to250 Hz) with the tidal volume often smallerthan ‘dead space’. The exact physiology ofgas exchange mechanism with these is notwell characterized though these machinescan achieve adequate ventilation at lowerpressure. They are more expensive andcomplex in their use.

Dozens of neonatal ventilators/modes areavailable today, each proclaiming to be better.But no one ventilator is really perfect for everytype of respiratory pathology.

New ways to ventilate neonates

High Frequency Ventilation(HFV): Threetypes of HFV are under current use ie. highfrequency oscillation (HFO), high frequency jetventilation (HFJ) and high frequency flowinterrupted ventilation (HFFI). High-frequencyventilation (HFV) has evolved to be anestablished method of treating neonates withrespiratory failure. Controversy howeverremains about when and how HFV should beused. Some use it as a primary mode of ventilationfor infants who require ventilatory support,whereas at the other extreme are those who viewit strictly as a rescue technique. Others use HFVin an early rescue manner in babies at high riskfor complications , or those who have developed

air leak, even if they are maintaining adequategas exchange on conventional ventilation.

The High Frequency Jet Ventilator (HFJV)delivers short pulses of heated and humidifiedgas at high velocity to the upper airway througha narrow injector lumen in a special 15-mmendotracheal tube adaptor that eliminates theprevious need for reintubation with a triple lumenendotracheal tube. Pulses of high-velocity gasstream down the center of the airway, penetratingthrough the dead-space gas, whichsimultaneously moves outward along theperiphery of the airway. Enhanced moleculardiffusion probably plays an important role in thegas exchange occurring in the distal airways andalveoli. The measured airway pressure is used toservocontrol the driving gas pressure andmaintain the desired peak inspiratory pressure.When desired, a conventional ventilator used intandem also provides ‘intermittent sigh breaths’in the form of background IMV breaths, typicallyat a rate of 2 to 10 BPM. The amplitude of theHFJV breaths is determined by the differencebetween the jet peak inspiratory pressure and theconventional ventilator PEEP.

The High Frequency Oscillatory Ventilator(HFOV) generates a quasi-sinusoidal pressurewave with a diaphragm driven by anelectromagnet. By varying the power applied tothe magnet, both the excursion of the diaphragmand the frequency at which it moves can beadjusted. The sinusoidal pressure wave that isgenerated by the diaphragm is transmittedthrough the airways to the alveoli. The HFOVbreaths are characterized primarily by theirfrequency, amplitude and the MAP. All three ofthese parameters can be independently adjusted.In addition, the bias flow and I/E ratio can beadjusted.

The High Frequency flow Interrupter (HFFI)is designed around microprocessor controlled

27


solenoids that open and close at high frequencies.The opening and closing of these solenoidsgenerates a pulse of high velocity gas, which istransmitted down the airways. The pulse of gasalso leads to a small recoil in the ventilator circuitthat leads to an active expiratory phase.

Physiology of high frequency ventilation: In allthree modes of HFV,the volume of individualbreaths delivered are near, or even less than thedead-space volume. Additionally, gas exchangepartly occurs by ‘enhanced molecular diffusion’resulting from increased mixing of gases in theairways. The exact mechanisms by which thishigh-frequency mixing occurs has been mostthoroughly studied with HFOV. The mechanismswhich are named, bulk flow, Pendelluft, Taylor-type dispersion, and radial diffusion, are welldescribed. In simple terms, one can think of thesesmall rapid breaths as shaking the gas in theairways and the alveoli, causing extremelyefficient mixing between the fresh gas deliveredto the upper airway and the gas at the alveolarsurface.

High-frequency ventilators, help improveboth oxygenation and ventilation. IncreasingMAP with any HFV results in improvedoxygenation. The relationship betweenventilation (CO2 removal) and ventilator settingsis more complex for HFV than it is forconventional ventilation. With conventionalventilation, CO2 removal is proportional toalveolar minute ventilation . With HFV however,CO2 is removed largely by the extremely efficientmixing of gas in the airways, also referred to asenhanced diffusion. An important differencebetween HFV devices and conventionalventilators is the relationship between thepressure amplitude measured at the hub of theendotracheal tube and the pressure amplitude thatis delivered to the alveoli. With conventionalventilation, pressure applied at the airwayopening is fully transmitted from the upper

airway to the alveoli. As rates increase with aproportional decrease in inspiratory andexpiratory time, there is insufficient time withinthe respiratory cycle for the pressure toequilibrate fully, leading to gas trapping or‘inadvertent PEEP’. With HFV, gas exchangeoccurs predominantly by enhanced diffusion andthe pressure amplitude or volume delivered tothe alveoli is significantly less than the amplitudemeasured at the airway opening. The optimalrange of frequencies selected for HFV isdependent on both the size of the patient and thepatient’s intrinsic lung mechanics. In general, thesmaller the baby, the higher the optimalfrequency, and vice versa. Short time constantsituations with poor compliance like in RDS canbe ventilated effectively at higher frequenciesthan those with longer time constants.There isno simple way to calculate ideal HFV frequencyfor each individual patient,and is based on clinicalexperience .

Ventilatory strategies of highfrequency ventilation

The greatest advantage HFV offers is theability to achieve uniform lung expansion and tosupport a patient at higher mean airway pressureswithout excessive tissue stretching andoverexpansion.

Initial settings on the HFOV could havemean airway pressure at least 2 cm H2O greaterthan the MAP the patient was receiving onconventional ventilation, frequency of 8 to 10Hz,and amplitude (AP) adjusted based onadequacy of chest wall movement orimprovement in transcutaneous PCO2 monitored.The PEEP is increased to the range of 6 to 8 cmH2O, depending on the degree of atelectasis andoxygen requirement.Inadequate PEEP hasaffected effectiveness of HFV in RDS. HFVallows use of higher mean and end-expiratorypressure safely, because of the lower AP.Background IMV at a rate of two to ten breaths

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per minute is initiated with an inspiratory timeof 0.4 to 0.5 seconds. The PIP is initiallymaintained at the original value on both the HFVand conventional ventilation to achieve alveolarrecruitment. Within a few minutes on HFV,however, the improved lung expansioncommonly results in better lung compliance. Ifthis occurs, the PIP should be lowered promptlyby 10% to 20% to avoid overventilation. Furtherweaning of PIP should be guided by adequacyof chest wall movement or transcutaneous PCO2monitoring.

Because optimizing lung inflation is a keypart of the strategy of HFV, patients on HFVusually need fairly frequent chest radiographs.The magnitude of mean airway pressureadjustment should be proportional to the degreeof underinflation or overinflation. At a givenfrequency, PaCO2 is primarily determined byHFV amplitude. Once a frequency appropriatefor the infant’s size and clinical condition ischosen, changes in frequency should only bedone if there is reason to believe that the timeconstants/compliance have changed. Adjustmentof amplitude are helped through seeing adequacyof chest wall movement or transcutaneous PCO2monitoring, in addition to blood gases. Oncestable, weaning should be attempted on a regularbasis though it is important to avoid causingsudden atelectasis by dropping MAP below thecritical closing pressure of the lungs. The FiO2should be weaned first in response to goodoxygenation. In most cases, MAP should not beweaned until the FiO2 is less than 0.4. Inadvertentdrop in MAP can be avoided by simultaneouslyincreasing the PEEP as needed .

After consideration of all initial trials, itseems reasonable to conclude that HFV shouldnot be used for the initial treatment of neonateswith any respiratory failure.Meta-analysis datadoes confirm this as well14. In preterms managedwith exogenous surfactant; there is no conclusiveevidence that HFV reduces the incidence of CLD,

and there is certainly no evidence that it affectsthe mortality of infants with RDS. Shouldconventional ventilation and surfactant fail,however, HFV is a reasonable form of rescuetherapy.

Patient-Triggered Ventilation (PTV)

It is well documented that neonates dofrequently make spontaneous breathingmovements while being mechanically ventilated.Those who actively expire against positivepressure inflations develop pneumothoraces,Such asynchrony may reduce the effectivenessof the ventilator, increase the work of breathing,and enhance the risk of barovolutrauma to thelung. It can also accentuate the negativecardiovascular effects of positive pressureventilation15. In contrast,blood gases improvedin those who breathed synchronously with theirventilator (i.e., the beginning of inspirationcoincided with the onset of each positive pressureinflation [synchronized ventilation).Synchronization could be achieved by increasingthe ventilator rate to match the baby’s respirationpattern or by reducing the inspiration time thoughthis is not always successful. An alternativemethod to achieve synchronization is to use theinfant’s own respiratory efforts to trigger thedelivery of positive pressure inflations such thatthey arrive at a defined point in the infant’srespiratory cycle (Patient-Triggered Ventilation,[PTV]).

Triggering devices used for PTV: Thetriggering device senses the infant’s respiratoryefforts and the signal from the triggering deviceis then fed to the ventilator such that it triggers apositive pressure inflation. The signal from a‘Graseby respiration monitor’, which detectedthe neonate’s respiratory efforts by changes inabdominal movement triggering a neonatalpressure capsule,was first used as a trigger device.The signal from the pneumatic capsule has alsobeen used to trigger ventilator breaths delivered

29


by nasopharyngeal prongs. Other triggeringdevices are now used ; most of these sensechanges in airflow or airway pressure duringinspiration. This technology achieves a greaterdegree of synchrony between the infant’sbreathing and the ventilator, and this mayimprove oxygenation if the infant’s breathing waspreviously asynchronous.

Patient- triggered ventilation (PTV) is used in twomodes: (1) In Synchronized IntermittentMandatory Ventilation (SIMV), a single triggeredbreath is given in equal windows of time, withthe other patient breaths in each window notassisted; this means that the rate can be slowlyreduced during weaning with all assisted breathswell synchronized. (2) In Assist/Control Mode(A/C), all breaths are triggered, so that the babycontrols the ventilator rate, and weaning isaccomplished by reducing the PIP gradually. Anumber of different advantages to these systemshave been suggested, but perhaps the mostpromising is a reduction in cerebral blood flowvariability.The major benefit of PTV is thatweaning from the ventilator is facilitated.).

Nasal Ventilation

The evidence for the use of IPPV, SIMV,or HFOV delivered by ‘nasal prongs’ is yetinconclusive and it is not possible to concludethat these modes are useful. Randomised trialscomparing nasal IPPV and nasal CPAP forapnoea of prematurity have yielded conflictingresults. Data from meta-analysis showed nodifference in carbon dioxide levels after four tosix hours of support, and trials did not report ongastrointestinal complications15, although anassociation between the use of ventilation throughnasal prongs and increased risk of gastro-intestinal perforation had been previously noted.

Conclusion

The rationale to use any form of assistedventilation should be to optimise patient-

ventilator synchronisation, improve patientcomfort, facilitate or reduce the duration ofventilation, and avoid undesirable respiratory/cardiovascular consequences. Newer ventilationmodes should only be introduced into routinepractice when proved efficacious in appropriatelydesigned studies and no adverse outcomes havebeen identified by long term follow up. It isimportant to realise that improper andunwarranted use of ventilators can be detrimentalto sick babies and ventilators if usedpromiscuously can be worse than the disease. Itis essential to hence entrust ventilatory care tothe experienced and knowledgeable.

References

1. Gomez M, Hansen T, Corbet A. Principles ofrespiratory monitoring and therapy, in Avery’sDiseases of the Newborn. Seventh edition,1998; 576-594.

2. Saunders RA, Milner AD, Hopkin IE. Theeffects of continuous positive airway pressureon mechanics and lung volumes in the neonate,BioI Neonate. 1976;29(3-4):178-86.

3. Sahni R and Wung JT. CPAP-A gentler,noninvasive approach to managing neonatalRDS. Journal of Neonatology.2001;15 (4),Oct.-Dec.,21-33.

4. Wung JT, Driscoll JM, Epstein RA, Hyman AI.A new device for CPAP by nasal route. CritCare Med 1975;3:76-8.

5. Aly HZ. Nasal prongs continuous positiveairway pressure:a simple yet powerful tool.Pediatrics 2001;108(3):759-761

6. Subramaniam P, Henederson-Smart DJ, DavisPG. Prophylactic nasal continuous positiveairway pressure for preventing morbidity andmortality in very preterm infants (CochraneReview). In The Cochrane Library, Issue4,2001. Oxford.

7. Karthik Nagesh.N ,Ventilatory Therapy in theNeonate – Current Concepts and NewerModalities; Perinatology, 1999,Vol.2(I):23-28.

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8. Verder H, Albertsen P, Ebbesen F, Greisen G,Robertson B, Bertelsen A, et al. Nasalcontinuous positive airway pressure and earlysurfactant therapy for respiratory distresssyndrome in newborns of less than 30 weeks’gestation. Pediatrics. 1999;103(2):E24.

9. Davis PG, Henderson-Smart DJ. Nasalcontinuous positive airway pressureimmediately after extubation for preventingmorbidity in preterm infants (CochraneReview). In The Cochrane Library, Issue 4,2001. Oxford.

10. Goldsmith JP, Karotkin EH. Introduction toassisted ventilation. In: Assisted Ventilation ofthe Neonate,3rd ed, W.B. Saunders Company,1996;1.

11. Eichenwald EC. Mechanical Ventilation. In:Manual of Neonatal Care, 4th edn, Lippincott –Raven 1998. 337.

12. Cools F. Offringa M TI ;Neuromuscularparalysis for newborn infants receivingmechanical ventilation. Cochrane Database ofSystematic Reviews. 2000 ,(4):

13. Davies MW,Davis PG.Nebulized racemicepinephrine for extubation of newborn infants,In the Cochrane Library of systematic reviews,2001.

14. Bhuta T. Henderson-Smart DJ TI. Rescue HighFrequency Oscillatory Ventilation VersusConventional Ventilation For PulmonaryDysfunction In Preterm Infants.CochraneDatabase of Systematic Reviews. 2000.

15. Greenough A. Update on modalities ofmechanical ventilation, Arch Dis Child FetalNeonatal Ed. 2002;87:F3-F6

WORKSHOP AND 12TH ANNUAL CONFERENCE OF ASSOCIATION

OF PEDIATRIC OTOLARYNGOLOGISTS OF INDIA

Date: 25th and 26th February 2006

Venue: New Delhi.

Contact:

Dr.Neeraj N Mathur173, AGCR EnclaveDelhi – 110 092.Ph: (91 11) 23408292, 23363728Extension 8292 (O), (91 11) 22378498, 22379890 (R)Mobile: 9811109637Fax: (91 11) 22549102 C/O Dr.MathurEmail: [email protected] of Conference: http://apoil2.free-webpage.org

NEWS AND NOTES

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FEEDING THE LOW BIRTHWEIGHT BABY

Sheila Samanta Mathai

Abstract: Feeding the Low Birth Weight (LBW)baby is a nutritional challenge. Breast milk feedsshould be started as soon as possible after birth.In babies more than 1500 grams full feeds shouldbe achieved in 5 days. In smaller, stable babiestrophic feeds with expressed breast milk (EBM)should be started from day 1 along with IVF for3-4 days, followed by advancing feeds.Full feedsshould be reached in 2 weeks. Feeds are givenby paladai, cup or feeding tube 2-3 hourly. Babiesless than 1200 grams, unstable babies and sickbabies need early total or partial parenteralnutrition but even in these babies trophic feedswith EBM are recommended. LBW babies needhuman milk with supplementation of proteins,minerals and vitamins till they attain 3 Kg inpreterms and 2 Kg in severely growth retardedbabies. Iron should be added at 2-4 weeks inpreterms. Supplementation is done either byHuman Milk Fortifiers (HMF) or individualsupplements when feeds reach 100 ml/Kg. Closemonitoring of growth is essential to prevent longterm malnutrition.Key words: Low Birth Weight (LBW), ExpressedBreast milk (EBM), trophic feeds, Human MilkFortifiers (HMF), supplementation

Low birth weight (LBW) babies, or thoseweighing less than 2500grams at birth, constituteapproximately 30-33 % of all live births in India.

11% of all babies weigh less than 2000 gramsand 3.7% weigh less than 1500 grams at birth1.More than half of these newborns are born fullterm. Out of an estimated 18 million low birthweight babies born worldwide annually, Indiaaccounts for about 7-8 million. This large groupof high-risk babies constitutes a major drain onthe national resources due to both immediateneonatal problems and long-term implicationslike chronic malnutrition, recurrent infections andneurodevelopmental delay. Although low birthweight babies constitute only about 14% of allbabies born worldwide, they account for 60-80%of all neonatal deaths2.

The goal of nutritional management of thelow birth weight baby is to provide optimalnutrients for continued, adequate ex–utero growthwithout stressing the metabolic or excretoryfunction of the infant. This apparently simple aimis notoriously difficult to achieve. Varied causesof low birth weight place these neonates indistinct categories, each with its own inherentrisks for nutritional inadequacies. The pretermbaby is vulnerable due to poor suck-swallowcoordination, small gastric capacity, incompetentgastro-esophageal sphincter, decreased activityof lactases, lipases and other enzymes andimmaturity of various metabolic and excretorypathways3. The growth-retarded baby, on theother hand, is particularly prone to feedintolerance, necrotizing enterocolitis andmicronutrient deficiencies4. In addition, a highincidence of early neonatal illnesses in allcategories of low birth weight babies withdifficulty in reaching full feeds quickly makethem particularly prone to nutritional problems.* Associate Professor (Ped) and Neonatologist

Armed Forces Medical College, Pune-411040

NEONATOLOGY

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What are the dietary requirementsof the LBW baby?

Sources of recommendations for thenutritional requirements of preterm babiesinclude the American Academy of Pediatrics(AAP) and European Society for PediatricGastroenterology and Nutrition (ESPGAN)4,5,6.The requirements shown in the table (Table 1)are for preterm babies but can be used for anybaby less than 2 kg. Thereafter term LBW babieswould need the same nutrition as normal, termneonates.

What is the ideal milk for the lowbirth weight baby?

It is unanimously agreed upon that humanmilk is the ideal nutrition for the first six monthsof life for normal growth and development of

the healthy, term infant4,7. Besides the nutritionaladvantages, there are numerous non-nutritionalbenefits like protection from infections, improvedgastrointestinal function and better long-termneurodevelopment8. However the optimumnutrition for premature infants is less welldefined. The AAP has acknowledged that humanmilk is beneficial to the premature infant. Breast-feeding is associated with a lower mortality thanartificial feeds even in LBW babies9,10. Butwhether or not unsupplemented human milk canmaintain accretion and growth rates comparableto those seen in–utero in the preterm, is debatable.

Preterm milk maintains a compositionsimilar to that of colostrum (higher in protein,nitrogen, sodium and calories as compared toterm milk) especially during the first month afterparturition. The transition from colostrum to

Table 1. Nutrient requirements and need for supplementation in preterm babies fed humanmilk5,6,10

Nutrient Breastmilk Recommended SupplementProtein 1.1 g/dL 2.7-3.7 g/kg/day Only if BM<180ml/kgFat 4.5 g/dL 4.5 g/kg/day NoCarbohydrate 7.1 g/dL 8-19gm/kg /day NoCalcium 33 mg/dL 120 mg/kg/day 66 mg/kg/dayPhosphorus 15 mg/dL 90 mg/kg/day 30 mg/kg/dayIron 0.3 mg/dL 2 mg/kg/day 2.5 mg/kg/dayZinc 0.18-0.5 mg/dL 1 mg/kg/day 0.5 mg/kg/daySodium 0.8 mEq/dL 2-3 mEq/kg/day 1-2mEq/kg/dayPotassium 1.4 mEq/dL 2-3 mEq/kg/day NoChloride 1.1 mEq/dL 2-3 mEq/kg/day NoVitamin A 50 IU/dL 600 IU/kg/day 500 IU/kg/dayVitamin D 8 IU/dL 400 IU/kg/day 400 IU/kg/dayVitamin E 5 IU/dL 6 IU/kg/day NoFolate 5 µg/dL 25 µg/day 20 µg/dayCalories 67 cal/100 ml Max 165cal/kg/day If BM<180 ml/kg/dayFluid Max 200 ml/kg/day No

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mature milk proceeds much more slowly afterpremature delivery. Preterm milk also has ahigher concentration of magnesium, iron, copper,zinc, vitamin A and secretory IgA4. The higherIgA content protects against intestinal infections.Preterms fed human milk manifest a lesserimbalance in plasma concentrations ofaminoacids like phenylalanine, tyrosine andmethionine compared to infants fed casein-dominant milk. Very long chain fatty acids foundin human and not in bovine milk have beenfunctionally associated with better cognition,growth and visual function. Preterms have betterabsorption of fat from human milk because ofthe large number of lipases present, which makesup for their immature pancreatic functions. TheVitamin E to Poly Unsaturated Fatty Acid(PUFA) ratio in preterm human milk is 0.9mg/g,which is adequate for Vitamin E absorbtion, andhence Vitamin E supplementation may not berequired in those preterms fed human milk.Preterms absorb more than 90% of the lactose inhuman milk and the excess lactose in the gutresults in a unique bacterial flora, softer stoolconsistency and improved absorption ofminerals11.

