PHOTOTHERAPY-A REVIEW

1. PHOTOTHERAPY-A REVIEW WILLIAM OH, MD BROWN MEDICAL SCHOOL FDA CONFERENCE, JUNE 11,2003

2. OUTLINE • HISTORICAL NOTES • MECHANISM-HOW IT WORKS • EFFICACY DATA • SIDE EFFECTS • LONG TERM OUTCOME

3. HISTORICAL NOTE FIRST PAPER ON PHOTOTHERAPY PUBLISHED IN 1958 (CREMER,LANCET) BASED ON THEIR IN VITRO OBSERVATION OF FALLING VALUES OF BILIRUBIN WHEN SERUM SAMPLES WERE EXPOSED TO LIGHT

4. HISTORICAL NOTES-CONT’D • SEVERAL CLINICAL TRIALS IN THE ’60s CONFIRMED THE EFFICACY OF PHOTOTHERAPY LEADING TO ITS USE AS STANDARD CARETRIALS ALSO SHOWED MORE EFFICACY AMONG LOW BIRTH WEIGHT INFANTS

5. MECHANISM • BILIRUBIN ABSORS PHOTON FROM LIGHT AT 450 nm ( IN VITRO) • PHOTOCHEMICAL REACTIONS • FORMATION OF THREE MAJOR PRODUCTS THAT ENHANCES ELIMINATION

6. ABSORPTION SPECTRUM OF BILIRUBIN

7. ABSORPTION OF LIGHT BY BILIRUBIN IN VIVO • BECAUSE BILIRUBIN IN VIVO IS BOUND TO ALBUMIN ,SPECTRUM OF MAXIMUM ABSORPTION IS SHIFTED TO THE RIGHT ( 450 TO 475 nm) • THIS EXPLAINS THE VARIABLE EFFICACY OF LIGHT USED IN CLINICAL SETTING

8. PHOTOCHEMICAL REACTIONS LIGHTBILIRUBIN ABSORBS PHOTON ‘ EXCITED’ BILIRUBIN ↓ ↓ ↓ ↓ PHOTO-OXIDATION ↓ STRUCTURAL ISOMEZARATION (LUMIRUBIN) ↓ CONFIGURATIONAL ISOMERIZATION ( 4E,15Z,4Z,15E AND 4E,15E PHOTOISOMERES)

9. PHOTO-OXIDATION • SINCE CREMER’S REPORT(1958), IT HAS BEEN ASSUMED THAT PHOTO-OXIDATION IS THE MECHANISM FOR  BILIRUBIN EXCRETION • 1984, ISOMERE FORMATION FOUND TO BE THE MAJOR MECHNISM

10. CONFIGURATIONAL ISOMERIZATION (4Z,15E)

11. STRUCTURAL ISOMERIZATION (LUMIRUBIN)

12. PHYSICAL PROPERTY OF BILIRUBIN AND ITS PRODUCT • NATIVE BILIRUBIN ( 4Z,15Z) HYDROPHOBIC AND LIPOPHYLIC • BILIRUBIN ISOMERES ARE LESS LIPOPHYLIC AND HYDROPHOBIC • ENHANCE ELIMINATION VIA BILE AND URINE

13. RATE OF FORMATION & ELIMINATION OF BILIRUBIN • RATE OF FORMATION:4Z,15E ISOMERES > LUMIRUBIN > PHOTO-OXIDATION PRODUCTS • RATE OF EXCRETION:LUMRUBIN >4Z,15E > PHOTOOXIDATION PRODUCTS • LUMIRUBIN APPEARS TO BE THE MAJOR FORM OF ELIMIATION

14. PHOTO-CHEMICAL REACTION & ELIMINATION OF BILIRUBIN

15. FACTORS AFFECTING EFFICACY OF PHOTOTHERY • DEPENDENT ON • TYPE OF LIGHT USED • LIGHT INTENSITY • SURFACE AREA OF SKIN EXPOSED TO LIGHT • DISTANCE FROM LIGHT TO BABY

16. TYPES OF PHOTOTHERAPY DEVICE • FLUORESCENT TUBES • DAYLIGHT(WHITE) • BLUE • GREEN • HALOGEN LAMPS • FIBEROPTIC SYSTEM • GALLIUM NITRIDE LIGHT EMITTING DIODES (L.E.D)

17. COMPARISON OF DIFFERENT LIGHTS % REDUCTION IN SERUM BILIRUBIN P<0.05 TAN KL ET AL: PEDIATRICS,114:132,1989

18. CONCLUSION (TAN) • PREFERABLE TO USE EITHER DAYLIGHT( PROVIDES ENHANCED CLINICAL OBSERVATION AND ADEQUATE EFFICACY) OR BLUE LIGHT (BETTER EFFICACY) • NOT GREEN LIGHT WHICH PROVIDES NEITHER

19. HALOGEN LAMPS • MORE COMPACT THAN FLORESCENT LAMP • CAN NOT BE BROUGHT TOO CLOSE TO INFANT ( RISK OF BURN)

20. FIBEROPTIC SYSTEM (WALLABY) • ADVANTAGES • NO EYE PATCH NECESSARY • MORE PORTABLE • CONVENIENT FOR MOTHER AND HOME THERAPY • DISADVANTAGE • LOW SPECTRAL POWER

