7
Indian J Pediat 47 : J09-115, 1980 PHOTOTHERAPY IN NEONATAL HYPERBILIRUBINEMIA P.K. Misra, M.D., D.C.H., and Ravi Kaul, Ph. D. Phototherapy in the management of photodecay was virtually arrested with or neonatal hyperbitirubinemia has been without riboflavin. 1~ shown to be highly effective in lowering Recently Kaul et al observed stimula- plasma bilirubin levels, t-z Despite the tion of bilirubin decomposition by efficacy of phototherapy in bringing supzroxide anion generating system? 1 about containment and/or significant These observations indicate that biliru- decrement of circulating plasma biliru- bin is degraded by radical species of binin the affected jaundiced neonates, oxygen (superoxide anion) besides well its place in the management of jaundice documented singlet oxygen mediated in newborns has been commented upon pathway. as being controversial. 4 The need for such a treatment cannot be overemphasi- Site of action sed as jaundice of mild to severe grade Earlier studies indirectly suggest that occurs frequently in newborn babies and skin provides an alternate medium for isknown to cause brai~l damage and/or catabolism of bilirubin. 12-t'~ However, death.S clinical, and experimental studies have demonstrated that skin is provided with a Mechanism of action mechanism for the uptake, concentration Phototherapy was first used by and metabolism of bilirubin and also Cremer et al 6 and has since been increas- provides a matrix for photoconversion, is, 16 Vogl suggested a local action of ingly applied. Light stimulates a lowering of serum bilirubin level by light on accumulated bilirubin. 1~ He converting bilirubin into water soluble proposed that 'photons' generated by products. 7 During photooxygenation photoexposure, penetrate almost 2 mm bilirubin acts as a ptlotosensitiser of its into the skin, which is likely site for the own decomposition. It was suggested decomposition of bilirubin. 17 Icteric that singlet oxygen - a high energy form skin provides a matrix for bilirubin of molecular oxygen-may be further photooxygenation, since skin has greater mediating the photooxygenation of affinity for free bilirubiu, is Thus the bilirubin, s'9 This was further supported primary site of photoconversion of by the finding that riboflavin induces bilirubin is the skin itself during photo- bilirubin photodecomposition nearly 25 therapy, administered prophylactically fold under aerobic conditions while and therapeutically. Recently Rubal- telli et al have observed that photoeon- version occurs in liver itself since shield- From the Department of Pediatrics, K.G. MedicalCollege, Lucknow. U.P. ing of hepatic area during illumination Reprint address: Dr. P.K. Misra, Professor significantly decreased the rate ofbiliru- of Pediatrics. bin decay in full term neonates, as

Phototherapy in neonatal hyperbilirubinemia

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Page 1: Phototherapy in neonatal hyperbilirubinemia

Indian J Pediat 47 : J09-115, 1980

PHOTOTHERAPY IN NEONATAL HYPERBILIRUBINEMIA

P.K. Misra, M.D., D.C.H., and Ravi Kaul, Ph. D.

Phototherapy in the management of photodecay was virtually arrested with or neonatal hyperbitirubinemia has been without riboflavin. 1~ shown to be highly effective in lowering Recently Kaul et al observed stimula- plasma bilirubin levels, t-z Despite the tion of bilirubin decomposition by efficacy of phototherapy in bringing supzroxide anion generating system? 1 about containment and/or significant These observations indicate that biliru- decrement of circulating plasma biliru- bin is degraded by radical species of binin the affected jaundiced neonates, oxygen (superoxide anion) besides well its place in the management of jaundice documented singlet oxygen mediated in newborns has been commented upon pathway. as being controversial. 4 The need for such a treatment cannot be overemphasi- Site of action sed as jaundice of mild to severe grade Earlier studies indirectly suggest that occurs frequently in newborn babies and skin provides an alternate medium for isknown to cause brai~l damage and/or catabolism of bilirubin. 12-t'~ However, death.S clinical, and experimental studies have

demonstrated that skin is provided with a Mechanism of action mechanism for the uptake, concentration

Phototherapy was first used by and metabolism of bilirubin and also Cremer et al 6 and has since been increas- provides a matrix for photoconversion, is,