Even at maximum levels of feeding(200ml/kg/day) the calcium and phosphorus inhuman milk represent only 25% of the amountthought to be required for normal bonemineralisation5,6. The recognition that growth andnutrient deficits of preterms can be improved withthe use of nutrient supplements has led toenthusiasm in the use of human milk fortifiersfor these infants12. Fortification, or adding of extranutrients, (either as single or multi-nutrientfortifier) to breast milk is different fromsupplementation where these extra nutrients aregiven in addition to and in-between feeds. Singleor multi-nutrient supplementation of human milkhas been associated with improvement in short-term growth and nutritional status. Balancedstudy data demonstrate that the use of fortified

human milk results in net nutrient retention thatapproaches or is greater than intrauterine ratesof accretion13. Fat absorption, however, has beenlower than expected. A greater fat absorption isreported with human milk fortifiers containinglower quantities of minerals. No fortifier to datehas adequate iron and hence iron supplementationis required. Considering the advantages of breastmilk most advisory bodies (AAP, CPS,ESPGAN) have opined that fortified breast milkis the recommended food for the preterm babies.It has been shown that the preterms fed fortifiedhuman milk have a shorter hospitalization as aresult of better health than infants fed pretermformula12. As it stands today, the generalrecommendation is that fortification be startedwhen the milk intake in a preterm baby of lessthan 1800 grams reaches 100ml/Kg and becontinued till a weight of at least 1800 grams isattained. However, it is essential that the infantreceives at least 180-200ml/kg/day of humanmilk. There after individual supplements areadded till 3-4 kgs weight is attained.

Fortification may seem the ideal solution topreterm nutrition but it is not without itsshortcomings. A major concern with Human milkfortifier (HMF) is whether the added nutrientsaffect human milk’s complex system of hostdefense and immune functions. However,analysis of large, prospective multi-center studieshave shown no significant increase in confirmedinfections and necrotizing enterocolitis (NEC) inthe group fed fortified human milk as comparedto that fed partially supplemented human milk13.Also, fortification has not been found to affectthe concentration of secretory IgA content ofhuman milk. When fortified human milk wasevaluated under simulated nursery conditions,bacterial colony counts were not significantlydifferent after 20 hours of storage at refrigeratortemperature but did increase from 20 to 24 hourswhen maintained at incubator temperature13. Theprocess of adding multi-component HMF (bovine

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derived) to the physiologically stable breast milkhas shown to result in poorer absorption of fat.Human milk fat digestion and absorption arefacilitated by the structure of the fat globules,the presence of lipases and the pattern of fattyacids. The addition of large quantities of mineralsto human milk may create an unfavorable milieufor human milk lipid absorption. Fortification ofhuman milk has not been found to significantlyinfluence gastric emptying time14.

How is fortification of human milkdone?

Human Milk Fortifier, available in sachetsin a powdered form, is added to EBM (2 gramsin 50 ml), which can be kept for upto 4 hours atroom temperature. Alternately the sachet isdivided into smaller aliquots and added to thequantity of milk expressed for a particular feed.

When should feeds be started in thelow birth weight baby?

Early enteral feeding with breast milk hasbeen found to be protective against necrotizingenterocolitis and gastrointestinal infections15,16.Stable LBW babies weighing more than 1500grams should be fed as soon as possible afterbirth, preferably within 30 minutes at which timeextrauterine adaptation should be complete.However, they should be given special care toensure feed acceptance. Since LBW babies havevery little energy stores, even short durations ofstarvation should be avoided. These babies maynot demand feeds like term neonates and henceneed to be given scheduled feeds every 2 hours.Very low birth weight babies (VLBW) babiesless than 1500 grams have to be manageddifferently. If they are between 1200-1500 gramsand stable, they may be started on trophic feedsfrom day 1 along with IV fluids. If less than 1200grams it is advisable to start on IV fluids for thefirst 48 to 72 hours and thereafter commence total

parenteral nutrition or trophic feeds dependingon the condition of the baby (Fig. 1).

What are trophic feeds?

Small EBM feeds at 10-20 ml/kg/day givenevery 2-6 hours to stimulate gastric maturity andfunction are known as trophic feeds or MinimalEnteral Nutrition (MEN). These have been foundto improve feed tolerance and shorten the timeto attain full feeds and decrease incidence ofnecrotizing enterocolitis and hospital stay17. Thishas also been shown to improve lactase activity18.It is not advisable to give formula as trophic feeds.

How should the LBW baby be fed?

Feeding can be divided into the transitionalphase (less than 1 week), growing phase and postdischarge phase. Most LBW babies regain theirbirth weight by 14-21 days. Thereafter, a weightgain of 10-15gms/kg/day is expected. LBWbabies generally need 150-175 ml/Kg/day by theend of the first week. During the transition phasethis can be given by tube feeds for babies lessthan 1500 grams and by cup or paladai for biggerbabies. Thereafter feeds are given either directlyfrom the breast for bigger babies (more than 1500grams) or by cup and spoon or “paladai” forsmaller, more fragile preterms (1200-1500grams). For this latter group, during the growingphase few tube feeds daily are preferable so asto ensure a definite amount of feed. Check forgastric residues and feed intolerance and decreaseenergy expenditure. Cup feeding has not beenshown to have adverse effects on physiologicalparameters and may be used in place of a paladaiif the mother is more comfortable with it.However one should ensure that the rim of thecup is thick, rounded and smooth and the size isappropriate to the size of the baby’s face19. Babiesless than 1200 grams who are well enough to bestarted on feeds, usually tolerate tube feeds onlyand should not be compelled to accept feeds in

35


any other form. However, non-nutritive suckingis recommended even for these babies so that theorofacial and gastric reflex maturity is enhanced4.

What are the problems associatedwith feeding?

Feed intolerance, increased gastric residues,gastroesophageal reflux, hypoglycaemia andfailure to gain weight are some of the commonproblems encountered during enteral feeding ofthe well, LBW baby. A weight gain of < 10 g/day is a cause for concern and one should lookfor inadequate intake, easy fatigability duringfeeding, cold stress, anemia or infection as acause. Initially some well LBW babies mayexhibit unexplainable feed intolerance and mayneed reduction of the feeds and supplementationwith IV fluids for a short time. Low-dose(6-12mg/kg/day) oral rrythromycin, which has apromotility action and decreased gastric emptying

time has been shown to improve feed tolerancein such babies20.

How should adequacy of nutritionbe monitored?

Daily weight gain, weekly length,hematocrit estimation and biochemical tests forearly diagnosis of osteopenia of prematurity area must. Even after discharge LBW babies shouldbe called weekly for follow-up for at least threevisits to ensure that adequate weight gain iscontinuing at home. Human milk fortifiers if usedshould be stopped when the baby reaches 1800grams of weight and calcium and phosphoroussupplementation should be continued till 3months or till the baby reaches a weight of 3 kgs.Prophylactic iron supplements at 4 mg/Kg/dayof elemental iron should be started at 4 weeks ofage in all stable preterms who do not haveevidence of infection.

1. Start feeds with EBM/Half strength milk5 ml 2 hourly

2. Gradually increase to 10 ml 2hrly onDay 1

3. Increase by 20-30 ml/Kg/day to reach fullfeeds by 5-7 days

4. Add Human Milk Fortifier when feedsreach 100ml/Kg/day till baby is 1.8 Kg

5. Add supplements of Ca/P and vitaminsthereafter till 3-4 Kgs

1. If < 1200 gms or > 1200 gms and unstablegive IV fluids for 72 hours and then proceedto TPN if still unstable. If stable after72 hours consider trophic feeds with PPN

2. If > 1200 gms and stable start trophic feedswith EBM along with IV fluids

3. Increase by 10-20 ml/Kg/day to reach fullfeeds by 14 days

4. Add Human Milk Fortifier when feedsreach 100ml/Kg/day till baby is 1.8 Kg

5. Add supplements of Ca/P and vitaminsthereafter till 3-4 Kgs

· No evidence of perinatal asphyxia· Hemodynamically stable· Weight >1500 grams· Bowel sounds heard

YES NO

Fig 1. Algorithm for starting feeds in low birth weight babies

⇓⇓⇓⇓⇓ ⇓⇓⇓⇓⇓

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2005; 7(4) : 309

Key Messages

1. LBW babies need to be put on breast milkas soon as possible after birth.

2. Those requiring IVF or PPN should alsobe given trophic feeds.

3. Supplementation in the form of HMF orindividual supplements of protein, mineralsand vitamins is recommended for pretermsand severely growth retarded babies.

4. Monitoring of growth is essential on follow-up.

References

1. State of India’s Newborns. NNF and Save theChildren / US. New Delhi/Washington DC,Nov 2004, 43-47.

2. Lawn JE, Cousens S, Jelka Zupan. For theLancet Neonatal Survival Steering Team.Neonatal Survival 1: 4 million neonatal deaths:When? Where? Why? Lancet 2005; 365: 891-900.

3. Schmitz RJ. Digestive and absorbtive function.In Pediatric Gastrointestinal disease. WalkerWA, Durie PR, Hamilton JR, et al (eds):Philadelphia, BC Decker, 1996, pp 263-279.

4. Fewtrell M, Lucas A. Feeding low birth weightinfants. In “Textbook of Neonatology”. EdsRennie JM, Roberton NRC. 3rd Edn,ChurchillLivingstone, London 1999; 338-360.

5. European Society for PediatricGastroenterology and Nutrition.Recommendations for infant feeding. ActaPediatr Suppl, 1982;302: 1.

6. Nutrition Committee, Canadian PediatricSociety: Nutrient needs and feeding ofpremature infants. Can Med Assoc J1995;152:1765.

7. Kramer MS, Kakuma R. Optimal duration ofexclusive breastfeeding (Cochrane Review).The Cochrane Library, Issue 3, 2004.

8. Chaudhari S, Bhalerao MR, Chitale A, PanditAN, Nene U. Pune low birth weight study- a sixyear follow-up. Indian Pediatr 1999; 36;669-676.

9. Williams AF. Role of feeding in thepathogenesis of necrotizing enterocolitis. SemiNeonatol, 1997;2: 263-271.

10. Narayan I, Prakash K, Gujral VV. The value ofhuman milk in the prevention of infection inthe high-risk low birth weight infant. J Pediatr1981; 99: 496-498.

11. Schanler RJ, Hurst NM, LauC. The use ofhuman milk and breastfeeding in prematureinfants. Clin Perinatol 1999; 26:379-398.

12. Kuschel CA, Harding JE. Multicomponentfortified human milk for promoting growth inpreterm infants (Cochrane Review). TheCochrane Library, Issue 1 2003.

13. Jocson MAL, Mason EO, Schanler RJ. Theeffects of nutrient fortification and varyingstorage conditions on host defense propertiesof human milk. Pediatrics 1997;100:240-243.

14. Ewer AK, Yu VYH. Gastric emptying inpreterm infants: the effect of breast milkfortifier. Acta Paediatr 1996; 85:1112-1115.

15. Lucas A and TJ Cole. Breast milk and neonatalnecrotising enterocolitis. Lancet 1990;336:1519-1523.

16. Shulman RJ, Schanler RJ, Lau C et al. Earlyfeeding, antenatal glucocorticoids and humanmilk decrease intestinal permeability in preterminfants. Pediatr Res 1998;44:519-523.

17. Agarwal R, Aggarwal R, Deorari AK, Paul VK.Minimal enteral nutrition. Indian J Pediatr2001; 68:1159-60.

18. McClure RJ, Newell SJ. Randomizedcontrolled study of digestive enzyme activityfollowing trophic feeding. Acta Paediatr.2002;91:292-296.

19. Howard CR, de Blieck EA, Hoopen CB,Howard FM, Lanphear BP, Lawrence RA.Physiologic stability of newborns during cupand bottle feeding. Pediatrics 1999; 104:1204–1207.

20. Ng E, Shah V. Erythromycin for feedingintolerance in preterm infants. sCochraneDatabase Syst Rev 2001(2): CD001815.

37


FETAL ORIGINS OF ADULTDISEASE – IMPLICATIONS FORTHE 21ST CENTURY

* Venkatesh Sampath

Abstract: The incidence of metabolic syndrome,type II diabetes and cardiovascular disease isincreasing both in the developed and developingcountries. This has imposed an economicalburden on society and led to intensive efforts indetection and treatment of these diseases. Whilethe cause of this phenomenon is likely to be multi-factorial, evidence is accumulating that adaptiveresponses made by the fetus in-utero tomalnutrition can result in increased susceptibilityto adult onset diseases, - the fetal originshypothesis. A better understanding of fetalprogramming is essential to initiate efforts aimedat prevention of fetal growth restriction andsubsequent adult onset cardiovascular disease.Key words: Fetal programming, metabolicsyndrome, malnutrition

The incidence of the metabolic syndrome isreaching epidemic proportions in Europe andUnited States and has the potential to risealarmingly in developing nations in the comingdecades. Defined as a combination of three ofthe following five disorders: rising bloodpressure, central adiposity, raised serumtriglycerides, lowered serum HDL cholesteroland fasting hyperglycemia1, this syndrome may

progress to type 2 diabetes mellitus andcardiovascular disease. While this phenomenonis multi-factorial, Dr. Barker and his associatesat the Medical Research Council’s EpidemiologyUnit at Southampton, England have proposed theconcept of fetal and early developmentalprogramming as being important in thedevelopment of cardiovascular diseases in theadult. In this article we shall outline the Barker’shypothesis2, present evidence for fetalprogramming from epidemiological and animalstudies, discuss mechanisms which underlie fetalprogramming and explore its clinical implicationsfor neonatologists and pediatricians.

The fetal origins hypothesis: Barker andcolleagues proposed that fetal undernutrition inmiddle to late gestation leading todisproportionate fetal growth is associated withhypertension, insulin resistance and dyslipidemiain later life2. While it is easy to conceive thatinjury to fetus can cause long-term harm (eg.teratogens), the fact that fetal adaptive responsesto malnutrition can result in increasedsusceptibility to adult-onset disease suggests thatmodulation of the genetic milieu in-utero isimportant in evolution of human disease. Fetusesexposed to malnutrition in-utero, make adaptiveresponses to maximize fuel uptake and conserveavailable nutrients. Such mechanisms establishedin utero while giving the fetus a survivaladvantage in the womb might programsusceptibility to adult onset diseases.“Programming” encompasses any stimulus orinsult in the developing organism which resultsin permanent long-term adaptive responses.

NEONATOLOGY

* Fellow in Neonatology,Division of Neonatology and PulmonaryBiology, Cincinnati Children’s HospitalMedical Center, Cincinnati, 45229, USA

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2005; 7(4) : 311

Epidemiological evidence for fetal originhypothesis: Most investigators have focused onthe relationship between birth-weight and adultdisease by studying large cohorts of people ingeographically localized areas. Leon et al

3 studied

a cohort of 14611 babies born in UppsalaAcademic Hospital, Sweden between 1915 and1929 and followed up till the year 1995.Cardiovascular disease showed a significantinverse relationship with low-birthweight both inmen and women. In comparison to men with thelowest birth-weight quartile for gestational age,mortality from cardiovascular disease in thesecond, third and fourth quartile was 0.81 (0.66-0.98), 0.63 (0.50-0.78) and 0.67 (0.54-0.82),clearly demonstrating the association with fetalgrowth and adult cardiovascular disease. Barkeret al

4 studied the relationship between adult

hypertension and low birth-weight in 449 menand women from Lancashire. They coulddemonstrate a 11mm decrease in systolic bloodpressure as birth-weight increased from less than5.5 pounds to greater than 7.5 pounds. Thehighest blood pressure occurred in small babieswith large placentas. They postulated that thediscordance in the placental and fetal size resultedin circulatory adaptation in the fetus whichprogrammed hypertension in adults. Hales andBarker

5,6 studied a cohort of around 400 men born

in Herfordshire between 1920-1930 into lateadulthood and established clear associationsbetween metabolic syndrome, type II diabetesand a low birth-weight (Figs 1a and 1b). Otherinvestigators have linked birth weight todevelopment of dyslipidemia and obesity.

The impact of poor maternal nutritionleading to low birth-weight and subsequentadulthood disease have been established bystudying large cohorts of women who wereexposed to famine and starvation duringpregnancy. During the Dutch famine (1944-1945)malnutrition was rampant and pregnant women

had an average daily caloric intake of only 500-800 calories. Exposure to starvation in lategestation was associated with adult obesity andglucose intolerance in infants and exposure inearly gestation was associated withhypertension7,8. Smaller babies from this cohort(especially females) faced a higher risk of adultonset diabetes. Similar studies undertaken inother disadvantaged populations in the USA,Caribbean, India and Australia have identifiedsimilar association between maternalmalnutrition and adult disease in their infants.Hales and Barker et al5 have proposed the “thriftyphenotype hypothesis” to explain the associationbetween low birth-weight and adult type IIdiabetes. They postulated that fetal malnutritionresulted in a decrease of the insulin secreting B-cell mass and function in the pancreas and alsoinsulin resistance. When such individuals with asmall phenotype are exposed to abundance ofcalories, their decreased B-cell function andinsulin resistance would result in type II diabetesand the metabolic syndrome. During theLeningrad siege (World War II), conditionssimilar to the Dutch famine existed but birth-weight was not correlated with impaired adultglucose homeostasis9. The important differencebetween the two populations was that inLeningrad, nutritional status did not improve evenafter the war so that children continued to bemalnourished. This suggests that catch-up growthin childhood against a background of fetalmalnutrition is essential for development for adultonset diseases. While data from epidemiologicalstudies clearly show that components of themetabolic syndrome can be programmed in-utero, use of animal models are essential forunderstanding the nature, duration and timing ofinsults to the fetus which programs adultdiseases.

Animal studies: As animals typically have ashorter life span and can be used in experiments

39


where their genetic and environmental influencescan be manipulated, animal models have emergedas powerful tools to study various componentsof the metabolic syndrome. While studies inanimals may not reproduce accurately thepatterns of disease observed in humans, it isremarkable how phenotypes observed in animalsclosely mimic the human metabolic syndrome.Caloric or protein restriction in animals mimicsconditions existing in many developing countriesand underprivileged members of westernsocieties and can help in studying the effects offetal programming. In this review, data from

restriction models and also models using high fator cholesterol diets in pregnant rodents will bepresented.Maternal dietary challenge and insulinresistance: Garofano et al10 used restricted calorieintake in pregnant rats to 50% ad lib and measuredbeta-cell mass and glucose tolerance in offspring.They also studied the effect of postnatalmalnutrition by comparing control animals withanimals that had been malnourished during fetallife only and with animals who had beenmalnourished during fetal life and early postnatallife. When compared to controls, rats who had

Fig 1. Association between birth-weight and (a) impaired glucose tolerance, (b) metabolicsyndrome.

O dds ratio for im paired glucose tolerance or type 2 diabetes according to birth w eight (lbs) am ong 370 m en aged 64 years born in H ertfordshire (adjusted for adult body m ass index). (5)

O dds ratio for the m etabolic syndrom e according to birth w eight (lbs) am ong 407 m en born in H ertfordshire (adjusted for adult body m ass index). (6)

Odds ratio –

impaired glucose tolerance

Odds ratio –

metabolic syndro

me

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2005; 7(4) : 313

been malnourished in fetal life had borderlineglucose tolerance and slightly decreased beta cellmass. Rats exposed to both fetal malnutrition andearly postnatal malnutrition had a 50% reductionin beta cell mass and profound insulinopenia andabnormal glucose tolerance. These experimentsand others clearly demonstrate that protein andor caloric restriction during pregnancy canpredispose offspring to impaired glucosetolerance, insulin resistance and decreased betacell mass. During periods of maternalmalnutrition the fetus diverts nutrients to criticalorgans like the brain at the expense of the liverand pancreas leading to possible permanentstructural and enzymatic changes. A reductionin beta cell mass, decreased mitochondria copynumber in the islet cells, decreased glucokinaseexpression and increased insulin resistance have

been demonstrated in rats as a result of fetalprogramming caused by dietary imbalances.These changes can persist to adulthood and leadto development of type II diabetes in adults.

Maternal malnutrition and blood pressure ininfants: Increased blood pressure is an importantcomponent of the metabolic syndrome andstudies in rats clearly demonstrate the effect ofmaternal malnutrition and blood pressure inoffspring. Vehaskari et al

11 restricted pregnant

rats to a 6% protein diet and measured bloodpressure in the offspring. By 8 weeks of age, bothmale and female offspring had a 20-25 mmincrease in systolic blood pressure and by 18months of age survival was significantlydecreased compared to controls. They could alsodemonstrate a 30% decrease in glomeruli in the

Nutritional divergence after fetal life

Hypertension ↓ Insulin secretion ↑ Insulin resistance and dyslipidaemia

Metabolic syndrome

Maternal malnutrition

Fetal malnutrition

Diversion of fuels away from liver, pancreas, kidneys, skeletal tissue to brain

Fetal growth restriction

↓ Renal mass & ↑ RAS ↓ Islet cell mass & function ↓Skeletal & liver tissue

Fig 2. Biological mechanisms underlying fetal programming of adult onset diseases.