21. FIBEROPTIC VS. CONVENTIONAL DECLINE IN SERUM BILIRUBIN (M/L/HR) N.S. P<0.05 FIBER CONV.

22. LIGHT EMITTING DIODES • NARROW BAND OF LIGHT SPECTRUM( BLUE-GREEN) • POWER EFFICIENT AND LOW HEAT EMISSION • SOMEWHAT EYE-IRRITATING TO THE STAFF

23. LIGHT SPECTRUM OF LED

24. RCT FOR LED VS HALOGEN LAMP SERUM BILIRUBIN (µM/L) ENTRY DURING (N=34)(N=35) SEDMAN, DS ET AL J PEDTRIC136:771,2000

25. DIFFERENT MODES OF PHOTOTHERAPY

26. CONTINUOUS VS INTERMITTENT PHOTO-THERAPY PERCENT REDUCTION IN SERUM BILIRUBIN ------N.S.------- N=69 N=47 CALDERA,R ET AL ANN PEDIAT 1984

27. CONTINUOUS VS INTERMITTENT PHOTO-THERAPY-2 RATE OF DECLINE IN SERUM BILIRUBIN M/L/HR N=10 N=13 N=10 N=12 -N.S.- RUBALTELI LAU

28. SINGLE VS. DOUBLE PHOTOTHERAPY DECLINE IN SERUM BILIRUBIN (M/L/HR) P<0.01 0<0.05 P<0.01 SINGLE DOUBLE SHARMA

29. HOME PHOTOTHERAPY-AAP GUIDELINES STATEMENT • AN ACCEPTABLE ALTERNATIVE • CRITERIA FOR ELIGIBLE INFANT SET BY INSTITUTION • APPROPRIATE FOLLOW UP FOR BILIRUBIN LEVELS • IF BILIRUBIN LEVEL DOES NOT DECLINE APPROPRIATELY, ADMIT FOR MORE INTENSIVE RX GUIDELINE FOR PERINATAL CARE, 5TH ED.

30. ACUTE SIDE EFFECTS OF PHOTOTHERAPY •  INSENSIBLE WATER LOSS • LOOSE OR WATERY STOOL •  RESPIRATORY RATE •  BODY TEMPERATURE

31. POTENTIAL COMPLICATION • TOXIC EFFECT ON THE OPTIC NERVE • DEMONSTRATED IN ANIMAL STUDY • EYE PATCH USED FOR PRECAUTION

32. LOW BIRTH WEIGHT INFANTS • NICHD STUDY ( ’80s) SUGGEST HIGHER MORTALITY RATE AMONG PHOTOTHERAPY GROUP • EFFECTS ON PATENT DUCTUS ARTERITUS • ASSOCIATION WITH INCREASE INCIDENCE OF BLINDNESS DUE TO RETINOPATHY OF PREMATURITY (ROP)

33. PHOTOTHERAPY AND PATENT DUCTUS ARTERIOSUS % N=36 N=38 ROSENFELD,W ET AL PEDIATRICS,78:10,1086

34. MULTIVARIATE ANALYSIS FOR PSB &PHOTOTHERAPY YEO KL ET ALPEDIATRICS 102:1426,1998

35. LIMITATION OF YEO’S DATA • RETROSPECTIVE ANALYSIS • SMALL SAMPLE SIZE (N=145) • EYE EXAMS NOT DONE UNIFORMLY • RESULTS HAVE NOT BEEN CONFIRMED

36. NEURO-DEVELOPMENTAL OUTCOME • NICHD TRIALS IN THE EARLY 80’S PROVIDED AN OPPORTUNITY TO EXAMINE THE NEURO-DEVELOPMENTAL OUTCOME OF PHOTOTHERAPY SCHEIDT,PC ET AL PEDIATRICS,85:455,1990

37. ONE-YEAR OLD OUTCOME (FULL TERM) SCORE N.S. N.S. PHOTO CONTROL N=105 99 SCHEIDT,PC ET AL PEDIATRICS,85:455,1990

38. SIX-YEAR OLD OUTCOME (PRE &FULL TERM INFANTS) IQ N.S. N.S. PHOTO CONTROL N=328 325 SCHEIDT,PC ET AL PEDIATRICS,85:455,1990

39. LOW BIRTH WEIGHT INFANTS (<2 KG) • NO DIFFERENCES WERE OBSERVED BETWEEN PHOTOTHERAPY AND CONTROL IN BOTH 0NE AND SIX YEARS: • NEUROLOGICAL FINDINGS(CP) • DEVELOPMENTAL PERFORMANCES

40. SUMMARY • PHOTOTHERAPY- EFFECTIVE TREATMENT FOR NEONATAL JAUNDICE • MECHNISM-IS WELL DEFINED • ACUTE EFFECTS ARE KNOWN AND MANAGEBLE • NO SIGNIFICANT ADVERSE OUTCOMES IN TERM INFANTS • SOME LINGERING CONCERNS IN LBW INFANTS-NEED FURTHER INVESTIGATION