16 Vogl suggested a local action of ingly applied. Light stimulates a lowering of serum bilirubin level by light on accumulated bilirubin. 1~ He converting bilirubin into water soluble proposed that 'photons ' generated by products. 7 During photooxygenation photoexposure, penetrate almost 2 mm bilirubin acts as a ptlotosensitiser of its into the skin, which is likely site for the own decomposition. It was suggested decomposition of bilirubin. 17 Icteric that singlet oxygen - a high energy form skin provides a matrix for bilirubin of molecular oxygen-may be further photooxygenation, since skin has greater mediating the photooxygenation of affinity for free bilirubiu, is Thus the bilirubin, s'9 This was further supported primary site of photoconversion of by the finding that riboflavin induces bilirubin is the skin itself during photo- bilirubin photodecomposit ion nearly 25 therapy, administered prophylactically fold under aerobic conditions while and therapeutically. Recently Rubal-

telli et al have observed that photoeon- version occurs in liver itself since shield-

From the Department of Pediatrics, K.G. Medical College, Lucknow. U.P. ing of hepatic area during illumination

Reprint address: Dr. P.K. Misra, Professor significantly decreased the rate ofbil i ru- of Pediatrics. bin decay in full term neonates, as

Page 2: Phototherapy in neonatal hyperbilirubinemia

1 l 0 "flit_: INDIAN JOURNAL OF PEDIATRICS Vol. 47, No. 385

Nature of photocatabolites

Bilirubin undergoes a variety of oxidative reactions. The mechanism and products of bilirubia photooxidation vary somewhat with nature of solvent. 19- zl Preliminary studies rovealed that like photooxygenation of bilirubin in vitro, there is an increased excretion of water soluble bilirubin catabohtes in jaundiced neonates subjected to phototherapy, However, only few metabolites resemble each other in vivo and in vitro photo- exposure 7.

The water soluble degradation pro- ducts of bilirubin that are excreted cons- titute mainly maleimids, propentdyo- pents and pentdyopents along with some acid components.-~ ~3 One common point to both the systems lies in accum- ulation of more and more water sol tble compounds. The photocatabolites isola- ted from urine of jaundiced neonates were observed to be nontoxic compared to bilirubin itself. 24

Dose response relationship

A dose response relationship in the treatment of hyperbilirubinemia by visi- ble light is shown to exist. This relates to the rather broad region of th~ spec- trum within which bilirubin and its initial breakdown products are most photoreactive (420-400 n m ) a n d to the major absorption band of bilirubin itself (450-455 nm). 25 The response of photo- therapy increases with increasing dose till a saturation point is reached beyond which no further increase in response occurs. 26

There is a general agreement that the blue portion of the visible light spectrum is most effective in the photooxidation of bilirubin. In fact a direct positive cor-

relation exists between blue light irra- diance received by jaundiced infant and decrease in bilirubin levels, e7 However, the use of blue light in phototherapy suffers from some disadvantages. The nursing staff develop number of distress- ing effects such as headache, nausea and vertigo. Further there is difficulty in assessing the infant 's skin color and clinical status under the blue light. 29 The efficiency ratio of blue: white lamps varies inversely with the total radiance at which they are compared. Increased radiance results in shorter duration of phototherapy. '25 Overall the rapidity of bilirubin decay was quite different with different fluorescent tubes., and the gra- d ien tofb i l i rub in decrease depends on the base line concentration.

Mode of phototherapy

Continuous phototherapy is being commonly used, but recently the efficacy of intermittent phototherapy !',.as been reported. It was proposed t}~tt during illumination a considerable part of biliru- bin bound in the skin is photooxi'dised and moves out whi!-' shutting the light off allows fresh bilirubin to pass into the skin, 29 however, others did not favour this hypothesis. :~~

Intermittent phototherapy was sugges- ted to be as effective as continuous illumination, at while another group observed that continuous phototherapy in the full term neonates was more effective tha~ intermittent illumina- tion. ~8 ttowever, no general concensus has emerged till date. Sa,~te~la et al observed deleterious effect of intermittent phototherapy on DNA as compared to continuous phototherapy. 32