41


kidney by 8 weeks of age which could possiblycontribute to the hypertension. Ozaki et al

12 used

a calorie restriction model and could demonstrateincreases in mean blood pressure in both maleand female offspring though the effect was seenearlier in males.

Maternal malnutrition, central obesity anddyslipidaemia: In rat models of maternal dietaryimbalance, offspring obesity is not a consistentfeature suggesting that maternal malnutritionalone is not enough to induce central adiposity ifpostnatal nutrition is normal. However Ozanneet al13 have demonstrated increased body weightin offspring of protein restricted mice fed a highcarbohydrate diet. Similar studies have shownthat increased adiposity in offspring is inducibleonly with a calorie rich or high fat diet.Dyslipidemia, characterized by increasedtriglyceride and low-density lipoprotein level anddecreased high-density lipoprotein levels iscentral to the diagnosis of metabolic syndrome.Studies of maternal nutritional restriction in ratsand guinea-pigs have not demonstrated increasedtriglyceride or cholesterol levels in offspring.Ghosh et al14 observed lowered HDL cholesteroland increased triglyceride concentrations in 160-day-old offspring of dams fed a lard rich dietduring pregnancy and suckling. This suggests thatfetal or postnatal nutritional excess and not fetalmalnutrition programs dyslipidemia.

In summary, data from animal models showthat abnormal insulin/glucose homeostasis isprogrammed by in-utero dietary restriction. Withregards to hypertension most studies suggest thatthis can be programmed in-utero too, though notalways. The data with regards to dyslipidemiaand central obesity is not conclusive, though ratsmay not be the best model and vigorous studieshave not been done using other animal models.

Biological mechanisms underlying fetalprogramming: The effects of fetal programming

can best be understood by understanding thephenomena of “phenotypic plasticity”,15

“metabolic imprinting’16 and “nutritionaldivergence” after birth. Metabolic imprintingencompasses adaptive responses made by anorganism during critical ontogenic window earlyin life in response to specific nutritionalconditions which can result in persistent effectslasting through adulthood. Phenotypic plasticityrefers to the phenomenon whereby one genotypegives rise to a range of physiological andmorphological states in response to differentenvironmental conditions during development.During critical periods of development it appearsthat genotypic expression can be influencedpermanently by adaptive metabolic responsesresulting in a specific phenotype. Nutritionaldivergence occurs when there is disparitybetween the nutrition of the fetus and nutritionof the more mature organism. When nutritionaldivergence is outside the predictive adaptiveresponse of the organism, disease results as themore mature organism loses the ability to altergenotypic expression to adapt to newerconditions.

Thus in the fetus, malnutrition results indecreased B-cell mass or islet function in thepancreas. This results in decreased fetal growth,smaller skeletal mass, smaller liver and kidneys.After birth, if such fetuses are exposed toprolonged periods of excessive nutrition insulinresistance, decreased insulin secretion,hypertension and dyslipidemia result. (Fig 2).

Neonatal perspectives: The fetal originshypothesis has raised many questions and posesmany challenges for neonatologists andpediatricians. Nutritional strategies adopted in theNICU are often inadequate, as many of prematureinfants are discharged home as SGA infants.Evidence is emerging that these infants developcomponents of the metabolic syndrome early inlife. Hofman et al17 studied premature infants with

42

2005; 7(4) : 315

gestational age less than 32 weeks between theages 4-10 years and showed that insulinsensitivity was decreased when compared withterm controls. Arends et al18 demonstrated analmost 60% reduction in insulin sensitivity andincreased systolic blood pressure in shortprepubertal children born small for gestationalage when compared to age-matched AGAcontrols. If fetal programming occurs inpremature infants, what are the nutritionalstrategies which will prevent malnutrition andsubsequent programming? Does catch-up growthpredisposes to the metabolic syndrome and whatis the optimal nutrition for premature and SGAinfants during childhood? These issues need tobe addressed as they are of great importance tothe future health of coming generations.

Challenges in the developing world: In thedeveloping world, up to a third of infants can beborn with growth restriction primarily due tomaternal malnutrition. With improvements inneonatal care, the proportion of premature andSGA infants who survive to adulthood is likelyto increase and could potentially contribute to theburden imposed on the society from diabetes andcardiovascular disease. This is a cause of concernas the World Health Organization estimates thatthe number of adults with diabetes in developingcountries will increase by 170% from 84 millionin 1995 to 228 million in 202519. A concertedeffort to improve nutrition of adolescent girls andwomen of child bearing age by protein, vitaminand iron supplementation is essential to preventfetal malnutrition. Such an approach will decreaseinfant mortality and possibly morbidity fromadult onset diseases.

Points to remember:

1. Maternal malnutrition results in fetalgrowth restriction and fetal programming.

2. Adaptive responses made by the fetus tomalnutrition can result in persistent longterm effects.

3. Nutritional excess or deprivation duringfetal life and early childhood can programadult onset diseases.

4. Fetal growth restriction puts infants at riskof adult onset type 2 diabetes, dyslipidemiaand cardiovascular disease.

References

1. Wilson PW, Grundy SM. The metabolicsyndrome: practical guide to origins andtreatment: Part I. Circulation 2003; 108:1422-1424.

2. Barker DJ. Fetal origins of coronary heartdisease. Brit Med J 1995; 311:171-174.

3. Leon, D, Lithell HO, Vagero D, et al. Reducedfetal growth rate and increased risk of deathfrom ischaemic heart disease: cohort study of15 000 Swedish men and women born 1915-29. Brit Med J 1998; 317(7153):241-245.

4. Barker DJ, Bull AR, Osmond C, Simmonds SJ.Fetal and placental size and risk of hypertensionin adult life. Brit Med J 1990; 301:259–262.

5. Hales CN, Barker DJP, Clark PMS, et al. Fetaland infant growth and impaired glucosetolerance at age 64. Brit Med J 1991; 303:1019-1022.

6. Barker DJP, Hales CN, Fall CHD, Osmond C,Phipps K, Clark PMS. Type 2 (non-insulindependent) diabetes mellitus, hypertension andhyperlipidaemia (syndrome X): relation toreduced fetal growth. Diabetologia 1993; 36:62-67.

7. Ravelli GP, Stein ZA, Susser MW. Obesity inyoung men after famine exposure in utero andearly infancy. N Engl J Med 1976; 295:349-353.

8. Roseboom TJ, van der Meulen JH, Osmond C,Barker DJ, Ravelli AC, Bleker OP. Adultsurvival after prenatal exposure to the Dutchfamine 1944–45. Paediatr Perinat Epidemiol2001a; 15:220–225.

9. Stanner SA, Bulmer K, Andres C, et al. Doesmalnutrition in utero determine diabetes andcoronary heart disease in adulthood? Results

43


from the Leningrad siege study, a crosssectional study. Brit Med J 1997; 315:1342-1348.

10. Garofano A, Czernichow P, Breant B. In uteroundernutrition impairs rat beta-celldevelopment. Diabetologia 1997; 40:1231-1234.

11. Vehaskari VM, Aviles DH, Manning J. Prenatalprogramming of adult hypertension in the rat.Kidney Int 2001; 59:238-245.

12. Ozaki T, Nishina H, Hanson MA, Poston L.Dietary restriction in pregnant rats causesgender-related hypertension and vasculardysfunction in offspring. J Physiol 2001;530:141-152.

13. Ozanne SE, Hales CN. Lifespan: catch-upgrowth and obesity in male mice. Nature 2004;427:411–412.

14. Ghosh P, Bitsanis D, Ghebremeskel K,Crawford MA, Poston L. Abnormal aortic fattyacid composition and small artery function inoffspring of rats fed a high fat diet in pregnancy.

J Physiol 2001; 533:815-822.

15. West-Eberhard MJ. Phenotypic plasticity andthe origins of diversity. Annu Rev Ecol Syst1989; 20:249-278.

16. Waterland RA, Garza C. Potential mechanismsof metabolic imprinting that lead to chronicdisease. Am J Clin Nutr. 1999;69(2):179-97.

17. Hofman PL, Regan F, Jackson WE, JefferiesC, Knight DB, Robinson EM et al. Prematurebirth and later insulin resistance. N Engl J Med.2004; 351(21):2179-86.

18. Arends NJT, Boonstra VH, Duivenvoorden HJ,Hofman PL, Cutfield WS, Hokken-KoelegaAC, et al. Reduced insulin sensitivity and thepresence of cardiovascular risk factors in shortprepubertal children born small for gestationalage (SGA). Clinical Endocrinology2005;62:44-50

19. King H, Aubert RE, Herman WH. Globalburden of diabetes, 1995-2025: prevalence,numerical estimates, and projections. DiabetesCare. 1998; 21(9):1414-1431.

NNF Manual of Neonatal Care

Editors: Jayashree Mondkar & Ranjan Kumar Pejaver

Contributions from leading Neonatologists of India. Covers all the important aspects of Prevention,Diagnosis and Management of various neonatal conditions.

Useful to Neonatal practitioners at all levels, may it be in Community practice or Hospitalbased units, also to students of Neonatology.

Rs. 360/- ISBN : 81-7286-373-X

Available at all leading Medical Book Stores or Contact

PRISM BOOKS PVT LTD NATIONAL NEONATOLOGY FORUM# 1865, 32nd Cross, BSK II Stage, 803, North ex Tower, Netaji Subash Place,Bangalore-560 070, India Ring Road, Pitampura, Delhi - 110034Tel: 26713991 / 26714108, Fax: 26713979 Tel : 27198647E-mail: [email protected]

NEWS AND NOTES

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2005; 7(4) : 317

NEONATAL SEPSIS - NEWERPERSPECTIVES

* Ranjan Kumar Pejaver

Abstract: Sepsis is the main cause of morbidityand mortality in newborns. As the clinicalfeatures are nonspecific, diagnosis is not easy.The diagnostic tests available have low predictivevalue and decreased sensitivity and specificity.Antibiotic abuse has resulted in further confusionin diagnosis and emergence of resistance toantimicrobials. It is now understood that sepsisis a complex syndrome caused by an uncontrolledsystemic inflammatory response (SIR), ofinfectious origin, characterized by multiplemanifestations and which can result indysfunction or failure of one or more organs andeven death. The sepsis cascade has stimulatedsearch for interventions at various levels of thisprocess. The article summarises the triumphs andagonies of this ongoing research in diagnosisand treatment of neonatal sepsis.

Key Words:Neonatal sepsis, diagnosis,management, septic shock.

Magnitude of the problem

Sepsis is the commonest primary cause ofmortality and morbidity among neonates. In ourcountry, current Neonatal Mortality Rate (NMR)is around 45/1000 live births. Among these, 40%occur on day 1, 56.3% within three days and73.3% occur in the first week of life. Sepsis

NEONATOLOGY

accounts for almost half the deaths that occurduring neonatal period. Globally, WHO estimates5 million neonatal deaths a year. 98% of theseoccur in developing countries. The commonestetiology is sepsis which constitutes more than onethird of the causes. Estimated incidence is7.1 to38/1000 live births in Asia; 6.5 to 23/1000 livebirths in Africa; 3.5-8.9 / 1000 live births in SouthAmerica and Carribeans; 6/1000 live births inUSA and Australia.

Neonatal sepsis could be of different variety,which would prompt different approaches inprevention, diagnosis and treatment. Early onsetsepsis(EOS) is that which occurs within 72 hoursafter birth and is due to microbes acquired beforeor during delivery. Late onset sepsis is thatwhich occurs due to microbes acquired afterdelivery. Nosocomial sepsis is hospital acquiredinfection. Colonisation refers to bacterialcolonization which is inevitable in all humanbeings and has its own advantage and usuallyoccurs in respiratory tract, gastrointestinal tractand skin.

What is the scene generally in mostplaces?

Clinical features of sepsis are highlynonspecific. This has led to both under diagnosisand over diagnosis. A high index of suspicion isrequired for early diagnosis of sepsis. For the lasttwo decades, the following set of investigationsare relied upon to diagnose sepsis:-

Total leukocyte count (TLC), absolute neutrophilcount (ANC), immature to total neutrophil count(I/T Ratio), C-reactive protein (CRP), micro ESR,buffy coat smear, acridine orange staining.

* Consultant Neonatologist,K R Hospital, BangaloreHon Professor of Neonatology,KIMS, Bangalore.

45


These laboratory tests are not of highspecificity or sensitivity. Eg: Sensitivity andspecificity of elevated CRP was found to be 75%and 86% and for white cell count disturbance67% and 90%.

Predictive value of these tests are low andthese tests are not available every where norstandardized. Lab tests are bypassed due to lackof availability or affordability in many places.

Culture of blood and various other bodyfluids is considered as the gold standard. It is tobe noted that even in the best of centres, yield ofblood culture has been less than 30%.

Regarding treatment in most centres especiallythe peripheries, antibiotics has been the onlymodality. Antibiotic therapy could be empiricdue to various reasons and at times, specific.There are several factors which make antibiotictherapy ineffective or at times hazardous. Tomention some:

a. Mothers would have received antibiotics.

b. Infants before transfer are already givenantibiotics.

c. Lack of antibiotic policy. (which is supposedto state the following ) is lacking in mostcenters.

- when to give/stop

- what to give.

- how much to give.

- how long to give.

As a result there is this mammoth problemof antibiotic resistance. Lack of monitoring of asuspected or proven case of sepsis, makes thefurther management difficult. Supportive therapythough available to some extent, is not given dueto, lack of knowledge, difficulties in availabilityor affordability.

Evolution of newer perspectives insepsis

Over the last several years we have come tounderstand that Sepsis is a complex syndromecaused by an uncontrolled systemic inflammatoryresponse (SIR), of infectious origin, characterizedby multiple manifestations, which can result indysfunction or failure of one or more organs andeven death.

It is just not a given microbe invading thebody and causing disease but a complexity ofpathogen-host relationship. Features of the hostthat influence this are portals of entry, hostimmunity, antibiotic exposure and prematurity.Features of microbe that have bearing arepathogenicity, dose and competition. There hasbeen a coordinated effort among the researchersto investigate the pathophysiology and the variousdynamic changes that happen in different systemsof the body as a response to sepsis. The sepsiscascade (Fig 1) explains these changes. Thereare several ways in which the microbe injuresthe cell and there are equally diverse ways inwhich the host responds. Microbes injure hoststhrough toxins directly or by an inflammatoryreaction, as a result of host’s own immuneresponse. Cytokines, a family of cell signalingpeptides are liberated, which can beproinflammatory or anti inflammatory in nature.Ultimately it is the end organ effect of thisinflammation that determines the seriousness.

It is now understood that the situation couldbe a spectrum from mild sepsis to hemodynamicalteration-to multi organ failure and septic shock.

Hypovolemia, peripheral vasodilatation,myocardial depression, increased endothelialpermeability and hypermetabolism occur.

The more the complexity andinterdependence of the pathophysiologicalmechanism of sepsis are understood, more

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diagnostic and therapeutic strategies based onsubstances, which modulate or interrupt theeffects of endogenous and exogenous sepsismediators can be sought.

Newer developments in diagnosis ofneonatal sepsis

Laboratory or complimentary, evaluation iscapable of revealing two distinct aspects of sepsis.The first is related to the search for the aggressive

agent, the second relates to the identification ofalterations in metabolism or homeostasis,indicative of systemic compromise or of specificorgan involvement.

Blood Culture is the definitive test, as thevast majority of neonatal infections are associatedwith bacteremia. Conventional culture andsensitivity tests take anywhere between 24-72hours for results. Newer rapid methods like‘Bactec’, ‘VersaTREK’ give us early clues

NO=Nitric Oxide, TSST=Toxic shock syndrome toxin, IL=Interleukin, TNF=Tumour necorsis factor,Th=T-helper cells, PMNs=Polymorphonuclear leukocytes, PAF=Platelet activating factor,SVR=Systemic vascular resistance

Fig 1. Sepsis cascade: Open tail arrow = area of potential intervention

S ource of infection N O synthase

M icro-organism

T oxins E ndotoxin, T S S T -1,S E B

E ndothelial cells

M acrophage T cells P M N s

IL -1 T N F IL -6 T h-1 T h-2 P A F A rachidonic acid m etabolites

IN F IL -4 T N F IL -5 IL -2 IL -10

V ascular leakage, m yocardial depression, decreased S V R

S epsis syndrom e

S eptic shock

47


regarding presence of bacteria. They measure thehead space pressure in the bottle relating tooxygen consumption or gas production. (carbonmonoxide, nitrogen, hydrogen) by the microorganism. They are designed to perform aerobic,anaerobic, and mycobacterial culture andsensitivity on the same system. However, methodof blood collection, contamination andinterpretation of the result have a bearing.Collection from multiple sites and repetition ofthe test may be more useful. Despite the greatefforts made, on average, blood cultures arepositive in 34% of ‘patients with sepsis’ varyingfrom 9 to 64%. In patients who have long durationICU stay, an investigation for systemic infectionby fungus is mandatory. Currently, fungi areresponsible for around 5% of sepsis.

Immunological studies: Antigen detectionstudies by counterimmunoelectrophoresis andothers have been used to detect the presence ofbacterial antigens in blood, urine or CSF. Theapplication in neonatal sepsis is still not widelypracticed. Rapid screening for Group βstreptococci (GBS) by latex particle agglutinationis one area where it is more used. This has beenfound to have 90% sensitivity, 70% specificity,positive predictive value of 12% and negativepredictive value of 99%.

Antibody detection tests: More valuable in viralinfections. Organism specific IgMs are available.Especially significant increase in titres on repeatsamples is diagnostic.

Genetic techniques: It is now possible to amplifyhighly conserved DNA sequences from a varietyof Gram-positive and Gram –negative organisms,as well as many viruses using PCR, whileavoiding the simultaneous amplification ofassociated human DNA. In a recent study,portions of DNA encoding the 16-S ribosomalRNA has been used to define an organism asbacteria. These are amplified using PCR byautomated methods allowing rapid diagnosis.

Sensitivity was 100%, and specificity 95.6%.This method has the potential to be automatedand to provide rapid diagnosis of bacteremia.Other DNA amplification techniques are alsobecoming available.

Detection of acute phase reactantsOrosomucoid (alpha1-acid glycoprotein),haptoglobin, alpha1 antichymotrypsin have allbeen used in assessing neonatal infections, butadd little to what is learnt from studying CRP.Fibronectin assay has been found to be usefulin diagnosing sepsis. Many septic preterm infantsdevelop significantly low plasma fibronectinconcentrations which may impair their ability tocombat infection.

Increase in serum lactate, plasma nitric oxide(by means of nitrite/nitrate plasma levels): canbe early indicators of SIRS. But means to measurethese are not available freely.

Serum granulocyte stimulating factor(G-CSF) concentration with a cutoff value of120pg/ml has been shown to have a sensitivityof 95% , a specificity of 73% and a negativepredictive value of 99% in the diagnosis of cultureproven neonatal sepsis.

Granulocyte elastase concentration elevationin amniotic fluid has recently been shown to havea useful predictive value for neonatal sepsis. Itmerits further evaluation as an early screeningtest.

Serum assay of certain cytokines: Interleukin1(IL -1), IL -6, IL-8,IL-10 and tumour necrosisfactor (TNF) are some of the substancesmeasured in diagnosing sepsis. As IL-6 plays acritical role in inducing CRP synthesis it shouldprovide an earlier indication to sepsis. It has beenfound to be more sensitive than CRP. In additionto elevated plasma concentrations, TNF alphaconcentrations have been found in lung lavagefluid of babies with pneumonia.

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Procalcitonin is a 14-kDa protein encoded bythe Calc-1 gene along with calcitonin andkatacalcin. The function and regulation of thisprotein are quite different from those of the othergene products. Blood concentration ofprocalcitonin is increased in systemicinflammation, especially when this is caused bybacterial infection. Studies of its behaviour inpatients with bacterial sepsis have led to theproposal that it may be a useful marker ofsystemic bacterial infection, with greaterspecificity and sensitivity than acute phaseproteins such as C-reactive protein. Severalstudies are in progress to establish serum levelsin various age groups and also to refine the assaytechniques.

Newer developments in the treat-ment of neonatal sepsis

Early intervention to prevent hemodynamicdisturbances, appropriate use of antimicrobials,toxin removing, increasing innate immunity anduse of inflammatory response blockers are thevarious modalities to be discussed.

Antimicrobials form the mainstay of treatmentof sepsis. During the last decade several newerantibiotics have been introduced, namely,Carbapenem group, (imipenem, meropenem);3rd and 4th generation cephalosporines; widespectrum penicillins (ticarcillin, piperacillin);monobactams (astreonams) and quinolones.Many antiviral agents are now available. Forfungemia amphoterecin and flucanazole are nowregularly used in intensive care units.

Supportive therapy: This is still very essentialfor a good outcome. Constant monitoring of vitalsigns, central venous pressure (CVP) and urinaryoutput is mandatory. Definitive resuscitatorystrategies with therapy oriented by goals include,correction of preload (CVP), post-load (meanarterial pressure), cardiac contractility andoxygen saturation. Maintainance of adequate

cellular perfusion and prevention of organdysfunction should be the aim.

Vigorous volumetric resuscitation andcontinous use of inotropes should be practiced.In childhood septic shock there is alwaysconsiderable volume deficit, which warrantsinfusion of large volumes of crystalloid solutions.It should be noted that even with a volumetricdeficit of 25% to 30% , the MAP remains stableat the cost of increased systemic resistance.

Adjunctive therapy: It is now evident thatthough antimicrobials form the mainstay, inimmunocompromised, premature and low birthweight babies, additional modalities will help incombating sepsis. It is based on the interventionand support at various points of the sepsiscascade.

Immunoglobulin therapy: Both prophylacticand therapeutic use of immunoglobulins havebeen tried in neonatal sepsis. There is evidenceof improved humoral immunity and enhancedopsonophagocytosis with immunoglobulintherapy. Hyperimmunoglobulins and refinedpreparations are now available. Meta-analysishas still not revealed distinct and statisticallysignificant benefits. It is recommended to useimmunoglobulins in selected cases. However,specific immunoglobulins have a definite role.Eg: Hepatitis immunoglobulin, varicellaimmunoglobulin etc.

Fresh frozen plasma (FFP) has been used toenhance humoral immunity. In vitro a lot ofevidence about its usefulness is available. Thereare also concerns about the safety as it is a bloodproduct. It is quite useful when DIC is associatedwith the sepsis.

Granulocyte colony stimulating factor (G-CSF); granulocyte macrophage colonystimulating factor (GMCSF) are important ininducing granulocyte production and activation

49


in the newborn during sepsis. The granulo-cytopenia that accompanies severe sepsis in anewborn is due to its lack. Several trials haveshown an increase in neutrophil counts andenhanced functional activity as judged by theC3bi expression. But there is still no concreteevidence that the ultimate outcome is improvedby these modalities.

Exchange transfusion(ET): provides humoralfactors, removes noxious products, such asbacterial toxins, fibrin degradation products, andcytokines. There have been reports of dramaticimprovements following ET, but well designed,prospective randomized controlled trials toconfirm this is absent.

Granulocyte transfusion: Obtained from donorblood or plasmapheresis, given to babies withsepsis, in particular when their illness has beencomplicated by neutropenia and granulocytestorage pool depletion as judged by bone marrowaspiration, has shown benefit. But overall, theliterature is not convincing.

Agents which bond with or neutralizecomponents in the bacterial cell wall: Use ofAnti-endotoxin antibodies, lipopolysaccharidebinding protein antagonist, CD14 receptorinhibitor and permeability increasing proteinantagonist have not yet proven to be practical anduseful in treating neonatal sepsis. Monoclonalantibodies in common or specific like E5 haveshown some success.

The process of polymorphonuclearneutrophil activation and degranulation causedby inflammatory mediators results in large scalefree radical production. Antioxidants likevitamin C and E, beta carotene, catalase andsuperoxide dismutase ,to neutralize free radicalsand scavange them are being used. Otherantioxidant agents, alpha tocopherol, dimethylsulphoxide, Q10 coenzyme, N- actylcystiene,glutathione and allopurinol are being evaluated.

It is believed that products of metabolismof arachidonic acid, by both cyclooxygenase andlipoxygenase routes and also prostaglandins andthromboxane appear to have role in target organdysfunction. Their inhibitors like indomethacin,ibuprofen appear to have beneficial effects atspecific points in the inflammatory cascade andon the survival.

Heparin has also been studied for its immunemodulatory properties and in vitro it inhibits thebond between L and P selectin leading toprotection against lethal endotoxemia. But largestudies have failed to substantiate this andhaemorrhages and its antithrombin activity maybe detrimental.

In experimental studies, use ofantithrombin prevented to a significant extent,endothelium-leukocyte interaction and capillarydamage. But in observational studies it was notfound to be of great use.

One treatment that has shown promise forsepsis appears to be recombinant human activeC protein, or drotrecogin-að. Active C proteinis an endogenous protein which promotesfibrinolysis and inhibits thrombosis andinflammation. In sepsis, because of the effectsof inflammatory cytokines, there is a reductionin the conversion of inactive C protein into activeC protein. The anti inflammatory effect ofdrotrecogin can come directly from the inhibitionof neutrophil activation, from the production ofcytokines induced by lipopolysaccharides, andfrom activated cell adhesion to the endothelium.The effect can also be indirect, by means ofinhibiting thrombin generation, which leads toreduced platelet activation, neutrophilrecruitment and leucocyte degranulation. In arandomized, multicenter, double-blind, placebo-controlled trial of continuous drotrecogin-að for96 hours or placebo, in 1,690 patients with severesepsis, overall mortality was lower at 28 daysamong the treated group, representing a reduction

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of 6.1% in the absolute risk of death. The drugwas cleared for use on the basis of this singletrial. Due to its potential to cause severehemorrhages and its high cost, it has beenrecommended that patients be extremelycarefully selected before receiving this treatment.

More than 30 randomised blind trialsinvolving 12000 patients showed that the use ofantibody blockers such as platelet activationfactor antagonists, antibradykinin, anti-prostaglandin, monoclonal anti-TNF antibody,IL-1 receptor antagonist, soluble TNF receptor,nitric oxide synthesis inhibitor did not change theclinical course or mortality, and sometimes evencompromised the patients.

Pentoxifylline is an anti-inflammatory drug . Itis a xanthine derivative and a phosphodiesteraseinhibitor possessing a broad spectrum of activitymodulating inflammation. Several trialsconducted , have shown a reduction in ‘all causemortality during hospital stay’. Current evidencesuggests that use of pentoxifylline as an adjunctto antibiotics in neonatal sepsis reduces mortalitywithout any adverse effects.

It has been observed that many criticalpatients, even those who are not diabetic, havehyperglycemia and a reduced response toendogenous insulin, possibly because of increasein the level of insulin-like growth factor bindingprotein. The use of exogenous insulin to maintainglycemia within normal parameters has provedto be of benefit, in terms of outcome. In sepsis,normoglycemia restores neutrophil phagocyticcapacity, antiapoptosis activity.

Another strategy which has been suggestedand has already won a place among sepsistreatment is the use of extracorporealsubstitution, such as continuous arterio-venous hemofiltration and plasmapheresis,especially in cases of severe sepsis . They maybe used at any phase of the inflammatory process

with the objective of reducing concentrations ofinflammatory mediators (exogenous andendogenous), and consequentially their potentialto cause damage to target organs

Steroids in sepsis: Corticosteroids have alwaysbeen considered to have some sort of cytokinesynthesis blocking action and being intermittentlyused in treatment of sepsis. Perhaps, its use verylate in the process and the side effects caused thedisrepute for its usage. The observation thatsevere sepsis may be associated with relativeadrenal insufficiency and resistance toglucocorticoid receptors induced by systemicinflammation has awakened interest again.

A randomized double blind placebocontrolled study by Annane D, et al showedbenefit with physiological doses ofcorticosteroids for 7 days with reduction induration of vasopressor usage and lower mortalitywhen compared with controls. Keh D, et alshowed that continuous ,low dose hydrocortisonein septic shock restored haemodynamic stabilityas compared with controls.

In conclusion, research continues lookingfor diagnostic and therapeutic avenues .Many atrials are small in size and encounter manyvariables. No single test for diagnosis, and nosingle therapeutic agent which is successfulconstantly and consistently has been found orprobably will be discovered.

Several combinations will have to be triedout. However,certain strategies are certainly ofbenefit, such as early recognition of sepsis,aggressive initial intervention againsthemodynamic disturbances and rational handlingof antimicrobials. Any advance in theunderstanding of these three strategies willundoubtedly increase the chances of a goodprognosis, although it is not expected that theincrease would be of any great magnitude. Thecombination of immunomodulatory therapies

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appears to be the future for research in this area.Corticoid use, for patients with or without adrenalinsufficiency is resurfacing as a promisingstrategy. Similarly, drotrecogin-að appears to bethe only substance which has demonstrated animpact on mortality, although in an unexceptionalmanner. Because of the peculiarities of children,the scarcity of studies and the complexity ofsepsis in this age group, pediatricians should bealert to new discoveries in this area.

Prevention of sepsis has to be given its dueimportance..Prevention of prematurity and LBWinfants, hand washing, aseptic techniques indelivery room, transport and wards is crucial.Rational antibiotic policy and proper protocolsin utilization of antimicrobials will reducedevelopment of resistance which is emerging asa global threat.

Bibliography

1. Sáez-Llorens X, McCracken GH. Sepsissyndrome and septic shock in pediatrics: currentconcepts of terminology, pathophysiology, andmanagement. J Pediatr 1993;123:497-508.

2 Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septicshock: a reassessment. Crit Care Med1997;25:1095-1100.

3. Levy MM, Fink MP, Marshall JC, et al. SCCM/ESICM/ACCP/ATS/SIS International SepsisDefinitions Conference. Crit Care Med2003;31:1250-1256.

4. Despond O, Proulx F, Carcillo JA, Lacroix J.Pediatric sepsis and multiple organ dysfunctionsyndrome. Curr Opin Pediatr 2001;13:247-253.

5. Leclerc F, Martinot A, Fourier C. Definitions,risk factors, and outcome of sepsis in children.In: Tibboel D, van der Voort E, editores. Updatein Intensive Care and Emergency Medicine 25.Intensive care in Childhood. A Challenge tothe Future. Berlin: Springer-Verlag; 1996; pp227-238.

6. Bochud PY, Calandra T. Pathogenesis of sepsis:new concepts and implications for futuretreatment. Brit Med J 2003;326:262-266.

7. Moscovitz H, Shofer F, Mignott H, BehrmanA, Kilpatric L. Plasma cytokine determinationin emergency department patients as a predictorof bacteremia and infectious disease severity.Crit Care Med 1994;22:1102-1107.

8. Bochud PY, Glauser MP, Calandra T.Antibiotics in sepsis. Intens Care Med 2001;27Suppl :33-48.

9 Guven H, Altintop L, Baydin A, et al.Diagnostic value of procalcitonin levels as anearly indicator of sepsis. Am J Emerg Med2002;20:202-206.

10. Vincent JL, Abraham E, Annance D, BernardG, Rivers E, Van den Berghe G. Reducingmortality in sepsis: new directions. Crit Care2002;6 Suppl 3:1-18.

11. Carcillo JA, Fields AI, Task Force Members.Clinical practice parameters for hemodynamicsupport of pediatric and neonatal patients inseptic shock. Crit Care Med 2002;30:1-13.

12. Albertson TE, Panacek EA, MacArthur RD, etal. Multicenter evaluation of a humanmonoclonal antibody to Enterobacteriaceaecommon antigen in patients with Gram-negative sepsis. Crit Care Med 2003;31:419-427.

13. Lauterbach R, Pawlik D, Kowalczyk D, et al.Effect of the immunomodulating agent,pentoxifylline, in the treatment of sepsis inprematurely delivered infants: a placebocontrolled, double-blind trial. Crit Care Med1999;27:807-814.

14. Annane D, Sébille V, Charpentier C, et al.Effect of treatment with low doses ofhydrocortisone and fludrocortisone onmortality in patients with septic shock. JAMA2002;288:862-871.

15. Keh D, Boehnke T, Weber-Cartens S, et al.Immunologic and hemodynamic effects of “lowdose” hydrocortisone in septic shock. Am JRespir Crit Care Med 2003;167:512-520.

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16. Arons MM, Wheeler AP, Bernard GR, et al.Effects of ibuprofen on the physiology andsurvival of hypothermic sepsis. Crit Care Med1999;27:699-707.

17. Derhaschnig U, Pernerstorfer T,Knechtelsdorfer M, Hollenstein U, Panzer S,Jilma B. Evaluation of antiinflammatory andantiadhesive effects of heparins in humanendotoxemia. Crit Care Med 2003;31:1108-1112.

18. Warren BL, Eid A, Singer P, et al. Caring forthe critically ill patient. High-dose antithrombinIII in severe sepsis: a randomized controlledtrial. JAMA 2001;286:1869-1878.

19. Cohen H, Welage LS. Strategies to optimizedrotrecogin alfa (activated) use: guidelines and

therapeutic controversies. Pharmacotherapy2002;22(12 Pt 2):223-

20 van den Berghe G, Wouters P, Weekers F, etal. Intensive insulin therapy in critically illpatients. N Engl J Med 2001;345:1359-67.

21. Busund R, Koukline V, Utrobin U,Nedashkovsky E. Plasmapheresis in severesepsis and septic shock: a prospective,randomised, controlled trial. Intensive CareMed 2002;28:1434-1439.

22. Krishnagopalan S, Dellinger RP. Innovativetherapies for sepsis. BioDrugs 2001;15:645-654.

23 Martin-Denavit T, Monneret G, Labaune JM,et al. Usefulness of procalcitonin in neonatesat risk for infection. Clin Chem 1999; 45: 440

NEWS AND NOTES

AIIMS GOLDEN JUBILEE SYMPOSIUM ON “PEDIATRIC MALIGNANCIES”

Date: 29th to 31st December 2005

Venue: New Delhi

Contact:

Dr.D.K.GuptaOrganizing ChairmanProfessor and HeadDepartment of Pediatric SurgeryAll India Institute of Medical SciencesNew Delhi – 110 029.Ph: 011-26594297, 26593309Mobile: 9810065280Fax: 011-26588663, 26588641Email: [email protected]

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X-RAY ABDOMEN IN THENEONATE

* Muralinath S

Abstract: This article is about the practical valueof plain x-ray in the evaluation of a neonate’sabdomen. A basic approach to the reading of anx-ray of the abdomen along with the essentialviews to be done at the bedside are considered.The focus is on the evaluation of the neonatalgastrointestinal tract.

Keywords:Neonate, X-ray abdomen, Bowel gas.

The plain x-ray of the abdomen is animportant study in the evaluation of problems ofthe abdomen in the neonate. Its major advantagelies in the fact that it is a relatively simple study,practically available anywhere and can be doneat the bedside. With the present day focus onadvanced imaging techniques, it is not surprisingthat less attention is now paid to the plain x-rayevaluation of the abdomen than in the past.Nevertheless, plain films remain a valuable toolin the assessment of abdominal abnormalities.Intestinal obstruction, free intraperitoneal air andintra abdominal calcifications are readily seen onplain films. More often than not plain films arean excellent guide to determining the properimaging study to perform for a particularproblem.

The abdominal radiograph is not asrewarding as the chest radiograph, yet it is an

important study. In the chest radiograph, thebilateral symmetry of structures and densities isof immense value and offer an excellent groundfor comparison. In the abdomen symmetry is ofminor consideration. In the abdomen, it is a matterof becoming familiar with the appearance ofrelatively fixed organs seen through the everchanging intestinal gas patterns. “ No one normalconfiguration looks exactly like another and theoverall “normal” picture comes only throughexamining many roentgenograms over manyyears”. - Swischuk.

In the evaluation of the x-ray of theabdomen, one will do well to focus initially onthe relatively fixed areas of the gastrointestinaltract and then move on to the others. Relativelyfixed hollow viscus like the stomach (nasogastrictube placement helps in its localization in difficultcases) in the upper abdomen and rectum in thelower pelvis are assessed; the solid abdominalviscera like the liver and spleen are thenevaluated. A general survey of the bowel gaspattern is then done. This is usually an everchanging pattern, with no obvious focal area ofprominence. Evaluation of the bowel gas patternand the anatomic localization of theintraabdominal gas is the key to the diagnosis inthe evaluation of diseases of the G.I. tract. Thediaphragmatic leaflets, the bony structures andthe soft tissues are then evaluated for normality.The overall visceral situs can be assessed andintra abdominal calcification is specificallylooked for and evaluated.

The essential and basic view to be done atthe bedside is the supine view of the abdomen.In the evaluation of abnormal intra abdominal

NEONATOLOGY

* Consultant RadiologistKanchi Kamakoti CHILDS Trust Hospitaland Dr.Mehta’s Hospital Pvt Ltd, Chennai.

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gas patterns (and fluid levels), alternativedecubitus views, prone and supine translateralviews may be taken. Erect view is seldom utilizedin neonatal practice at the bedside. A sick neonateis unnecessarily subjected to stress and thealternative views mentioned can provide all theinformation, if one is tuned to interpret theseviews. It is imperative that unnecessary andunwarranted stress should never be placed on thesick neonate, and views that require minimalhandling of the neonate are resorted to instead.

The focus of this article is on the role ofplain x-ray of the abdomen in the evaluation ofGI tract disorders in the neonate.

In the evaluation of the hollow viscus in theneonate, the assessment of bowel gas pattern isthe key. The bowel gas in the neonate isessentially swallowed air. In the term infant, theswallowed air at birth reaches the stomach and

duodenum by 30-60 minutes, the jejunum by 2-4 hours, the ileum by 4-6 hours, the colon by 12-18 hours and the rectum by 24 hours; by whichtime most of the newborns would have passedmeconium. From the above statement it is evidentthat knowledge of the time at which the studywas done is essential in the interpretation ofbowel gas pattern/distribution. Diminished bowelgas is seen in conditions that impair swallowing(eg. CNS depression, prematurity) and absentbowel gas when there is anatomic discontinuity(eg. oesophageal atresia without fistula) (Fig.1).Thus observation of bowel gas pattern can be aclue to the diagnosis.

Analysis of the gas pattern can be broadlygrouped in to : Abnormal intraluminal andabnormal extraluminal gas. Extraluminal gas maybe intramural or extraintestinal.

Abnormal intraluminal gas patterns

Airless, opaque non-distended abdomen isseen in oesophageal atresia without fistula, as theair does not reach the intra abdominal bowel(Fig1). Diminished bowel gas is seen inconditions that impair the act of deglutition.Repeated vomiting and prolonged nasogastricaspiration can result in diminished bowel gas. Inall these conditions there is no abdominaldistention. When the abdomen is opaque, airlessand distended it is usually due to dilated fluidfilled bowel loops and/or ascites.

Excessive bowel gas with abdominaldistension is seen when there is an impedimentto the onward transit of gas distally; thisimpediment may either be functional or organic.The more distal the impediment/obstruction,more pronounced is the abdominal distension.When there is intraluminal gaseous distension ofthe abdomen, the crucial distinction that one hasto make is between paralytic ileus and mechanicalileus; for one is a medical condition and the othera surgical entity. The plain x-ray plays a vital

Fig 1. Gasless abdomen in OesophagealAtresia

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role in the decision making process. In paralyticileus there is generalized distension/dilatation ofthe entire hollow viscera of the abdomen (Fig.2a),i.e. there is no differential distension of the GItract. In other words, all portions of the GI tractdilate in proportion to each other, and in theclassic case the colon remains larger than thesmall bowel. The dilated bowel loops are lessorderly (appear chaotic) and look disorganized.In mechanical ileus the picture is different. Thegut proximal to the obstruction dilates and thedistal bowel collapses. There is no proportional

dilatation of the entire gut. The number of dilatedloops will depend on the site of obstruction;proximal obstruction will show a few loops whiledistal obstruction shows many. Hence, induodenal atresia it is the “double bubble” and inileal atresia it is multiple loops. The gas distal tothe obstruction will depend on the degree ofobstruction. In complete obstruction the distalbowel will be devoid of gas and in incompleteobstruction, the distal bowel gas will be presentbut diminished. In duodenal atresia, there willbe no gas distal to the site of duodenal obstruction– “Double bubble”; where as in duodenal stenosisor septum with a hole diminished gas will be seenin the distal gut. In mechanical ileus the dilatedloops (number of loops will depend on the levelof obstruction) are visualized discretely and arerather orderly in appearance. In the supine viewthe loops are often seen stacked one over the other– the stepladder pattern. This is characteristic ofmechanical ileus (Fig.3a). When there isconfusion regarding distal bowel obstruction (ileal atresia, meconium plug etc.,) and paralyticileus; a simple prone-translateral view (whichdisturbs the infant the least) will settle the issue.

Fig 2a. Paralytic Ileus

Fig 2b. Prone translateral - Air in rectum

Fig 3a. Mechanical Ileus Fig 3b. Prone translateral - No rectal gas

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In paralytic ileus one will see gas in the rectum(Fig.2b) whereas in mechanical ileus the rectumwill be devoid of gas (Fig.3b). This study shouldbe done before any rectal procedures orexamination, as that would introduce air in therectum and mar the inference.

Abnormal, extraluminal gas pattern

Extraluminal gas may be in the intestinalwall itself (intramural). Intramural air usually isassociated with a loss of intestinal mucosalintegrity secondary to intestinal ischemia orsevere inflammation with resulting necrotizingenterocolitis. The classic radiographic appearanceof intramural air consists of linear or curvilinearcollection of gas within the bowel wall.Unfortunately this is not so in all cases, in somethe collection of intramural gas appears so bubblythat it is difficult to differentiate it fromintraluminal meconium admixed with gas. Inthese situations, clinical correlation is mandatory.

Extraintestinal gas – pneumoperitoneum –usually indicates a hollow viscus perforation, butoccasionally can also be seen secondary tothoracic airleak (Pneumomediastinum). In thesupine position, pneumoperitoneum manifests asincreased transradiancy of the abdominal cavity,that diminishes the hepatic density and outlinesthe falciform ligament; giving rise to the “football sign” (Fig.4a). The diagnosis rests essentially

on the fact of distinguishing gas that appears notto fit in with intraluminal gas patterns. It issurprising to see how large collections of free airmay remain undetected in the supine view forthe uninitiated. When in doubt a supinetranslateral (Fig.4b) or a left lateral decubitusview may be taken to identify the free air lyingbelow the anterior abdominal wall or betweenthe liver and the right lateral wall of the abdomen.To state again, an erect view is seldom required.