Page 3: Phototherapy in neonatal hyperbilirubinemia

~ltii~.k AND KAUL : PItOTOTHERAPY IN HYPERBILIRUBINEMIA III

Phototherapy apparatus

Phototherapy is administered in pediatric wards of King George's Medical College, Lucknow by a locally improvised apparatus fitted with ten white fluorescent tubes (Osram-C,-ol daylight, 40 W). The source of light in single surface ('SS') is fixed at a distance of about one meter yielding intensity of light measuring ~etween 400-500 foot candies at the exp,;sed body surface. The intensity of the light is periodically checked by exposure meter. The posi- tion of neonate is ('hanged frequently to give exposure to different surfaces of the body. 33

Double surface ( 'DS') phototherapy is a modification of single surface photo- therapy apparatus, having ten fluores- cent tubes on either side of a glass table. It exposes both dorsal and vemral sur- face of neonate simultaneously kept naked on the glass table. 34

Neona'es are kept in phototherapy chamber continuously ti!l their serum bi~irubin levels fall to 6-7 mg/dl except during fe,ding and c'eaning. The eyes ~.fthe neonateb are protected by thick black cloth s!:ields.

Efficacy of 'DS' over 'SS' phototherapy

The efficacy of double surface photo- therapy over single surface phototherapy wa~ evaluated by measurement of plasma bilirubin in two sets of patients. Patients exposed to double surface exhibited t/2 of 33 hours as con,pared to 77 hours in single surface confirming our earlier observation that skin prcvides a matrix for bilirubin decay because large surface area is exposed to light ~imultaneousiy. 34 However, Tan failed to get added

efficacy by double surface photo- theragy, s5

Indications for use

(a) Prophylactic. Phototherapy when used prophylactlcally before the appearance of jaundice within 24 hours of life, was highly effective in reducing the incidence of clinical jaundice, The peak levels of biiirubin attained are also much lower than in t~e control group, s Several other studies also support its prophylactic role in neonatal jaundice particularly in prematures.~,3~, a7

(b) Therapeutic. Photothelapy has been found effec:ive in the prevention as well as treatment of 'Coomb's negative' hyperbilirubinemia irrespective of its etiology, a In our study phototherapy was started at plasma bilirubin level of 10mg/dl or more and continued till ~he levels fell to 6-7 mg/dl, a The mean duration of phototherapy was 50.8 hours with a range of 24-96 hours. Babies having higher initial bilirubin concentration m the blood had a higher rate of fall in the first 48 hours Serial estimations of plasma bilirubin in the hyperbilirubinemia group subjected to phototherapy revealed statistically signi- ficant falt as compared to control group not given such therapy. It was also able to keep the bilirubin concentration below the 'risk zone' when started at an initial level below 18mgldl. Similar observations have been made by others.;'3,36, 37

(c) Hemolytic hyperbilirubinemia. Clinical trials with phototherapy have also been extended to hemolytic hype- bilirubinemia due to Rh and ABO isoim- munization.3S, 42 In such states photo- therapy has been shown to reduce the rate of rise of bitirubin followed thereat'-

Page 4: Phototherapy in neonatal hyperbilirubinemia

1 1 2 TIlE INDIAN JOURNAL OF PI-DIATRICS

ter by continuous fall. In a severe hemolytic state in the initial period of therapy it may not be able to contain the bilirubin in the safe zone of less than 20mg/dl, and hence the neol~ate may require exchange transfusion but the number of exchanges needed is reduced.40, 4e

Management of neonatal hyperbiliru- binemia with exchange transfusion remains a highly specialised technique requiring well developed blood banking services, ideally situated in immediate vicinity. The procedure is costiy, requires good laboratory services and is traumatic to the neonate limiting its use only to few centres in the country.

In Rh hemolytic disease of newborn (HDN) p!~ototherapy should be started prophylactically soon after birth and plasma bilirubin levels closely monito ed. The time of initiation of light treatment, the type and intensity of light, its con- t inui tyand the period for which it is administered apart from the severity of Rh disease and the rate of bilirubin rise per hour in the initial phase, are import- ant determining factors for the success of phototherapeutic management of hy~erbilirubinemia of Rh disease. Majority of neonates suffering from ABO HDN show a rate of rise of serum biliru-

bin of the order of (,.5mg/dl/hour and lessaS, 1~ and thus phototherapy can effectivelycoatain hyperbilirubinemia in such cases. However, fall of hemoglo- bin as a result of hemolysis requires sim- ple transfusion to correct the anemia. In severe cases of hyperbilirubinemia requir- ing exchange transfusion rebound rise of bilirubin can be well controlled by it.