It is the clinical presentation that necessitatesand directs the imaging strategy. It is the clinicalcorrelation that often draws the right conclusionwhile analyzing images from the point of viewof diagnosis. GI tract disorders may present asexcessive drooling, choking with feeds,respiratory distress, vomiting, abdominaldistension, non-passage/delayed passage ofmeconium, bleeding per rectum or as sepsis. It isthe presentation that determines the need forimaging. When the presentation is excessivedrooling, choking with feeds and respiratorydistress, the suspicion is oesophageal atresia withor without fistula. A plain film of the chest andabdomen with an NG tube placed will settle thediagnostic issue. In oesophageal atresia, the NGtube will be coiled in the upper pouch with anairless abdomen; when there is associated fistula,NG tube will be seen coiled in the upper pouchbut the abdomen will be quite gaseous (Fig.5).

Fig 4a. Pneumoperitoneum - Supine Fig 4b. Pneumoperitoneum - Supinetranslateral

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‘H’ type fistulas are difficult to diagnose andrequire a more specialized imaging approach.

In the case of vomiting, the nature of vomituswhether bilious or non-bilious provides a clue to

the site of obstruction. Bilious vomiting denotesobstruction distal to the ampulla of Vater.Hypertrophic pyloric stenosis and duodenalobstruction (intrinsic or extrinsic) will presentradiographically as distended stomach, but thenature of the vomitus will reveal the site ofobstruction. In hypertrophic pyloric stenosisthere will be distended stomach (Fig.6a) alongwith some distal gas as the obstruction isincomplete. The diagnosis is confirmed by USimaging (Fig.6b). In duodenal atresia, the classic‘double bubble’ is often seen with no distal gas(Fig.7a), as the obstruction is a complete one.Duodenal stenosis, web / membrane with a holeand annular pancreas, all may have a similarappearance, but usually there will be some distalFig 5. Oesophageal atresia with fistula

(→→→→→ denotes coiling of tube)

Fig 6b. US - IHPS

Fig 6c. US - Normal

Fig 6d. US - MalrotationFig 6a. Distended Stomach

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air. Down’s syndrome is commonly associatedwith duodenal atresia and a survey of the pelviswill reveal that association (Fig.7b). The mostimportant duodenal obstruction (which is anextrinsic one) that has to be diagnosed as earlyas possible is malrotation with volvulus. This isa surgical emergency. An early diagnosis is amust, as a delayed diagnosis of volvulus mayseverely compromise the bowel because ofischemia. In the neonate, upper abdominalfullness or scaphoid abdomen withhaematochezia is taken as malrotation withvolvulus unless proved otherwise. Plain film willshow a distended stomach with paucity of distalgas when there is associated volvulus. Thevomitus / aspirate is bilious. An ultrasound maybe done to evaluate the orientation of the superiormesenteric vessels; normally the vein is seen tothe right of the artery and this orientation isreversed in malrotation (Fig.6 c and d). Thedefinitive diagnosis is made by an upper GIcontrast study (Fig 8). In jejunal atresia, a fewloops beyond the duodenum will be seendistended with no distal gas; distal the atresia,more are the number of dilated loops.

In the evaluation of abdominal distension,it will do well to remember that not allobstructions produce distension (proximalobstructions do not manifest as abdominaldistension and vomiting reduces that further) andnot all distensions are due to obstruction –paralytic ileus is the classic example. Hence thefirst step is to determine whether the distensionis due to organic/obstructive cause or functional/paralytic one. This distinction is mandatory asthe former may warrant a surgical interventionwhile the latter a conservative medical approach.The differentiating features between the two havealready been dealt with. In general, distal theobstruction greater the abdominal distension.Distal obstruction may present as delayed passageor non-passage of meconium. In distal bowelobstruction due to ileal atresia and meconiumileus or meconium plug syndrome, theradiographic distinction may not be clear-cut.Generally air and fluid will be seen in ileal atresia,while it is mostly air in meconium relateddisorders. The so called classic “soap bubble”appearance of meconium and air admixture maybe seen in cases of meconium ileus. Furtherimaging and contrast studies are required to

Fig 7a. Duodenal atresia Fig 7b. Duodenal atresia/Down’s syndrome

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elucidate these cases. Intraabdominal (linear oramorphic) calcification may be seen in meconiumperitonitis with or without pseudocyst.

Abdominal distension with delayed passageof meconium raises the suspicion ofHirschprung’s disease. Barium enema is theimaging study of choice in the evaluation ofHirschprung’s disease. An important differentialdiagnosis in abdominal distension with delayed

passage of meconium is hypothyroidism. Thepresentation practically mimics Hirschprung’sdisease. A high index of clinical suspicion isrequired for detecting this entity.Radiographically, the clue lies in the evaluationof the knees; in hypothyroidism there is delay inthe appearance and in the maturation of theepiphysis of the lower end of femur and upperend of tibia (Fig.9a & b). This is an excellentclue. The final assessment is provided by thehormonal study.

Non-passage of meconium will be seen incolonic atresia and anorectal malformations.Once an anorectal malformation is identified;imaging must be performed to assess the localanatomy as well as the known associations(VACTERL). It is worthwhile to remember thatin anorectal malformation, a good clinicalexamination of the perineum is far morerewarding than radiographic evaluation. Forradiographic documentation a prone translateralview with a marker at the anal site will suffice.“Invertograms” are hazardous. They do notprovide any additional or worthwhile informationand have no place in modern practice to assesswhether the anomaly is high or low (supralevatoror infralevator). Many lines and measurements

Fig 8. Malrotation - Barium

Fig 9a. Normal – Femoral and Tibialepiphysis

Fig 9b. Hypothyroid – Small Femoral andabsent tibial epiphysis

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have been advocated to assess where the airfilledrectum terminates so as to determine whether itis a high or low anomaly. These are not safeguidelines, because the bowel moves up anddown as the infant cries or strains. The decisionsregarding management (colostomy or otherwise)is individualized and rests primarily on thefindings of physical examination.

Necrotizing enterocolitis (NEC) is the mostcommon gastrointestinal emergency in prematureinfant. It is a common, serious and sometimesfatal disease. The major risk factor is prematurity.It is seen as a complication in Hirschprung’sdisease and other congenital bowel obstructions.It’s precise aetiology is unclear and is thought tobe multifactorial. The ileo-caecal region iscommonly affected, though any portion of thegut may be involved.

Once NEC is suspected on clinical grounds,abdominal radiographs are obtained.Unfortunately the radiographic findings are oftennon-specific especially in the early stages. Inearly NEC there is a diffuse non-specific gaseousdistension. This is the most common pattern,similar to that seen in many premature infantswithout NEC. This pattern reflects the functionalimmaturity of the gut in many preterm infants

and is difficult to distinguish from those withearly NEC. In doubtful cases it is safer to err onthe side of overdiagnosis because a delay indiagnosis and institution of treatment may provecatastrophic. A more useful sign of early NEC isdistension localized to focal loops only. A dilatedloop that remains relatively unchanged (in serialfilms) is a feature of advanced disease. The moredefinitive radiographic findings are pneumatosisintestinalis (intramural air) (Fig.10a), portalvenous gas and pneumoperitoneum. Acharacteristic of NEC is linear or cystic intramuralair with submucosal and/or subserosal air. Thecystic collections are usually subserosal, whereas the linear form is usually submucosal. Diffusepneumatosis usually is a marker of advanceddisease. Another pathognomonic sign of NEC isportal venous gas. It is seen as finely branchingradiolucency extending from the portahepatis tothe periphery of the liver. It is picked up early onultrasound as bright, shifting echogenic fociwithin the portal vein (Fig.10b). Pneumatosisintestinalis and portal venous gas are not asominous as they were thought to be.Pneumoperitonium implies perforation. It is theonly universally accepted indication for surgery.

As both the clinical and radiographic signsof early NEC are non-specific; a high index ofsuspicion based on the risk factors is mandatoryfor the early diagnosis and management of NEC.

Fig 10a. Pneumatosis - intestinalis Fig 10b. Air in portal radicles - USG

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With all the current imaging modalitiesavailable, the plain x-ray of the abdomen is stilla valuable study. Even in an emergency, the studycan be carried out at the bedside with least effortand minimal stress on the sick neonate.

The abdominal radiograph provides a greatdeal of information. It is excellent in theevaluation of bowel gas patterns, looking forevidence of obstruction.It does well in thedetection of abnormal intraabdominal gas like,extraluminal gas in pneumoperitonium,intramural gas (pneumatosis intestinalis ) andportal venous air.

The film can also be evaluated for metabolicbone disease and dysplasias. Abnormal

calcifications and intraabdominal fluid can beassessed. Plain films are important in theevaluation of various venous and arterialcatheters/lines.

Key points to remember

1. Plain x-ray of abdomen is a valuable study,especially at the bedside.

2. Evaluation of the bowel gas patterns andintraabdominal gas are the key in GI tractdiseases.

3. Look for association (eg. duodenal atresiaand Down’s syndrome).

4. In the evaluation of NEC a high index ofsuspicion is mandatory.

NEWS AND NOTES

CIPP VII7TH INTERNATIONAL CONGRESS ON PEDIATRIC PULMONOLOGY

Date: 8th to 11th July 2006

Venue: Montreal Congress Center, Montreal, Canada.

Contact:

Anne F. Bidart, MDCIPP VII Secretariat27 rue Massena 06000 Nice, FranceEmail: [email protected]: 33(O) 497038597Fax: 33 (O) 497038598.

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FOLLOW UP OF THE HIGH RISKNEONATE

* Lakshmi V** Shanmughasundharam R

The neonatal care in India has improvedconsiderably in the last two decades. With theemergence of excellent tertiary care centers fornewborns, we are now seeing many children onfollow-up who have been born as premature/low-birth weight baby, or, have been very sick in thenewborn period. Neonatal follow-up programshould be viewed as an essential component ofhigh-risk newborn care.

The goals of the follow-up programincludes:

1. Monitoring growth and nutrition.2. Identification of early neuro-developmental

problems for early effective intervention.3. Audiological and visual screening and

intervention wherever necessary.4. A valued support for the family whose life

is often disrupted by the birth of a prematureor critically ill newborn.

High risk neonates who need follow-up includes:

1. Babies with birth weight less than 1500grams

2. Preterms less than 34 weeks

3. Babies with neurological complications -Grade III-IV, intraventricular hemorrhage(IVH), hypoxic ischemic encephalopathy(HIE), seizures, periventricular leucomalacia(PVL), neonates with abnormal neurologicalfindings

4. Ventilated babies

5. Neonates with ongoing pulmonary disease,chronic lung disease (CLD)

6. Neonates who have recovered fromsepticemia.

7. Neonate who had metabolic complicationslike hypoglycemia, hypocalcemia,hyperbilirubinemia more than 25mg/dL

8. Miscellaneous: Congenital infection, feedingdifficulties, failure to thrive, etc.

Assessment of growth

Low birth weight (LBW) infants areparticularly at risk for growth problems.Monitoring the growth pattern is a valuableindicator of well-being of the high-risk infant.Poor growth may reflect inadequate nutrition,chronic illness or psycho-social difficulties.Many factors may alter the subsequent growthin a baby like in bronchopulmonary dysplasia(BPD), the caloric requirement is much higherthan a normal preterm baby. Neonatal necrotisingenterocolitis (NNEC) of greater than stage IIImay have some degree of mal-absorption. Babieswith neurological illness may have feedingdifficulties and palato-pharyngeal incoordinationresulting in aspiration. Gastroesophageal reflux(GOR) in a preterm baby may also result in poorgrowth pattern. It is crucial to ensure optimal

NEONATOLOGY

* Consultant** Head, Division of Neonatology,

Dr. Mehta’s Hospitals Pvt. Ltd,Chennai

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nutrition and to monitor growth parametersclosely.

When monitoring the growth of a preterm,it is essential to correct or adjust the age ofprematurity (correct age equals chronological ageminus the number of weeks born prematurely).Growth parameters are usually plotted on astandard growth chart by using corrected age.Monthly measurement of length, headcircumference and weight must be plotted on thechart.

To determine if growth in a preterm baby isadequate the original gestational age (GA) mustbe accounted as the catch-up growth is fastestduring 36-44 weeks after conception. PretermAGA infants will catch up with a term AGA’sgrowth by 2-2½ years of age. Head circumferenceis the first measurement to catch up, followed bycatch-up of weight and linear growth.

Among low birth weight infants, small forgestational age infants have less catch up growththan appropriate for gestational age infants. Theytend to have less than normal weight and lengthat 3 years.

Nutritional assessment

Many low birth weight (LBW) infants havefeeding problems. Caloric intake, fluid intake andvitamin and mineral supplementation should bemonitored during weekly visits. For most healthypreterm infants, 110-130 Kcal/kg/day helps toachieve adequate growth. Some infants withchronic disease such as BPD may need as muchas 150 Kcal/kg/day. Increase in the caloricdensity over 24 Kcal/oz may predispose to hyper-osmolar dehydration.

Vitamins and minerals

Vitamin D, calcium, phosphorus, iron, folicacid and zinc are specially important for low birthweight infants. All breast fed infants should

probably receive vitamin supplementation duringthe first year of life. Recommended dailyallowance of multivitamins may be administered.Iron supplementation should be started two weeksto two months after birth, and continued for 12-16 months. Supplemental iron is given in thedosage of 2-4 mg/kg/day. Zinc should be givenin the dose of 0.6 mg/kg/day. Calciumsupplementation in the dose of 200 mg/kg/dayand phosphorus in the dose of 100 mg/kg/dayshould be given with supplemental vitamin D 400IU/day to all infants discharged home on breastto milk.

Immunization

Immunization should be given to the pretermneonates at the appropriate chronological age assoon as feasible. Pertussis vaccine/componentshould not be withheld in any child with CP ormuscle tone abnormality as long as there is nounderlying seizure disorder or progressiveneurological illness. The acellular pertussisvaccine is preferred over the whole-cell pertussisvaccine in infants with neurological problem withseizures. Pertussis component should not bewithheld in babies with BPD as they may haveserious consequences. Oral polio vaccine shouldbe administered at appropriate postnatal age.

Other vaccines, such as those againsthaemophilus influenza type B, hepatitis B,measles, mumps, and rubella, should be given atthe standard chronological age.

RSV immune globulin: Intravenous use ofrespiratory syncytial virus immune globulinshould be considered for use in infants under theage of 24 months of age with CLD who requiredoxygen therapy in the preceding six months andin infants of a gestational age of 32 weeks or less.

Pneumococcal conjuate vaccine (PCV): Allpreterm and low birth weight infants areconsidered at increased risk for pneumococcaldisease. These infants should receive full dose

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of PCV beginning at two months of chronologicalage.

Influenza: All preterm infants should beoffered influenza vaccine beginning at six monthsof age and as soon as possible before thebeginning, and during influenza season.

ROP Screening

It has been estimated that the incidence ofROP is 30% among infants with less than 1500 gbirth weight and 31 weeks of gestation. All babiesless than 2000 g birth weight who have beenventilated and given oxygen need retinalexamination in the early post-natal period. It isbest to do the first examination between 4-6weeks after birth. If no ROP is detected, and ifvascularisation of retina is completed, no furtherexamination is needed. If peripheral retina isavascular, re-examination is needed every weekuntil normal vascularisation occurs or ROPdevelops. If ROP is present, staging is done. Ifthreshold disease is noted, treatment is advisedwithin 48 hours. If sub-threshold disease is noted,re-examination is done weekly till either diseaseregresses or progresses to threshold stage.

Following resolution of ROP, yearly eyeexaminations are suggested to look for refractoryerrors. Rare complications like nystagmus, lateretinal detachment, glaucoma, cataracts andvitreous membranes may be seen; early lasertherapy to the retina can avoid many of thesecomplications.

A fixed strabismus at any age is abnormaland needs a referral to ophthalmologist. A childwith intermittent strabismus at 1 year of ageshould also be referred. Simple screening testsfor visual acuity in the first year of life include:infant’s ability to follow examiner’s face at 1-2months, response to stimuli with a reciprocalsmile, observing the infant during spontaneousplay for eye tracking, reaching for objects andattentiveness to visual stimuli at 3-4 months.

Hearing screening

1-3% of infants in NICU develop hearingloss. TORCH infection, meningitis, anatomicalmalformation of head and neck, hyper-bilirubinemia, neonatal seizures, mechanicalventilation, HIE, PPHN, ototoxic drug usage,prematurity, VLBW, NICU stay and familyhistory of sensorineural hearing loss (SNHL), aresome of the risk factors associated with hearingloss in neonates. Audiological screening byBERA should be done at 3 months of age toidentify any hearing loss and intervene by 6months if any. Hence repeat evaluation shouldbe done at 6 months if first screening is abnormal.Hearing aid can be used early in infancy and isthe primary method of treatment so that there isno delay in speech development.

Developmental screening

The main aim of neurological assessment isto find out the effect of pre-natal and peri-natalevents on the brain and to assess the functionalintegrity of the complex nervous system. Thesingle most important point concerningdevelopment is that the infant’s abilities willcorrespond more closely to the post conceptionalage than post delivery age.

Neurological assessment

Awareness of the pattern and changes ofmotor function within the first year of life allowsus to separate the normal from the abnormal andto assess whether motor abnormalities aretransient or persistent. The evaluation ofneuromotor function is of paramount importancein establishing links between perinatal events andlater outcome.

Amiel-Tison Method of Assessment:Evaluation of muscle tone is a fundamental partof this assessment. There is a waxing and waningpattern of muscle tone from 28 weeks of gestationto the end of first year of life. From 28 to 40

65


weeks of gestation, acquisition of muscle toneand motor function spreads from the lowerextremities towards the head in a caudo-cephalicdirection. After 40 weeks, the process is reversedso that relaxation and motor control proceeddownwards from the head to the lower extremitiesin a cephalo-caudal direction in the next 12-18months (Fig. 1 and Fig. 2).

Examination should be done at three, six,nine and twelve months. For preterms, correctedage or post-conceptional age should be usedrather than chronological age. Duringexamination, infants should be awake and notcrying, lying straight with head in midline.

At the end of first year, motor developmentmay be normal, transiently abnormal orpermanently abnormal.

Cognitive assessment

Early and effective means of monitoringcognitive development is crucial in themanagement of high-risk infants. Cognition ininfancy can be best described as combination ofmultiple factors including infant’s sensorimotorstatus, gross-fine motor development as well associal and language development.

The widely used developmental scales are:1. Trivandrum Developmental Screening Chart

(TDSC): It is an acceptable simple tool for abusy practitioner and at community level.17 test items in it include motor, mental,hearing and vision and given a range of3-97th centile. A vertical line is drawn at thatchronological age. If the child fails to achieveany items short of 3rd centile, the child isconsidered to have developmental delay.

Fig 1. Assessment of passive tone

oo o o o

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2. Baroda Development Screening Test(BDST): This simple screening test has 22motor and 32 mental items. They aregrouped age wise monthly up to 12 months,3 monthly till 18 months and 6 monthly till30 months. A child who fails requires adetailed assessment.

3. Gessell Developmental Schedule: Offersprocedure for evaluating observed behaviorof children from 1 month-6years of agecomposed of 4 scales motor development,adaptive behaviour, language and personalsocial behaviour. It is a screening tool.

4. The Bayley Scale of Infant Development(BSID): Comprises of mental, motor andinfant behavior scale. It is for children 2-30months of age. It is most often used tocharacterize the infant’s developmentalstatus.

5. Denver Developmental Screening Test(DDST). There are four scales assessing fineand gross motor abilities, language and

personal social development for upto 6 yearsof age. It is a sensitive indicator fordevelopmental delay in preterms.

Behavioral problems

The behavioral problems causing concernto parents of premature infant include negativism,temper tantrum, head banging, hyperactive,and/or attention deficit. Behavior problems cancontribute to difficulties in relation to both schoolperformance and other health issues.

Early intervention and physicaltherapy

Ideally all babies discharged from NICUneed some form of special care. One of the mainaim of follow-up service is to identify delayedor abnormal development so that earlyintervention can be started. Early interventionconsists of identifying a baby who already hasor is at potential risk for developing one or theother handicap and subsequently providingremedial measures to lessen its effects.

Fig 2. Assessment of active tone

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The goal of the physical therapy is tooptimize the motor function of an infant withemphasis on establishment of functionalmovement by modifying abnormal movementpatterns and postures into functional effectivepatterns, providing appropriate motorexperiences, and providing adaptations tocompensate for motor deficits. Both transient andlong term motor problems in infants requireassessment and treatment by physical therapist.Treatment can be given through earlyintervention program by physical therapist andspeech therapist.

Neonatal care is incomplete withoutadequate follow-up. So, both the neonatalintensive care and follow-up services have to bedeveloped together. Follow-up of these childrenin the hospital setting and in the community willhelp them to achieve their maximum potential.