Side effects of photolherapy No serious untoward effects of photo-

Vol. 47, No. 385

therapy except skin rashes and diarrhea in some cases have been found, a Increased losses of body fluids and poor gain in weight, mild temperature disturbancesaJ, a4 and occasionally bronze discoloration of skin 45 have been noted under the effect of phototherapy. Follow up studies of newborns thus treated have not shown any effect on physical growth, hearing and vision. 12,46 47 Further, only 3 out of 31 children followed upto 36 months showed some degree of mental retardation which u, as related to very 'high bilirubin' levels at the time of initiation of phototherapj . 45 There was no correlation between the duration of phototherapy and developmental retar- dation

Phototherapy at peripheral centels

It is suggested that peripheral photo- therapy units may be established all over the country at various levels viz, district hospitals, tehsil hospitals, and village hospitals wherever ele("ricity is available. Such units should be under the supervision of a 'Central Surveillance Unit ' at the level of tl'e medical college, being looked after by a doctor and assis- ted by technician and paramedical staff. The training imparted to medical and paramedical staff will not only orient them towards the problem of neonatal jaundice but also equip them in under- taking relevant aspects of neonatal care and family planning methodology as well as motivation.

Every peripheral unit armed with competent technical staff shall screen serum bilirubin levels in neonates In order to avoid the cumberscme problem ofbi l i rubin estimation by colorimetr:, 48 each unit when provided with a biliru-

Page 5: Phototherapy in neonatal hyperbilirubinemia

MISRA AND KAUL : PHOTOTHERAPY IN ItYPERBIL1RUBINF.MIA 113

binometer', shall ensure ready avail- ability of the reports to concerneddoctor, who in turn will instruct his paramedical staff about the mode and initiation of of phc, totherapy.

In conclusion, various studies have revealed that phototherapy can be regard- edas a cheap, effective, efficient and safe method of management of neonatal hyperbilirubinemiabeing simple enough (compared to exchange transfusion) for wider use .qt minimal recurring cost. -Ihe technique used could also contribute to reduction in mortality in the affected babies, as also in the incidence of brain damage, thereby helping in the reduction of burden on the family and community, otherwise required for caring of babies suffering from such preventable brain damage

References

1. LuceyJ. Ferriero M, Hewitt J :Prevent ion of hypcrbitirubinemia of prematuri.'.y by photoiberapy. Pediatr ics41:1047,1968

2. Maisle~ MJ : Bitirubin - on understanding and influencing its metabolism in the newborn infant. Pad Clin N A m 19:447, 1972

3. Bajpai PC, Misra PK, Das VK, Tripathi TK, Kapoor CL : Evaluttion of phototherapy in ABO homolytic disease of the newborn. Indian J Mad Res 61 : 1658, 1973

4. Editorial : Phototherapy in neonatal jaundice Br Mad J ii : 62, 1972

5. Gerves JM, Day RL : Intelligence quotient~ of children who have recovered from erythroblastosis fetalis. J Pediatr 36:342, 1950

6. Cremer RK, Perryman PW, Richards DH : Influence of light on the hyperbilirubinemia. Lancet 1 : 1044, 1958

7. Bajpai PC, Srivastava KL, Singl: B, Krishna Murti CR, Kapoor CL : Urinary photocafa- bolites of bflirubin in jaundiced neonates. |ndian J Med Res 64 : 529, 1976

8. Mc Donagh AF : The role of singlet oxygen

in bilirubin photo-oxygenation. Biochem Biophys Res Commun 44 : 1306, 1971

9. Bonnett R, Stewart JCM : Singlet oxygen in the photooxidalion of bilirubin in hydroxylic solvents. Biochem J 130 : 895, 1972

10. Sanvordekar DR, Kostenbauder HB : Mechanism for riboflavin enhancement of bilirubin photodecomposit ion in vitro. J Pharm Sci 63 : 404, 1974

11. K a u l R , Kaul H K , Bajpai PC, Krishna Murti CR : Evidence for the possible involve- ment of the superoxide radicals in the photodegradation of bilirubin. J Bioscience 1 : 377, 1979