Bibliography

1. Desmond M, Wilson G, Alt E, et al. The verylow birth weight infant after discharge fromintensive care. Anticipatory health care anddevelopmental course. Curr probl pediatr1980;10:1-56.

2. Lundstorm U, Sumes MA, Dallman PR. Atwhat age does iron supplementation becomesnecessary in LBW infants? J pediatr 1977;91:878-883.

3. Varghese S, Jain S, Gupta N, etal. Magnitudeof Retinopathy of Prematurity. Experience in alarge maternity unit with a medium size levelII nursery. Indian J Ophthalmol 2001;49:187-188.

4. Hutchison AK ,Sanders RA , ONeil JW,Lovering A, Wilson ME. Timing of initialscreening examination in Retinopathy ofPrematurity. Arch Ophthalmol 1998 ;116: 608- 612.

5. Davis, Barnford J, Wilson I, Ramkalawan T,Forshae M, Wright S .A critical review of therole of neonatal hearing in the detection ofcongenital Hearing impairment. Health Technolassessment 1997;1:10.

6. Frankenburg WK, Dodds JB, Fandal AW etal.Denver Developmental screening testReference Manual 1975 .Revised edition

7. Stewart A. Early prediction of neurologicaloutcome when the very preterm infant isdischarged from the Intensive care unit.AnnPediatrics 1985;32:27.

8. Stewart A. Assessment of preterm infant andprognosis. In Beard R and Sharp F (eds.),Preterm labour and its consequences. London:Royal College of Obstetricians and Surgeons,1985; pp.25-36.

9. Nair MKC, George B, Philip E. TrivandrumDevelopmental Screening Chart. IndianPediatr 1991;28:869-872.

10. Prabhjot Malhi , Pratibha Singhi. Screeningyoung children for delayed Development.Indian Pediatrics 1999;36:569-577.

11. In Amiel-Tison C, Grenier A(Eds).Neurological assessment during the first yearof life. New York and oxford; OxfordUniversity Press 1986;96-145.

12. Pathak AT, Khurana B. Baroda DevelopmentalScreening test for infants, Indian Pediatr 1991;28:29-35.

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FETAL DIAGNOSIS ANDTHERAPY

* Karthikeyan G

Abstract:Advances in medical technology havemade the fetus accessible for diagnosticassessment as well as therapy by various invasiveand non invasive tests and procedures. Thisarticle will review the current status of thescreening and diagnostic technologies that areapplied in fetal medicine as well as thetherapeutic modalities available.

Key words: Prenatal diagnosis, Fetal therapy,Fetal transfusion, Amniocentesis

Congenital malformations are assumingincreasing importance in bringing down theperinatal mortality in India. With the advent ofsurfactant therapy and state of the art neonatalunits the survival of neonates with respiratorydiseases and other major medical problems hasseen a quantum improvement. The prevalenceof a major congenital malformation is about 2 –3 % and not all of them are treatable1. Identifyingthe at risk foetus and wherever possible initiationof therapeutic measures targeting the fetusassumes prime importance in reducing themortality and morbidity due to congenitalmalformations. The concept of fetus as a patientand foetus personhood and the question of fetus’sright to life versus the right of pregnant womenare ethical questions that are hot debates in fetal

NEONATOLOGY

medicine. This article will summarize the currentstatus of fetal diagnostic techniques and fetaltherapy.

Fetal diagnosis or prenatal diagnosis

Fetuses with chromosomal aneuploidy(Trisomy 21, Klinefelter’s syndrome 47XXY,Turners 45 XO), those with isolated majorstructural malformations (cardiac defects, neuraltube defects, defects of abdominal cavity etc) andcertain inherited genetic disorders (cystic fibrosis(CF), thalassemia, haemoglobinopathies, Taysach’s disease, Gaucher’s disease etc) are theones that can be identified using the availablefetal screening and diagnostic techniques (Table1).

Who should be offered prenatal screening?

1. Fetuses at high risk of genetic disorders assuggested by clinical criteria like singletonpregnancy at >35 years age, dizygotic twinpregnancy at age > 31 years, previous siblingwith autosomal trisomy, Klinefelter’ssyndrome or Turner’s syndrome, parentswith chromosomal anomalies liketranslocation etc and those fetuses with anidentified major structural malformation byultrasound.

2. Sibling with a cardiac defect places thefoetus at a high risk of similar defect(atrioventricular defect recurred in 80%,other septal defects in 60% and outflow tractdefects in 47% in a recent study2). Targetedechocardiography is offered at 20-22 weeksto these fetuses.

3. Screening for neural tube defects (NTD) is

* Consultant Neonatologist andPaediatric IntensivistG. K Baby Hospital,Coimbatore, Tamilnadu

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offered to those with family history of NTD,those with exposure to teratogens likehyperglycemia in mothers with type 1diabetes mellitus, hyperthermia and drugslike valproate, carbamazepine andisotretinoin and to those belonging to highrisk ethnic groups like India, China, UnitedKingdom and Egypt.

4. Screening for certain genetic disorders isdone in the relevant ethnic groups like cysticfibrosis in Caucasians, Tay Sach’s,Canavan’s disease and Gaucher’s disease inJews and hemoglobinopathies in certainAsian and African ethnic groups.

The screening techniques

1.Maternal serum alpha fetoprotein (AFP)

AFP is the major serum protein of theembryo analogous to albumin and itsconcentration in the fetal serum steadily increasesupto 13 weeks and then decreases. It leaks into

the amniotic fluid by diffusion and then into thematernal serum wherein it is detected in steadilyincreasing quantities after 12 weeks. Open fetalbody wall defects augment the AFP leak andresult in raised amniotic and maternal serum AFPlevels.

Maternal AFP estimation is done between14th and 22nd weeks and results expressed asMultiple of Median (MoM) of the unaffectedpopulation values. A MoM of 2.5 is consideredthe upper limit of normal. Levels between 2.5 to3.5 MoM are indiscriminate and a repeat sampleis advised. Levels greater than 3.5MoM indicatea fetus at high risk and warrants a high resolutionultrasound which can identify a neural tube defector other causes of raised maternal serum AFP(Table 2 ). Where a diagnosis is not possible bysonographic examination, amniotic fluid AFPestimation is done coupled with acetylcholinesterase assay and the presence of latterenzyme is confirmative of the presence of an open

Table 1. Techniques used for fetal diagnosis

1. Screening techniques:a) Maternal alpha foetoprotein (AFP) assayb) Second trimester Down’s syndrome screening [Maternal serum AFP, hCG, oestradiol and

Inhibin]c) First trimester screening [maternal serum hCG, Pregnancy associated plasma protein (PAPP-

A) and Nuchal translucency]d) High Resolution ultrasound scane) Fetal Echocardiography

2. Diagnostic techniques:a) Second trimester (14 – 20 weeks) amniocentesisb) First trimester (11 – <14 weeks) amniocentesisc) Chorionic villus sampling (CVS) 10 – 13 weeksd) Percutaneous Umbilical Cord Blood Sampling (PUBS)e) Fetal tissue biopsy (liver, skin, muscle)f) Pre-implantation genetic diagnosisg) Fetal cells in maternal circulation

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NTD. Karyotyping is offered to those withelevated amniotic fluid (AFP) levels but absentacetyl cholinesterase enzyme, as the incidenceof chromosomal abnormalities is increased fivefold in such fetuses.

Since 95% of NTD occur in mothers withno previous history, it is recommended thatmaternal serum AFP screening be offered to allpregnant women in the second trimester.

2. High resolution ultrasound

High resolution ultrasound can identifymajor structural malformations of the fetus butthe results are operator dependent and in thelargest trial to evaluate the usefulness of

sonography in detecting the major fetal anomaliesin 15,151 low risk pregnant women, (RADIUStrial, Routine Antenatal Diagnostic Imaging withUltrasound), only 17% of major anomalies werepicked up by routine sonography at 15 – 22 weeksgestation and a second scan at 31-35 weeksgestation3. Currently the major usefulness ofsonography lies in estimation of NuchalTranslucency (NT) which is used in Down’ssyndrome screening. Fetal echocardiography isoffered to those at risk of congenital heart defectsand again its results are operator dependent.Recently real time Magnetic ResonanceImaging(MRI) of the fetus has been used toidentify defects that cannot be detected bysonography like isolated cleft palate4.

3. Down’s syndrome screening

Triple test or Multiple Marker Screening:Mothers carrying a fetus with Down’s syndromehas low levels of AFP and estriol and elevatedlevels of hCG. The analysis of these three analytesin the maternal serum together with maternal agehas been validated as a useful second trimesterscreening test to identify Down’s syndromefetuses with a 60-75% detection rate. Somecentres include a fourth analyte, inhibin. Womenwith a positive screening test are offeredamniocentesis for karyotyping and confirmationof the diagnosis.

First trimester screening: Identification oftrisomies in the first trimester offers more choicesof safe pregnancy termination and thus it isadvantageous to the mother. Combination ofmaternal serum hCG and Pregnancy AssociatedPlasma Protein A (PAPP-A) with NuchalTranslucency (NT) measurement done at 10-13weeks gestation identifies 85% of Down’ssyndrome cases at a false positive rate of 9.4%(BUN Study)5. While hCG levels are raised, thePAPP-A levels are reduced in Down’spregnancies when compared to normalpregnancies.

Table 2. Conditions with abnormalmaternal serum AFP levels

Elevated levels:1. Neural tube defects2. Abdominal wall defects – omphalocoele,

gastroschisis3. Multi foetal gestations4. Foetal death5. Congenital skin defects6. Cystic hygroma7. Oesophageal or intestinal obstruction8. Chorioangioma of placenta9. Urinary obstruction

10. Renal anomalies (polycystic or absentkidneys)

11. Underestimated gestational age12. Maternal hepatoma or teratomaLow levels:1. Chromosomal trisomies (Down’s

syndrome)2. Gestational trophoblastic disease3. Fetal death (later stages)4. Overestimated gestational age

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4. Carrier screening in genetically inheriteddisorders:

Parents at high risk of cystic fibrosis (thosewith CF affected first or second degree relativeand Caucasians) are offered carrier testing toidentify common CF mutations including the

F508 and if both parents are tested positivethen foetal DNA testing is offered.

Diagnostic techniques

Diagnostic techniques are used to confirmthe diagnosis in at risk fetuses identified byscreening techniques discussed above and alsoto reassure the parents in cases of false positivescreening test results.

1. Second trimester amniocentesis

This procedure is performed between 14 to20 weeks and amniotic fluid (20 cc) is obtainedunder sonographic guidance using a 20 – 22 Gspinal needle for fetal karyotyping.Complications are fetal loss in 0.3 - 0.5%, vaginalspotting or amniotic fluid leakage in 1-2% andchorioamnionitis in less than 0.1%.

2. First trimester amniocentesis

This procedure is done between 11 and 14weeks of gestation and although the technique issimilar to traditional amniocentesis, less fluid canbe withdrawn usually only 1 ml for each week ofgestation. Complications include a fetal loss rateof 0.4 – 0.9%as compared to a 0.3- 0.7% for midtrimester amniocentesis and 1.5 % for chorionicvillus sampling and an increased incidence ofpositional foot deformities 0.75- 1.6% versus a0.1 % background rate. Membrane rupture is alsomore likely after early amniocentesis andsignificantly more cell cultures fail necessitatingan additional amniocentesis. For this reason, thisprocedure is not performed in many centres.

3. Chorionic Villus Sampling (CVS)Placental villi are obtained either

transcervically or transabdominally at 10-13weeks of gestation. Since results are obtainedearly in pregnancy it alleviates parental anxietyin case of normal results and also offers earlierand safer choices of pregnancy termination incase of abnormal results. Transabdominal CVSis safer than transcervical CVS, has a fetal lossrate of 1.5% as compared to 0.3-0.7% with midtrimester amniocentesis.

4. Percutaneous Umbilical Cord BloodSampling (PUBS) or cordocentesis

This procedure is used to obtain fetal bloodby puncturing the umbilical vein at or near itsorigin from the placenta with a 22 G needle undersonographic guidance. Its uses are

a) In the assessment, treatment and follow upof red cell and platelet alloimmunization(see later)

b) Karyotyping of fetal blood obtained can beaccomplished within 24-48 hours and thusobviates the delay associated with culture ofskin fibroblasts obtained by amniocentesis.Hence it can be used when amniocentesis orCVS results are confusing and when rapiddiagnosis is necessary.

c) Fetal blood thus obtained can be used forimmunological studies, viral cultures,metabolic and hematological studies andacid base analysisComplications include fetal loss in 1.4%,

cord vessel bleeding in 50%, cord haematoma in17%, feto maternal bleeding in 66% with anteriorplacentation and 17% with posterior placentation.Most of them are transitory.

5. Fetal tissue biopsy

Fetal tissue can be obtained by ultrasoundguided biopsy; for example muscle biopsy todiagnose muscular dystrophy or mitochondrialmyopathy and skin biopsy to diagnoseepidermolysis bullosa.

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6. Preimplantation genetic diagnosis

Either polar body or a totipotent stem cellobtained by blastomere biopsy is subjected togenetic tests like Fluorescent in situ hybridization(FISH) analysis. Only healthy embryos are thenimplanted into the womb. Diseases like cysticfibrosis, thalassemia, sickle cell disease, X linkeddisorders can be prevented by this advanced butstill experimental technique.

7. Fetal cells in maternal circulation

A small number of fetal cells circulate inthe blood stream of pregnant women and thesecan be isolated using cell sorting techniques andused for evaluation of genetic diseases likehemoglobinopathies and fetal red cell D – antigentyping. Nevertheless it is difficult to obtain a pureuncontaminated specimen of fetal cells frommaternalcirculation.

Fetal therapy

Therapeutic options available are1. Pregnancy termination: Single fetal

termination or multifetal reduction2. For twin to twin transfusion syndrome3. Fetal transfusion4. Fetal medical therapy (Table 3)

5. Fetal surgery (Table 4)6. Stem cell transplantation7. Gene transfer

Pregnancy termination

This is offered to fetuses with irremediablestructural anomaly or chromosomal disorder.Prenatal diagnosis allows parents to make aninformed decision after consultation with amultidisciplinary team that comprises of thepediatrician, genetic consultant and theappropriate pediatric sub specialist. Fortechniques of pregnancy termination readers canrefer to any standard text book of obstetrics.

Twin to Twin transfusion syndrome

This can complicate about 15% ofmonochorionic twin pregnancies. The donortwin is anemic, growth restricted witholigohydramnios while the recipient twin isplethoric, plump with poly hydramnios. Thetherapeutic options available are therapeuticamniocentesis (for recipient twin), septostomy,and laser occlusion of placental anastomosis andselective feticide of the donor twin.

Fetal transfusion

Rh D Alloimmunization: Two significant

Table 3. Fetal medical therapy

Medical disorders Treatment and rationale1. Congenital adrenal hyperplasia Maternally administered cortisol to minimize

virilization of female fetus2. Congenital hypothyroidism Intra amniotic thyroxine which will be ingested

by the fetus.3. Fetal thyrotoxicosis Maternally administered propyl thiouracil4. Fetal supra ventricular tachycardia Maternally administered digoxin, flecainide or

amiodarone is given to fetus through umbilicalvein or intramuscular injection into the buttock

5. Fetus at risk of congenital syphilis or Maternal treatment with appropriate antibiotics toxoplasmosis

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advances have influenced our management of Rhalloimmunized fetuses. One is the ability to non-invasively identify the Rh D genotype of thefoetus by typing the fetal cells circulating inmaternal blood using the polymerase chainreaction assay. The other is the advent ofvelocimetry of fetal middle cerebral artery topredict foetal anemia which has superceded thetraditional Liley’s nomogram6. Peak systolicvelocities (PSV) greater than 1.5 multiples ofmedian (MoM) of the specific gestational ageidentifies a fetus with moderate or severe anaemiawith 100% sensitivity and 12% false positive rate.PSV shows a good correlation to the Liley’snomogram which uses serial optical densitymeasurements of amniotic fluid at 450nm thatreflects the bilirubin content of amniotic fluid andhence fetal hemolysis6.

If monitoring of PSV of middle cerebralartery indicates fetal anemia then fetal bloodsampling and transfusion are mandated. Theearliest agreed gestation wherein this can beinitiated is 18 weeks. Either cordocentesis or intra

hepatic vein puncture can be used. The latter istechnically difficult but has a lesser incidence offetal distress. Fetal loss due to the transfusion is1 – 2 % in uncomplicated cases but it can be ashigh as 20% in hydropic fetuses. Group Onegative, cytomegalovirus negative and irradiated(to prevent graft versus host disease) packedRBCs with a hematocrit of 75 – 90% to minimizevolume of transfusion is used aiming at a posttransfusion fetal hematocrit of 55 – 60%6.Weekly measurement of PSV of middle cerebralartery is indicated in follow up of these fetusesto assess the need for further transfusions.

The same principles are applied in themanagement of red cell alloimmunization due tominor group incompatibilities as well as anaemiadue to parvo virus B19 infection. A singletransfusion is all that is needed in most cases offetal parvo virus infection although viralmyocarditis adversely influences the outcome1.Fetal medical therapy

Fetal medical conditions can be treated by

Table 4. Fetal surgery

Surgical disorders Procedures performed

1. Obstructive uropathies Vesico amniotic shunts to decompress thecollecting system and prevent progressivehydronephrosis.

2. Hydrothorax or thoracic masses Thoraco amniotic shuntsleading to pulmonary hypoplasia

3. Cystic adenomatoid malformation Open fetal lobectomy, thoracic shuntscausing hydrops fetalis

4. Congenital diaphragmatic hernia Ex-utero fetal surgery but this is strictlyinvestigational as outcomes are suboptimal andpostnatal outcomes are improving

5. Sacro coccygeal teratoma Debulking surgery6. Cleft lip and palate7 Feto endoscopic approach and repair which

obviates numerous orthodontic, dental and plasticsurgeries that are needed after birth.

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maternal medications that cross placenta. Theconditions and the treatment modalities are givenin Table 3.

Fetal surgical therapy

The major advantages of fetal surgery arescarless wound healing and callus free bonehealing. The risk of fetal loss due to surgeryshould be weighed against the chances of fetaldeath without surgery and informed consent betaken. Percutaneous shunt placements are thecommonly performed procedures (Table 4).Fetoscopy and video endoscopic surgery promiseto be less invasive and hence are more acceptablethan open surgical techniques.

Stem cell transplantation

As fetus is immunoincompetent until18 weeks, it is theorized that it would be tolerantto foreign antigens before that time. Stem celltransplantation may offer a life time cure to manyhemoglobinopathies, severe combinedimmunodeficiency syndrome etc. This therapyis experimental.

Gene therapy

This is the ultimate panacea for thegenetically inherited disorders that will otherwisenecessitate termination of pregnancy. Andersonproposed certain criteria for gene therapy in 19848

which have not been met so far and hence fetalgene therapy is still in its nascent stages confinedto experimental trials. The criteria for therapeuticgene transfer are

1. The normal gene can be inserted into thetarget cells and remain there long enough tohave the desired effect.

2. The level of gene expression in the new genewill be appropriate

3. The new gene will not harm the cell or theindividual.

Points to remember

1. Measurement of various analytes in thematernal serum, high resolutionultrasonography and carrier screening ingenetic disorders are the main screeningtools available in prenatal or fetal diagnosis.

2. Maternal serum alpha fetoprotein (AFP),estriol and human chorionic gonadotrophinconstitute the triple screen that is performedin the second trimester to identify the fetusat risk of Down’s syndrome

3. First trimester screening for trisomiesconsists of maternal serum AFP, PregnancyAssociated Plasma Protein–A and NuchalTranslucency

4. Mid trimester amniocentesis and transabdominal chorionic villus sampling are therecommended diagnostic techniques toassign a diagnosis following positivescreening tests

5. Fetal anemia severe enough to warrantintervention is identified by Peak SystolicVelocity in Middle Cerebral artery of greaterthan 1.5 multiples of median for the specificgestational age and this has replacedtraditional Liley’s nomogram in themanagement of Rh alloimmunization.

References

1. Prenatal Diagnosis and Fetal Therapy In:William’s Obstetrics 22nd Edn. CunninghamFG, Leveno KJ, Bloom SL et al, McGraw –Hill Company Inc., 2005; pp 313-338.

2. Gill HK, Splitt M, Sharland GK, Simpson JM.Patterns of recurrence of congenital heartdisease: An analysis of 6,640 consecutivepregnancies evaluated by detailed fetalechocardiography. J Am Coll Cardiol 2003; 42:923 – 929.

3. Ewigman BG, Crane JP, Frigolotto FD, LeFevre ML, Bain RP, Mcnellis D. Effect of

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prenatal ultrasound screening on perinataloutcome. RADIUS Study Group. N Engl JMed. 1993; 329: 821-827.

4. Kazan – Tanny JF, Levine D, McKenzie C etal. Real time magnetic resonance imaging aidsprenatal diagnosis of isolated cleft palate.J Ultrasound Med 2005; 24:1533-1540.