12. Behrman RE. Hs iaDYY : Summary of a symposium on phototherapy for hyperbili- rubinemia. J Pediatr 75 : 718, 1969

13. Schmid R : More light on neonatal hyper- bilirubinemia. N Engl J Mad 285 : 520, 1971

14. Schmid R:Bi l i rub in metabolism in man. N Engl J Mad 287:703, 1972

15. Kapoor CL, Krishna Murti CR, Bajpai PC: Role of human skin in the photodecomposi- lion on bilirubin. Biochem J t42:567, 1974

16. Bajpai PC: Experimental studies in the mechanism of phototherapy, ht New Developments in Pediatric Research. Pro- ceedings of XV [nternaticnal Congress of Pediatrics New Delhi. ed. Gl:ai OP. 1 : 261, 1977

t7. Vogl TP : Phototbcrapy of neonatal hyper- bilirubinemia : bilirubin in unexposed area of the skin. J Pediatr 85 : 707, 1974

18. Rubaltelli FF, Zanardo V, Granati B : Effect of various phototherapy regimens on bilirubin decrement. Pediatrics 61 : 838 1978

19. Gray CH, Kulczyeka A,, Nicholson DC: Photodecomposition of bilirubin and other bile pigments. J Chem Soc Perkin Trans 1 : 288, 1972

20. Ostrow JD, Nicholson DC, Stoll M S : Derivatives of alkaline degradation of bili- rubin. Gastroenterology 60 : !86, t971

21. Bonnett R, Stewart 3CM : Photooxidation of bilirubin in hydroxylic solvents. J Chem Soc Perkin Trans I : 224, 1975

22. I_ igh~nerDA:In vitro photooxidation pro- ducts of biiirubin. In Phototherapy in the Newborn : An Overview. (ads) Odell GB, Sckafl'-r R an,3 Simopouios AP. NationM

Page 6: Phototherapy in neonatal hyperbilirubinemia

114 THE INDIAN .IOURNAL OF PEE./ATRICS

Academy of Scienccs, Washington DC. 1974, pp 34.

.7.3. Bonnet R, Stewart JCM : Photooxidation of bilirubin in hydroxylic solvents : propentdyo- pent adducts as major product. J Chem Soc Chern Commun 596, 1972

24. Kaul R, Misra PK, Kaul HK, Bajpai PC : Nontoxicity of biodegradation products of bilirubin on human erythrocytes. Indian J Med Res 1980 (In press)

25. Sisson TRG, Kendall N, Shaw E, Kecha- varz Oliai L : Phototherapy of jaundice in the newborn infants 1I. 12ffect of various light intensities. J Pcdia~r 81 : 35, 1972

26. Tan K L : T h e nature of the dose rcsponse relationship to pho',ofl:erapy for neonatal hyperbilirubinemia. J Pediatr 90 : ,-148, 1977

27. Ballowitz L, Geutler G, Goebel A, Kroch- mann J : Dose response relationship in phototherapy (Pcr.~,cnnd communication)

28. Sisson TRC, Kendall N : Avoidance of undesirable effects of blue light in photo therapy. J Pedimr 82: 163, 1973

29. Zachman RM : Alte:nalive phomtherapy in neonatal llspeibiliru-r'.inemia. 12i(~1 Neonate 25 : 283, 1974

30. Batlowitz L, Gentler G, K r o c h m a n n J : P b o t o t h e r a p y i n G u n n r a t s - a s l u d y to assess the photobiologicaily most cffeclive radiant energy anddo~cresponsc relationship. Biol Neonate 31 : 229, 1977

31. Vogl "I'P~ HcgyiT, tliatt IM, Polin RA, Indyk I_ : Intermillcnt pkctotherapy in the treatment of jaundice in the premature infant. J Pediatr 92 : 627, 1978

32. Santella RM, Roscnkranz HS, Speek WT: Intracel!uar deoxyribonucleic acid modify- ingac t iv i tyof in te rmkte l : t phototherapy. J Pediatr 93 : 106, 1978

33. Bajpai PC, Misra PK, Das VK, Singh D, Kapoor CK, Krishna Murthi CR :Photo- therapy in h3perbi! i lubinemiaof the new- born. Indian J Med Res 61 : 577, 1973