5. Wapner R, Thom E, Simpson JL, et al FirstTrimester Maternal Serum Biochemistry andFetal Nuchal Translucency Screening (BUNStudy Group). First trimester screening for

trisomies 21 and 18. N Engl J Med. 2003; 349:1405-1413.

6. Kumar S, Fiona R. Management of pregnancieswith Rh D alloimmunization. Brit Med J 2005;330: 1255 – 1258.

7. Papadopulos NA, Papadopoulos MA, KovacsL., et al. Foetal surgery and cleft lip and palate:Current status and new perspectives. Brit J PlastSur. 2005 ;58: 593-607.

8. Anderson WF. Prospects for human genetherapy. Science 1984 ; 226 : 401-409.

NEWS AND NOTES

CME ON “COMMON EMERGENCIES IN CHILDREN”

Date: 19th

March 2006

Venue: Chandigarh

Contact:

Dr.Arun K BaranwalDepartment of PediatricsGovt. Medical College and HospitalSector – 32 B, ChandigarhPh: 0172 – 2665253 Ext. 2514, 2503 (O)9417402242 (M) and 0172 – 2647948 (R)Fax: 91-172-2608488, 2609360.Email: [email protected]

12th East Zone Pedicon & 20th Assam State Pedicon

Date: 19-20 November, 2005

Venue: Guwahati, Assam

Contact:Dr. Garima Saikia,‘Child Health Clinic’, AK Azad Road, Rehabari, Guwahati 781 008,Ph.0361-2260177 (r), 2544310 (c), Cell: 98640-13453, 94351-17865,Email: [email protected]

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FREQUENTLY ASKEDQUESTIONS IN NEONATALOFFICE PRACTICE

1. Is phimosis normal in newborn? What arethe indications for circumcision?At birth the prepuce and glans penis areadherent and cannot be retracted. Phimosistherefore is physiological in newborn up tothe age of 1 year. This per se is not anindication for any intervention. Circumcisioncan be advised after 5 years if the prepucecannot be retracted after a trial of corticosteroid local application. If the infant hasballooning of the prepuce, recurrent balanoposthitis and recurrent UTI, circumcisionmay be considered at an earlier age.

2. What are the important causes for scrotalswelling in a newborn baby and when issurgery recommended?In a baby scrotal swelling can be due tohydrocoele or hernia. Hydrocoele isaccumulation of fluid in tunica vaginalis.In hernia the content of scrotal swelling isbowel loop. In majority, hydrocele is noncommunicating and disappears by 1 year ofage. In some, hydrocele is communicating(persistingly patent processus vaginalisconnecting the scrotum to peritoneal cavity)and is likely to persist. If hydrocele is largeand tense (early surgery) or persistingbeyond 12-18 months, surgical repair isindicated. On the other hand, hernia shouldbe operated at the earliest, as there is a riskof incarceration or strangulation.

3. What are the various anterior abdominalwall hernias?Umbilical hernia is very common and isconsidered normal, especially in pretermbabies. The vast majority of themspontaneously resolve. It is not advisable todo strapping since it delays, rather than helpclosure. Umbilical hernias usually disappearby 5 to 6 months, but they may persist untilthe age of four or five. Incarceration iscommon, strangulation is extremely rarethough it has been documented. If the ringis more than 2 cm it is less likely to closespontaneously and surgery is advocated.Supra umbilical hernias may require surgery,although only for cosmetic reasons. Anepigastric hernia may not get corrected onits own, but does not require treatment unlessit causes discomfort. Divarication of the rectiis a self-limiting condition and is obviousbetween the ages of three and six years, itdisappears without treatment by about tenyears.

4. How do we detect squint in the baby?The eyes of a healthy neonate are frequentlynot aligned and intermittent squint iscommon in the first few weeks of life. Squintmay be due to transient sixth nerve palsy,birth trauma and transient disorders ofvertical gaze. If it persists beyond six weeks,ophthalmological opinion is essential.

5. What are the causes of watery / sticky eyesin a neonate?Nasolacrimal duct obstruction is common inneonates and may lead to persistent watery/

NEONATOLOGY

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sticky eyes. This usually clearsspontaneously by 12 months of age. Frequentgentle massaging at the inner angle of theeyes on the nasal side may be helpful. Ifsymptoms persist beyond 12 months,probing of the duct may be necessary toestablish tear drainage. Rarely it may be dueto acute dacryocystitis.

6. What are the common causes of papularfacial lesions in a newborn?Eruptions similar to acne vulgaris such ascomedones, papules, pustules may be seenover the face and are due to the effect ofmaternal androgens on the pilosebaceousunit. They are usually seen predominantlyin boys and resolve spontaneously withouttreatment. Mild keratolytics like salicylicacid may be used in severe cases. If lesionspersist, virilising syndrome should besuspected.

7. What are the various presentations of‘nappy rash’ and its management?Erythema, edema, papules, blisters, followedby scaling can be seen in the nappy area withmaximum intensity over the convex surfaceof the thighs and buttocks sometimes alsoover the genitalia. It is due to various factorslike irritant effect of ammonia liberated fromthe fecal organisms in wet napkin,maceration, sweating, high humiditiy,bacterial and candidal colonization andsometimes even frank infection. Thetreatment is to keep it clean, dry and wellaerated. Anti barrier cream like vaseline andtopical steroid / antibacterial / anti fungal canbe applied in severe cases.

8. What is cradle cap?Greasy scaling over the vertex of the scalpis called a cradle cap. It usually denotes anincrease in normal scaling and may be dueto infantile ichthyosis or seborrhoeicdermatitis. It responds well to liquid paraffin

and washing, rarely requires topical steroidsor antibacterial agent.

9. What is miliaria and why does it occur?

Miliaria or prickly heat or sweat rash iscaused by obstruction of sweat ducts. Thelesions occur when sweat is unable to escapeon to the surface and over which bacterialcolonization occurs. Neonates are usuallyprone to miliaria due to immaturity of thesweat ducts and nursing being done in awarm environment. Eruptions are either tinyvesicles or erythematous papules, whichdevelop around sweat ducts. They areusually seen over the chest and areas offriction, but may be seen elsewhere.Erythematous lesions may produce itching.The treatment is to reduce the humidity andsweating.

10. What are Mongolian spots?

Mongolian spots are benign pigmentedlesions often found at birth. These lesionsmay be small or large, grayish blue or bluishblack and irregular in shape. They are neverelevated or palpable, most commonly seenin lumbo sacral region, but upper part of theback, buttocks, shoulders, arms, legs andface are occasionally involved. They resultfrom an infiltration of melanocytes deep inthe dermis. They usually fade by the firstyear of life, probably due to decreasingtransparency of the overlying skin rather thana true disappearance of the lesions.

11. What is the common skin rash seen in aneonate in the first 2 days of life?

The common skin rash seen during the first2 days of life is erythema toxicum. It presentsas a scattering of macules, papules andsometimes vesicles that usually occur on theextremities and face. It affects 50- 70% ofterm infants and the cause is not known. Therash usually appears on the first or second

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day after birth and is self-limiting. Thenewborn is active, alert and feeds well. Itmay cause alarm when the vesicles andpapules are numerous and if the lesions arepustular. If the vesicles are punctured andthe fluid examined eosinophils are seen. Theincidence of erythema neonatorum decreaseswith decreasing gestational age. Rarely seenin infants < 30 wks.

12. What are the causes of bowing in aneonate?

Mild bowing of the lower extremities is anormal finding in a baby up to 18 months oflife. Generally the bowing is 15o andconfined to the tibia (genu varum) butoccasionally it can be noted in the distalfemur also. It is often symmetrical andaccompanied by internal tibial torsion.Pathological bowing is rare in a neonate andcan be due to metaphyseal dysplasia,Blount’s disease and rickets, which can bedistinguished radiologically.

BOOK REVIEW

79

Name : Flexible fiberoptic bronchoscopy in childrenEditor : Dr. D. VijayasekaranReview : The book on ‘Flexible fiberoptic bronchoscopy in children’, the first book by an

Indian author dwells on the fundamentals of flexible bronchoscopy. Beginners inthis field will find it very useful when they are proceeding onto do flexiblebronchoscopic procedure. The author has not only given, the indications but also haselaborated on the how to do the procedure under local anesthesia. The author alsogives details on how to clean and maintain the instrument properly. The book alsohas case scenarios with bronchoscopic pictures. The clinical scenarios could havebeen discussed more elaborately. The picture quality could be improved further insubsequent editions.

Publishers : M/s. Kural Publications18, Harris Road,Chennai - 600 002. India

Price : Rs. 500/-

Name : Breastfeeding: A guide for new mothersEditor : Dr. Meenakshi KrishnanReview : The book covers issues like reasons to breastfeed, facts about breast feeding and

problems faced by nursing mother. Added attraction is the frequently asked questionsrelated to breastfeeding. As additional information, the book also covers the nutritionwhile nursing, medication and nursing mother, as well as how to continuebreastfeeding while working. The facts are delivered in a simple language for themothers to understand and will be of immense help for paramedicals also who areinvolved in the promotion of breastfeeding.

Publishers : East West Books (Madras) Pvt. Ltd.,New Delhi - 110 002. India

Price : Rs. 120/-

2005; 7(4) : 351


SYSTEMIC LUPUSERYTHEMATOSUS IN CHILDREN-CLINICAL SPECTRUM ANDMANAGEMENT

* Uma Sankari Ali

Abstract : Systemic lupus erythematosus is anautoimmune multisystemic disease whoseetiology is unknown. The etiology of lupus isunknown. Lupus in children tends to presentacutely with multisystem involvement. Adisciplined approach to the evaluation of everysymptom and sign along with appropriatelaboratory evaluation leads to the correctdiagnosis. When treated adequately the naturalhistory is favorably altered to produce a goodoutcome with improvement in the histopathology.Leading cause of death in almost all series thenand now remains infections followed closely byrenal failure.

Keywords : Systemic lupus erythematosus,Children, Clinical features, Management

Systemic lupus erythematosus (SLE) is anautoimmune, multisystemic, potentially fataldisease that predominantly affects young postpubertal women. 20% of all cases of SLE beginin childhood usually after 5 years of age. Thepredominantly female involvement is not soapparent when lupus occurs in prepubertalchildren, the female to male ratio being 2:1 ascompared to 8:1 in adults1,2.

The etiology of lupus is unknown. It maybe triggered by one or more known or unknownenvironmental factors in a geneticallypredisposed host. There is a multigenicpredisposition to the development of SLE thatmay contribute to the susceptibility at differentcheckpoints involving immune dysregulation,enhanced apoptosis, production of autoantibodiesand decreased clearance of immune complexes.

Although rare, patients with geneticdeficiencies of complement components C1q,C1r, C1s and C4 and C2 are highly predisposedto develop SLE. Complement deficienciesprobably predispose to SLE because ofdisturbance in the processing and clearance ofimmune complexes.

Hormonal factors play an important role inthe expression of SLE with androgenssuppressing and estrogens and prolactinaggravating SLE. Environmental factors thatprecipitate SLE include ultraviolet light, drugs,toxins and infections 3.

Clinical manifestations

Lupus in children tends to present acutelywith multisystem involvement. Fever withmusculo skeletal symptoms, weight loss,anorexia and fatigue are the common presentingfeatures. Arthiritis which is non-erosive and non-deforming is found in 60 to 75% of children andis often a presenting feature1,3,4. The well knownmalar rash is neither pathognomonic nor foundconsistently in patients. It is seen in not morethan 50% of the cases and is less commonly seenin Indian children 4. Anemia is a common findingseen in almost 75% of the Indian children.

NEPHROLOGY

* Pediatric NephrologistChief, Nephrology Division and PICUBJ Wadia Hospital for Children, Mumbai.

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Pleuritis with or without obvious signs is presentin 25%-45% of the children. Overt pericarditisor pericardial effusions are uncommon but 2Decho detection of pericarditis is seen in one-thirdof the patients1,3,4 (Table 1).

Photosensitivity is common, though theinformation is not often volunteered by thepatient. Raynaud’s phenomenon and discoidlupus are rare but significant findings. Alopeciais seen in many children with active disease andin the given setting highly suspicious of lupus.Oral and genital ulcers are painless and may beeasily overlooked.

Renal involvement is very common and isone of the main determinants of the long-termoutcome. It is seen in about 60% of the patientsat presentation. The cumulative incidence ismuch higher and renal involvement eventuallyoccurs in more than 75% of the cases. Clinicalmanifestation may be initially silent withasymptomatic proteinuria or hematuria detectedonly on routine urinalysis. With progressionthere may be acute nephritis, nephritic syndrome,tubulo-interstitial diseases, hypertension andrarely acute renal failure. Findings on urinalysisvary with the severity of the disease. There maybe just leucocyturia, hematuria and / orproteinuria in milder cases. In classical lupusnephritis the urine shows not only massiveproteinuria but also shows telescoped sedimentwith RBCs, WBCs and a variety of castscharacteristic of different stages ofglomerulonephritis. The presence of nephritic-nephrotic features, a telescoped urinary sedimentwith low C3 along with elevated titres of ANAand ds-DNA makes the diagnosis of lupus fairlycertain even when renal involvement occurs asan isolated feature5,6

Renal biopsy is essential as it determines theaggressiveness of the therapy as well as the longterm prognosis. The WHO classification

describes six histological varieties. Diffuseproliferative glomerulonephritis (WHO class 4)carries the worst prognosis with a high risk ofprogression to chronic renal failure.7

The presence of crescents, endocapillaryproliferation, karyorrhexis, neutrophilicinfiltration, fibrinoid necrosis are indices ofactivity and warrant intensive therapy. Thepresence of tubular atrophy, fibrosis and sclerosisare indicators of chronicity that may not benefitfrom immunosuppression.8 Although there is afair correlation between the clinical severity andthe histopathology, this is not absolute. Childrenwithout overt nephritic syndrome and with milderurinary findings can sometimes reveal severediffuse proliferative glomerulonephritis onhistopathology (Table 2).

CNS involvement is not a commonpresenting manifestation but is seen overall in30 to 45% of the patients. Manifestations maybe seen in the form of seizures, altered behaviour,focal deficits or frank psychosis. Though it maybe difficult to diferentiate it from steroid inducedpsychosis and infective causes can be a cause ofmajor diagnostic difficulties. Rapid investigationto exclude infections is needed before institutingaggressive immunosuppression as a mistaken,diagnosis can have a disastrous outcome 9

Infectious complications are extremelycommon and are the major cause of death. Theyoccur in both treated and untreated lupus and canpose serious diagnostic and managementproblems. In the presence of fever, respiratorysymptomatology or CNS involvement considerinfection. Blood cultures and cultures frominvolved sites are a must before startingtreatment. High WBC counts and neutrophilicleucocytosis are not features of SLE and generallyindicate the presence of infections. Howevercounts are often not elevated despite infections.Apparently normal counts may represent

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infection induced elevation from previously lowcounts. A highly elevated CRP titre is alsoindicative of infection. Tuberculosis, fungal andother opportunistic infections also should be keptin mind. Prophylactic antibiotics should bestrictly avoided3

Diagnosis

Although lupus is a multisystemic diseasethe organ involvement need not be simultaneous;it can occur sequentially at any interval of time.Therefore it is not uncommon for a child topresent with predominantly single organinvolvement posing diagnostic difficulties.Mistaken and missed diagnosis is the rule ratherthan the exception.

A high index of suspicion is required todiagnose lupus. Fever with arthritis is oftendiagnosed as rheumatic fever or rheumatoidarthritis. The associated anemia is often notinvestigated in detail and is presumed to benutritional. Another common mistaken diagnosisis tuberculosis because of the prolonged fever,constitutional symptoms and accompanyingpleuritis. It is very uncommon to have a negativemantoux test in a child with pleurisy due totuberculosis and hence one should be very waryof treating a child with pleurisy as TB in theabsence of mantoux positivity. Childrenpresenting mainly with fever are often treated asenteric fever or empirically with antimalarials.The widal test may be falsely positive due to ananamnestic reaction.

A disciplined approach to the evaluation ofevery symptom and sign along with appropriatelaboratory evaluation leads to the right diagnosis.Detailed assessment of anemia including areticulocyte count and a Coomb’s test as well asroutine urinalysis helps to point out to thepresence of multisystemic involvement. 2Dechocardiogram is a useful adjunct to detect thepresence of a silent myopericarditis.

It must be remembered that although multiorgan involvement is common it is not unusualfor a child to present with a single organinvolvement. Presentation with a hemolyticanemia or thrombocytopenia or a nephriticnephrotic syndrome may pose diagnosticdifficulties unless unusual features are taken noteof. The ACR (American College ofRheumatology) criteria of 1982 needs 4 out of11 criteria to be met for making a diagnosis oflupus10. This has been shown to have a sensitivityof 96% and a specificity of 100% in the diagnosisof childhood lupus. The revised 1997 criterionhas substituted false +ve VDRL with false +veVDRL for >6 months and the presence of LEcell phenomenon is no longer included as acriterion. This has been substituted byantiphospholipid antibodies. The diagnosticspecificity of these revised criteria is yet to bevalidated. 11

Although not part of the ACR criteria,measurement of serum complement is a usefuladjunct investigation. It is invariably loweredduring active disease especially in those withrenal involvement. Reduction of C3 usuallyprecedes the development of a clinical relapse.

The loss of recognition of self, leading tothe production of auto antibodies against nuclearantigens is the hallmark of SLE. Most notableamongst these antibodies is the anti nuclearantibody (ANA) which is so consistently foundin more than 95% of all active untreated SLEthat it constitutes one of the 11 criteria fordiagnosis. However, it has low specificity as itis found in a number of viral infections as wellas drugs. Antibodies to double stranded or nativeDNA is highly specific for lupus. Antibodiesagainst Ro and La are important, as their presencein pregnancy is associated with the developmentof neonatal lupus and congenital heart block.They are the only antibodies that can cross theplacenta. The presence of antiphospholipid

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antibodies-lupus anticoagulant and anticardiolipin antibodies is associated with a highincidence of intravascular thrombosis,spontaneous abortions and fetal death. Howeverthey are not specific for lupus and can be foundin many other conditions 3.

Treatment

The treatment of SLE requires a carefulevaluation of the presence as well as severity ofthe organ and systems involved. It must beremembered that SLE is a dynamic disease.When treated adequately the natural history isfavorably altered to produce a good outcome withimprovement in the histopathology. Ifinadequately treated it can progress either overtlyto a more aggressive disease or insidiously tosilent destruction of organs.

Non-steroidal anti-inflammatory drugs havea limited role in childhood SLE. Their main useis in children with predominant musculoskeletalsymptoms without organ or system involvement.Such a situation is rarely encountered inchildhood SLE. Close monitoring is needed inpatients treated without immunosuppression todetect the insidious development of systemicinvolvement. Regular CBC and urinalysis isrequired along with careful clinical evaluation.

For the vast majority of patients steroidsform the mainstay of therapy. Children withsystemic involvement and those withconstitutional symptoms such as fever, anorexia,fatigue and weight loss require steroid therapy.The standard steroid induction therapy consistsof prednisolone 1-2 mg/kg/day in divided dosesfor 4-6 weeks till clinical, laboratory andserological remission is attained. This isindicated by normalizing C3 and negative ANA,dsDNA.

Children with only constitutional symptomsor those with mild systemic involvement can be

treated with lower doses of prednisolone,0.5-1 mg/kg/day in divided doses. However, theresponse may take several weeks or even monthsto occur.

In children with life or organ threateningdisease, a more rapid induction can be attainedwith IV methylprednisolone at 15-30 mg/kg/doseonce daily for 3 to 6 doses. Some of theindications for high dose steroids are CNSdisease, acute renal failure, acute hemolysis,severe thrombocytopenia and pulmonaryhemorrhage.

Maintenance therapy

Once remission is attained it needs to bemaintained with lower doses of steroids to avoidsteroid toxicity while maintaining a disease freestate. Steroids need to be maintained at a dosesufficient to maintain clinical, serological andlaboratory remission. Steroids need to becontinued for several years (not less than 3 years)and in many cases indefinitely.

Tapering should be done very slowly by 10mg if the patient is on > 50 mg/day; by 5 mg ifthe patient is on 20-40 mg/day and by 2.5 mg ifthe patient is on less than 20 mg/day. Taperingcan be done monthly if the patient is taking dailysteroids and 2 to 3 monthly if the patient is takingalternate day steroids. Not all children canmaintain total control on alternate day steroids3.

Second line drugs

All second line drugs are additives tocorticosteroids and not substitutes. Theindications for second line therapy include steroidunresponsiveness, poorly controlled disease,relapse while tapering steroids, steroid toxicity,presence of CNS involvement, serve renal diseaseor life threatening organ involvement.

The various drugs that have been used assecond line are

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CyclophosphamideAzathioprineCyclosporineMethotrexateMycophenolate mofetil

Cyclophosphamide is the drug of choice forsevere renal or CNS involvement. The high riskof toxicity precludes its use in less severe disease.When indicated, it should be used under thesupervision of a pediatric nephrologist or a personexperienced in its use. The NIH trial in adultswith SLE and renal involvement found a betterlong term outcome with a lower incidence ofprogression to CRF in the group that receivedcyclophosphamide when compared to thosereceiving prednisolone alone or prednisolonewith azathioprine12. IV cyclophosphamide isgiven as 500 mg to 750 mg/m2 monthly for 7months followed by three monthly infusions. Itslong term use is associated with secondaryamenorrhea with ovarian failure in 100% of adult

females above the age of 30. Similar therapyhas been recommended for children with class 4lesions. However their place in the managementof childhood lupus nephritis needs to be betterdefined. The risk of gonadal toxicity with pulsecyclophosphamide in prepubertal children has notbeen defined13. It must be remembered thatincidence and severity of SLE varies in differentethnic groups. SLE favourable results are notalways found with this regime in all ethnicgroups. A less toxic and gonad sparingalternative would be to treat initially with oral orIV cyclophosphamide followed by maintenanceimmunosuppression with azathioprine14.Indiscriminate use of cyclohosphamide inchildren whose disease severity could bemanaged with less toxic approaches should bestrongly condemned.

Azathioprine is the oldest second line drugused to treat SLE. It is well suited for treatmentof less severe disease as a steroid sparing drugor to prevent relapses while tapering steroids andas maintenance therapy after the disease is wellcontrolled with steroids and cyclophosphamide.

Although not widely used, three drugs thatmay be useful in selected cases are methotrexate,cyclosporine and mycophenolate. All three couldhave a steroid sparing role in steroid dependentSLE permitting reduction in steroid dosageswithout inducing a lupus flare. Mycophenolatehas also been tried in cyclohosphamide resistantlupus. Methotrexate may have a beneficial rolein resistant arthritis or skin lesions and ininterstitial lung disease 15,16.

Hydroxychloroquine is a useful adjunct andshould be used in all patients needing steroidtherapy. It has a steroid sparing effect andattenuates some of the adverse effects of longterm steroids on lipid metabolism. Regularophthalmic check up is essential to detect retinaltoxicity 17.

Table 1. Clinical manifestation inchildhood SLE

Cassidy Cameron Ali(58 (50cases) cases)

Arthritis 72% 76% 60%Malar rash 51% 56% 30%Alopecia 16% 20% 25%Oral ulcers 12% 16% 10%Anemia 43% 47% 75%Thrombo- 22% 27% 10%cytopeniaPleuritis 31/40% 36/45% 25/30%/ PericarditisRenal inv 84% 86% 75%CNS inv 9% 31% 45%

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Autologous bone marrow transplantationhas been used with short term success inadolescents with SLE. However the long termoutcome is not yet known. The use of biologicalmodulators such as IV immunoglobulin orplasmapheresis is largely anecdotal and at presenthas no place in the routine management of SLE.

General measures

General measures play a very important rolein the successful management of lupus. Theseinclude good nutrition, avoidance of fatigue,protection from sun exposure and avoidance ofdrugs that could trigger SLE.

Exposure to sunlight or UV radiation shouldbe strictly avoided not only in children withphotosensitivity but in all cases of SLE.Sunscreen with a sun protection factor (SPF) ofat least 15 should be used daily when going outduring the day even if it is not sunny. UltravioletB results in photo degradation of native DNA inthe skin thereby increasing its immunogenicity.Light induces apoptosis of keratinocytes whichmay develop small surface blebs that may containlupus auto antigens such as Ro rendering themavailable as immunogens which may triggeractivity of SLE3. Drugs such as chlorpromazinewhich has a similar action should be avoided.

Pubertal girls should avoid oralcontraceptives.

One of the vital requirements for managinglupus is the continuity of care by a team ofphysicians with experience in the managementof SLE and in the use of immunosuppressivetherapy. Continued close surveillance with theaim of total control of the disease and theinclusion of a pediatric nephrologist in the careof the patient from its inception to provideongoing renal surveillance and care are importantingredients for a successful outcome.

Outcome

The mortality has dropped from 42% seenin the 60s to less than 20% today. The mortalityin our setup has been about 28%. However, theleading cause of death in almost all series thenand now remains infections followed closely byrenal failure 1,3,6,18,19.

The quality of life of long term survivors isreasonably satisfactory. In our own follow-upof 12 long term survivors (5-17 years follow-up)7 are in remission with normal renal function andare off therapy. Three of the 7 had WHO class 4on histopathology. Five are still on therapy, 3 ofwhom are in good control with normal renalfunction. One patient with class 4 is inadequatelycontrolled and has hypertension. She isintermittently non-compliant. Only one patientis in CRF. This patient was transferred 10 yearsago to an adult care where his monitoring andtreatment had been very inadequate.

Table 2. WHO histopathological classification and clinical correlations

Class Description Clinical features1. Normal No renal involvement2. Mesangiopathic Asymptomatic hematuria, proteinuria3. Focal proliferative Nephritis, nephrotic syndrome4. Diffuse proliferative Nephrotic syndrome, nephritic features, azotemia5. Membranous Nephrotic syndrome6. Sclerosing Chronic glomerulonephritis, CRF

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The social adjustment of these patients hasbeen good. Barring one girl who has droppedout of school, the remaining are either in collegedoing well in studies or working. Two girls aremarried, one has had 2 successful pregnanciesand the other is now seven months pregnant anddoing well. Lupus may flare during pregnancyand requires close monitoring.

Points to remember

1. Multisystemic, potentially fatal disease.2. A high index of suspicion is required to

diagnose lupus.3. Steroids form the mainstay of therapy.

Second line drugs are additives tocorticosteroids and not substitutes.General measures play a very importantrole in th successful mnagemnt of lupus.

References

1. Platt JL, Burke BD, Fish AJ, et al. Systemiclupus erythematosus in the first two decades oflife Am J Kidney Dis 1982;11:S212-S222.

2. Cameron JS. Lupus nephritis. J Am SocNephrol 1999; 10:413-424.

3. Petty RE, Cassidy JE. Systemic LupusErythematosus In: Textbook of pediatricRheumatology, 4th edn, Eds, Cassidy, Petty,WB Saunders, Philadelphia 2001; pp 396-449.

4. Ali US, Dalvi RB. Systemic lupuserythematosus in Indian children. IndianPediatr 1989; 26:868-873.

5. Cameron JS. Nephritis in childhood andadolescence. Pediatr Nephrol 1994; 230-249.

6. Niaudet P, Salomon R. Systemic lupuserythematosus. In: Pediatric Nephrology, 5th

Edn, Eds, Avner ED, Harmon WE, Niaudet P;Lippincott, Williams & Wilkins, 2004; pp 865-886.

7. Appel GB, Cohen DJ, Pirani CL, et al. Longterm follow-up of lupus nephritis; a study basedon the WHO classification. Am J Med 1987;77:612-620.

8. Austin HA, Munez LR, Joyce KM, et al.Prognostic factors in lupus nephritis.

Contribution of renal histological data. Am JMed 1983;75:382-391.

9. Steinlin MI, Blaster SI, Gilday DL, et al.Neurological manifestations of childhood lupuserythematosus. Pediatr Neurol 1995; 13:191-197.

10. Tan EM, Cohen AS Fries IF, et al. The 1982revised criteria for the classification of systemiclupus erythematosus. Arthritis Rheum 1982;25: 1271-1277.

11. Hochberg MC. Updating the American Collegeof Rheumatology revised criteria for theclassification of systemic lupus erythematosus.Arthritis Rheum 1997;40:1725-1729.

12. Steinberg AD, Steinberg SC. Long termpreservation of renal function in patients withlupus nephritis receiving treatment that includescyclophophamide versus those treated withprednisolone alone. Arthritis Rheum1991;34:945-950.

13. Niaudet P, Treatment of lupus nephritis inchildren. Pediatr Nephrol 2000; 14:158-166.

14. Mok CC, Ho CT, Chan KW, et al. Outcomeand prognostic indicators of diffuseproliferative glomerulonephritis treated withsequential cyclophosphamide and azathioprine.Arthritis Rheum 2002;46:1003-1013.

15. Silverman E. What’s new in the treatment ofpediatric SLE. J Rheumatol 1996; 23:1657-1662.

16. Szer IS, Spencer CH. Mycophenolate mofetiltreatment of severe renal disease in pediatriconset systemic lupus erythematosus. JRheumatol 2001; 28:2103-2108.

17. The Canadian hydroxychloroquin study group.A randomized study of the effect ofwithdrawing hydroxychloroquine sulfate insystemic lupus erythematosus. N Engl J Med1991;324:150-157.

18. Meislin AG, Rothfield NF. Systemic lupuserythematosus in childhood. Analysis of 42cases with comparative data on 200 adult casesfollowed concurrently. Pediatrics 1968; 42: 37-46.

19. King KK, Kornreich HK, Bernstein BH, et al.The clinical spectrum of systemic lupuserythematosus n childhood. Arthritis Rheum1977;20:287-295.

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2005; 7(4) : 359

ACUTE ABDOMEN IN THE CHILD - I

* Vijayalakshmi G** Natarajan B

*** Ramalingam A

We have already dealt with recurrentabdominal pain in a child in earlier issues. Thisarticle will focus on a child with acute abdominalpain. When faced with a distressed, anxiousparent and a history of events, which is not clearimaging of the abdomen can help you to evaluatethe patient. Ultrasound will address your primaryconcern – whether a surgical procedure isindicated or not. It may not always give you theexact answer, but it will definitely help to narrowdown possibilities.

One catastrophic event is perforation. Anx-ray of the abdomen is a more sensitive modalityfor the presence of free air and it is easy to identifyair under the domes of diaphragm. The othersurgical emergency is intestinal obstruction. Thex-ray will show dilated loops of bowel upto thepoint of obstruction but it will not always showthe cause for the block. Other modalities likebarium meal series, ultrasound or CT will helpto delineate the cause.

The imaging algorithm for acute abdomentherefore includes the x-ray of the abdomen as afirst step. This is followed by ultrasound. CT

can be of some help but the disadvantage is theenormous radiation that it entails which is notgood for a growing child.

The commonest cause for acute abdomen isacute appendicitis. The ultrasound features area thickened, non-compressible appendix. Thisis seen as a blind ending, aperistaltic tube in theRIF. (Fig.1). Sometimes it is distended with fluidwith a bright fecolith within it. The mesentericfat surounding it is swollen and bright. Athickened oementum may protectively drape overit and is seen as a horizontally placed echogenicband just under the anterior abdominal wall. Allthese appearances are seen well with a highfrequency probe of 5 or 7 MHz. Ultrasound maynot help in diagnosing appendicitis if it is verymild or if the examination is done very early inthe course of the disease. The technique ofgraded compression with the probe may not bepossible due to the presence of pain. Theassociated ileus may result in gas filled loops ofbowel in the RIF that may block the ultrasound.Therefore, practically speaking, it is reasonableto proceed with surgery when there is a classicalpresentation of RIF pain and tenderness even ifultrasound does not produce clear evidence. Thevalue of ultrasound in these instances is more torule out other problems.

As inflammation proceeds peri-appendicealfluid may collect. Abscess formation is seen asa fluid loculation with a gas component that isseen as white specks within. The appendicularmass consists of thickened aperistaltic bowelloops and omentum surrounding an appendixthat is now ill-defined. (Fig 2).

RADIOLOGIST TALKS TO YOU

* Addl Professor, Dept. of RadiologyChenglepet Medical College and Hospital.

** Lecturer*** Reader

Dept. of RadiologyICH & HC., Egmore, Chennai.

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The same process of walling off aninflammatory process is seen with Meckelsdiverticulitis also. A mass of thickenedaperistaltic bowel loops with small localizedperitoneal fluid collections seen in the suprapubicor umbilical region should lead to a suspicion ofMeckel’s. In other words a mass like anappendicular mass seen medial to the usuallocation of the appendix should also prompt adiagnosis of Meckels. Fig.3 is that of a 19 yearold boy who was diagnosed as appendicular masswhich later turned out to be perforated Meckels.

Another problem in children that can leadto a false diagnosis of appendicitis is mesenteric

adenitis. Mesenteric adenitis is part of asystemicviral infection. There is a cluster of enlargednodes in the RIF with surrounding mesenteric(Fig 4) thickening and hyperperistaltic bowelloops. Enlarged nodes and mesenteric thickeningcan also occur in appendicitis but local ileus ratherthan hyperperistalsis is seen. This may be thedifferentiating feature. However it is practicallydifficult to rule out appendicitis totally and it isbetter to be careful before reporing appendicitisas mesenteric adenitis.

In the next issue we will continue to see moreinstances of how imaging will help in evaluatingthe acute abdomen.

Fig. 1 Fluid filled, non-compressible appen-dix

Fig. 2 Appendicular mass. W is wall of thebowel. O is omentum

Fig. 3 Mesenteric adenitis Fig. 4 Perforated Meckel’s

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2005; 7(4) : 361

AMNIOTIC BAND SYNDROME - ACASE REPORT

* Thiraviam Mohan M* Gopal Subramoniam

Introduction

Amniotic Band Syndrome (ABS) is a set ofcongenital anomalies attributed to amniotic bandsthat stick, entangle and disrupt fetal parts. In viewof its rarity, we report a case of newborn withmultiple constriction bands.

Case report

A term, small for gestational age, femalebaby weighing 2.2 kg was born to a 31 years oldprimi by elective ceasarean section for breechpresentation. There was no history ofconsanguinity miscarriages in mother, orcongenital deformities in the family, The babywas not asphyxiated. She was noticed to havemultiple congenital anomalies talipesequinovarus deformity of left foot, absent rightfoot and syndactyly of both hands. Her headcircumference was 32.5 cm and length 48 cm.There was no facial anomaly. There weremultiple constriction bands observed in the lefthand and both legs. The other systems werewithin normal limits. The ultra sonogram ofabdomen and cranium was normal. With thesefindings a diagnosis of amniotic band syndromewas considered.

Discussion

Amniotic Band Syndrome is a set ofcongenital anomalies caused by entrapment offetal parts in fibrous bands1. It is also called asannular constriction bands, intrauterineamputation, Streeter’s dysplasia, ADAMComplex (Amniotic deformity, adhesion,mutilation), amniotic band sequence.

The incidence of Amniotic Band Syndromeis 1:1200 births2. It is not a genetic disorder butthought to be due to amniotic rupture in earlypregnancy which exposes baby to the fibrousbands originating from the chorion.

Two theories have been suggested to explainthe mechanism of fetal anomalies. Endogenoustheory suggests that the defects result from focaldevelopment errors in formation of limbconnective tissue. Exogenous theory by Torpin3

suggests these bands result in entanglement offetal parts reduced blood supply, leading toconstriction rings and amputations.

The clinical features include distal ringconstriction, limb deformity, intrauterineamputaion, syndactyly, progressive lymphodemaand peripheral nerve palsy. Associated anomaliesinclude cleft lip, cleft palate and clubfoot in 50%of cases. In the case of asymmetric fetalanomalies regardless of presence or absence offibrous bands, Amniotic Band Syndrome shouldbe considered.

The diagnosis can be made by ultrasound.During the first trimester an appearance of a“Cobweb containing a fetus” is suggestive ofABS4. Visualisation of amniotic bands attached

* Department of PediatricsDr.Jeyasekharan Hospital & Nursing HomeNagercoil, Tamilnad

CASE STUDY

89


to the fetus and the restriction of fetal movementsis another observation5. If there is foetal deaththe diagnosis is confirmed by autopsy.

Treatment options for this include surgery6

in which the amniotic bands that threaten toamputate limbs are separated. Syndactyly needsplastic surgery to correct the webbed fingers. Incase of growing hands, distraction augmentation

manoplasty is done. Cleft lip and palate andstrabismus also need correction.

References

1. Seidman JD, Abbondanzo SL, Watkin WG,Ragsdale B, Manz HJ. Amniotic bandsyndrome; report of two cases and review ofthe literature. Arch Pathol Lab Med 1989;113:891 – 897.

2. Kalousek DK, Bamforth S. Amnion rupturesequence in previable fetuses. Am J Med Genet1988; 31:63 – 73.

3. Torpin R. Amniochorionic mesoblastic fibrousstrings and amniotic bands; associatedconstricting fetal malformations or fetal death.Am J Obstet Gynecol 1965; 91:65 – 75.

4. Schwarzler P, Moscosco G, Senat MV et al.The cobweb syndrome: first trimestersonographic diagnosis of multiple amnioticbands confirmed by fetoscopy and pathologicalexamination. Human Reprod 1998; 13:2966 –2969.

5. Randel SB, filly RA, Callen PW, Anderson RC.Amniotic Sheets. Radiology 1998, 166: 633 –636.

6. Quintero RA, Morales WJ, Philips J, Kalter CS,Angel JL. In utero lysis of amniotic bands.Ultrasound Obstet Gynecol 1997; 10:307 – 308.

Fig 1. Showing constriction bands in (L) indexfinger, (L) leg & (R) leg (shown by arrows)

SATELLITE WORKSHOP ON NEONATAL VENTILATION

Date: 6th to 9th April 2006

Venue: Chhattisgarh

Contact:Dr.Sanwar Agrawal, Ekta Institute of Child HealthShantinagar, Raipur – 492 001. Chhattisgarh.Ph: 0771-2424426, 27.Email: [email protected] and [email protected]

NEWS AND NOTES

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2005; 7(4) : 363

AUTHOR INDEX

Anitha Srilakshmi R (60)Arulprakash (162)Arvind Saili (187)Arvind Shenoi (201)Ashish Bavdekar (53)Balameena S (261)Criton S (233)Deenadayalan M (160)Devinder Mohan Thappa (94)Diwakar KK (278)Gopal Subramoniam (361)Ian McColl (83)Indumathi S (15)Jayakar Thomas (82,112)Jitender Nagpal (246)John Matthai (60)Karthikeyan G (341)Karthik Nagesh N(287)Khadilkar V (264)Khadilkar AV (264)Kumaresan G (38)Lalitha Janakiraman (160)Lakshmi V (335)Leema Pauline (38)Madhumati Otiv (53)Mahesh A (261)Malathi Sathiyasekaran (74, 160)Mamta Muranjan (206)Manoj Peter Menezes (201)Maya Chansoria (162)Meena P Desai (46)Meer Mustafa Hussain K (71)Muralinath S (220) (326)Namasivayam Ambalavanan (192)Narayanan P (178)Natarajan B (65, 157, 251, 359)

Panchapakesa Rajendran (261)Panna Choudhury (246)Paramesh H (254)Parthasarathy A (74)Poovazhagi (71)Porkodi R (261)Potharaju Anil Kumar (133)Potharaju Nagabhushana Rao (133)Prakash V (71)Rajkumar Agarwal (206)Rakesh Kain (162)Ramalingam A (65, 157, 251, 359)Ranjan Kumar Pejavar (317)Ratnakumari TL (71)Ravisekar CV (68)Sandipan Dhar (88)Sangeeta Amladi (101)Sanjeev Gulati (21)Seenivasan V (68)Shahbaz A Janjua (106)Shanmughasundharam R (335)Shanthi S (5)Sheela Samanta Mathai (304)Shivbalan So (160)Shivaswamy KN (94)Soumya Swaminathan (31)Stephen Abraham C (38)Sundararaman PG (68)Thiraviam Mohan M (361)Uma Shankari Ali (352)Vasanthamallika TK (68)Vasanthy (261)Venkataraman P (68)Venkatesh Sampath (310)Vijayalakshmi G (65, 157, 251, 359)Vishnu Bhat B (178)

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SUBJECT INDEX

Acute liver failure (53)

Acute renal failure (21)

Adverse cutaneous drug reactions (94)

Approach: respiratory distress newborns (187)

Approach: unconscious child (38)

Amniotic band syndrome (361)

Bacterial meningitis (133)

Birth asphyxia – Definition and current conceptsin management (178)

Camptodactyly (261)

Bacterial skin infections (101)

Collagen vascular disorders (83)

Congenital esophageal stenosis (160)

Current guidelines: septic shock (15)

Cutaneous manifestations: viral infections (233)

Drug resistant tuberculosis (31)

Emergencies: Pediatric dermatology (112)

Feeding low birth weight babies (304)

Fetal diagnosis and therapy (341)

Fetal origins of adult disease (310)

Fibrodysplasia ossificans progressive (162)

Follow-up: high risk neonates (335)

Hypernatremic dehydration in newborn (71)

Hypothyroidism and bilateral ovarian cyst (264)

Inborn errors of metabolism (206)

Management: neonatal, childhoodhypothyroidism (46)

Management: shock (5)

Neonatal hyperbilirubinemia (278)

Neonatal necrotizing enterocolitis (201)

Neonatal sepsis (317)

Pediculosis, scabies (106)

Persistent cough (254)

Prevention of adult disease in children (246)

Probiotics (60)

Radiology

Jaundice (65),

Neonatal jaundice (157)

Renal cystic disease (251)

Acute abdomen (359)

Suprasellar arachnoid cyst (68)

Surfactant therapy (192)

Systemic lupus erythematosus (352)

Urticaria (88)

Ventilation strategies: Respiratory distress (287)

X-ray chest: neonates (220)

X-ray abdomen: neonates (326)

92

2005; 7(4) : 365

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