34. Srivastava KL, Misra PK, Kaul R, Bajpai PC: Double surface 'DS' photothcrapy vs single surface 'SS' photothcrapy in neonatal jaundice. Indiau .i Med Res 1980 (In press)

Vol . 47, N o . 385

35. Tan KL : Comparison of the effectiveness of single direction and double direction photo- therapy for neonatal jaundice. Pediatrics 56 : 550, 1975

.,46. Porto SO : In vitro and in vivo studies on the effect of photothcrapy upon bilirubin. In Bilirubin Metabolism. Birth Defccts-- Original Article Scries. National Founda- tion. March of Dimcs, New York. 6 :83 , 1970

37. Behrman RE, Brown AK, Curric MR, Hastings JW, Odell GB, Schaffer R, Setlow RB, Vogl TP, Wuitman RJ : Preliminary report of the committee on p!~ototherapy in the newborn infants. J Pediatr 84 : 133, 1974

38. Bajpai PC, Tripathi TK, Singh D, Kapoor CI. : Phototherapy in Rh incomparability hyperbiiirubinemia. Indian J Med Res 61 : 221, 1973

39. BajpaiPC, Misra PK, Das VK, Singh D : Phototherapy it, I~yperbilirubinema of the newborn. Indian J Med Res 61 : 577, 1973

40. Kaplan E, Hera F, Seb.eye E, Robinson LD : Photothcrapy in ABO hemolytic disease of the ncwborn infants. J Pediatr 79 : 911, 1971

41. Sisson TRC, Kendall N, Glauser SC, Knu t sonS , Bunyaviroch 12: Phototherapy of jaundice in newborn infants I. ABO blood group incomparability. J Pediatr 79 : 904, 1971

42. Reid M, McClureC, Marks GME, t-lv, ood JH : Phototherapy in rhesus hemolytic disease. Lancet 1 : 879, 1972

43. Oh W, Karechi H : Phototherapy and insen- sible water loss in the newborn itafants. Am J Dis ChiJd 124 : 230, 1972

44. Wu Paul YK : Immediate and long term effects of phototherapy on preterm infants. In Phototherapy in Newborn: An Overview. (eds) Odcl! GB,-Schaffer R and Simopulos AP. National Academy of Sciences, Washinglon DC. 1974, pp 150.

45. Kopelman, AE, Brown RS, Odell GB : The bronze baby syndrome. A complication of phototherapy. J Pediatr 81 : 466, 1972

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MISRA AND KAUL i PHOTOFHERAPY IN HYPERBILIRUBINEMIA 115

46. Misra PK, Srivaslava KL, Singh B, Bajpai PC:Follow up of newborns treated with phototherapy. Indian J Med Res 1980 (In press)

47. Hodgman JE, Teberg A : Effect of photo- therapy on subsqucn! growth and develop- ment of the premature infants. In Bilirubin

Me~abolisrn. Birth Defects--Original Article Series. National Foundation, March of Dimes, New York. 6 : 75, 1970

48. Malloy lIT, Evelyn KA : The determination of bilirubin with photoelectric colorimeler. J Biol Chem 119 : 481, 1937

BOOK REVIEW

Liver anti Biliary Trac! Disease in Child- ten D. A1.AGII_LE alad N. O D 1 E V R E , pp. 348. John Wiley, New York and Flammarion, Paris. 1979, Price $37.50,

methods o f investigation is inadequate. Liver disorders encountered in t ropical regions are very briefly described and some do no t find any ment ion at all.

The b o o k summarizes the extensive experience o f two reputed French pedia- tric hepatologists and their colleagues, The contents are a curious mix of anary- sis of case material da ta and subject review. The authors discuss the various common clinical disorders o f the liver encountered in infants and children. Particularly outs tanding are the sections on bilirubin, cholestasis a n d neonatal hepatitis. Other areas are dealt with less satisfactorily. The initial chapter on

Professors Alagille and Odievre have dotte a useful job by sharing their clinical experience and knowledge. However , the b o o k fails to provide comprehensive coverage and is unlikely to compete with the two texts on the subject published recently by Churchill Livingstone and Butterwort~s.

R.K. Chandra , M.D. F R . C . P ( C )

Cambridge, MA, USA