Sister Jean Ward, phototherapy, and jaundice – a unique human and photochemical relationship Where we came from and where we are going. M. Jeffrey Maisels, MD, DSc Oakland University William Beaumont School of Medicine and Beaumont Children’s Hospital Royal Oak, MI [email protected] Conflicts of Interest • I have no relevant financial relationships with the manufacturers of any commercial products and/or providers of commercial services discussed in this CME activity • I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation Ancient Phototherapy: Heliotherapy Ikhnaton & Nefertiti ~1000BC “The use of light ….may have been originally practiced in India by midwives, who placed unclothed infants with jaundice in the sunlight to cure them.” Lucey NEJM 1969;280:1075 “Sister. J. Ward, the sister in charge of the premature unit (chosen because of her known skill in rearing puppies) was a keen fresh air outdoor fan, and on warm summer days would wheel the more delicate infants out into the courtyard, sincerely convinced that the combination of fresh air and warm sunshine would do them much more good than the stuffy overheated atmosphere of an incubator…….One particularly fine summer’s day in 1956, during the ward round, Sister Ward diffidently showed us a premature baby, carefully undressed and with fully exposed abdomen. The infant was pale yellow except for a strongly demarcated triangle of skin very much yellower than the rest of the body. I asked her, ‘Sister, what did you paint it with – iodine or flavine, and why?’ Sister Ward explained that…….it was a jaundiced baby, much darker where a corner of the sheet had covered the area. ‘It’s the rest of the body that seems to have faded.’” R.H.Dobbs and R.J.Cremer, Arch Dis Child 1977;50:833 Mislaid pre-exchange tube of blood ……….. “When eventually found (on a window sill), it was noticed that the serum was green instead of yellow and the bilirubin content was far below what was expected……..There was no escaping the fact that while exposed to sunlight there had been a reduction in the bilirubin content of the sample.” “It seemed that we had stumbled on something that might have a practical application.” Dobbs and Cremer, Arch Dis Child 1977;50:833 Photo-sensitivity of Serum Bilirubin R.J.Cremer, P.W. Perryman, D. H Richards, Brenda Holbrook Biochem J 1957;66: 60P (Proceedings of the Biochemical Society, Newcastle Upon Tyne) • Icteric sera exposed to daylight, sunlight, and artificial light • Bilirubin levels decreased rapidly INFLUENCE OF LIGHT ON THE HYPERBILIRUBINAEMIA OF INFANTS R.J. Cremer* M.B. Lond., D.C.H Paediatric Registrar P.W. Perryman M.Sc. Lond. Biochemist D.H. Richards F.I.M.L.T. Chief Technician, Biochemistry Department General Hospital, Rochford, Essex Lancet 1958;1:1094-1097 8 40 watt “light blue” fluorescent tubes Sunlight Blue Light n 13 9 Bilirubin before phototherapy (mg/dL) 17.4 ± 4.3 14.7 ± 3.4 2.5 ± 7 18.3 ± 8.5 3.9 ± 2.9 4.3 ± 1.9 Exposure duration (h) Bilirubin decrease (mg/dL) PHOTOTHERAPY PUBLICATIONS 1958-1967 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Cremer Franklin Ferreira Ferreira Ferreira Berezin Mellone Peluffo Arocha de Pinango Berezin Capozzi Lancet 1958;1:1904 Lancet 1958;1:1227 Rev Ass Med Brasil 1960;6:201 An Brasil Ginec 1960; 49:149 J Pediat (Rio) 1960;25:12 Matern Infanc (S. Paulo) 1960;19:169 Rev Paul Med 1960;57:47 Arch Pediat Urug 1962;33:98 Arch Ven Puer Ped 1963;26:153 Matern Infanc (S. Paulo) 1963;22:529 Matern Infanc (S. Paulo) 1963;22:529 PHOTOTHERAPY – PUBLICATIONS 1958-1967 12. De Carvalho 13. Obes-Polleri 14. Mininni 15. Croso 16. Gomiratosandrucci 17. Ballabriga 18. Sandrucci 19. Broughton 20. Obes-Poleri 21. Ansaldi 22. Alison 23. Stambler 23. Obes-Polleri Matern Infanc (S. Paulo) 1964;23:427 Rev Chile Ped 1964;25:638 Rev Clin Pediatr 1964;73:297 Minerva Pediat 1964;16:131 Minerva Pediatr 1965;17:394 Rev Esp Pediat 1965;21:121 Minerva Pediat 1965;17:394 Arch Dis Childh 1965;40:666 Arch Pediatr Urug 1966;37:533 Minerva Pediatr 1966;18:201 Ann Pediat 1966;1:118 Pediatria (Bucur) 1966;15:273 Arch Pediatr Urug 1967;38:77 Jornal De Pediatria 1960;25:347-391 First use of this term 77 jaundiced infants “Phototherapy is very efficient in correcting hyperbilirubinemia” “We do not advise this treatment for the hemolytic baby” Jerold Lucey, University of Vermont 10 GE 20 watt daylight bulbs Lucey, Ferreiro, Hewitt, Pediatrics 1968;41:1047 Phototherapy from 12 – 144 hours. Rx 58, Control 53 Pediatrics 1968;41:1047 How Does it Work? Anthony F. McDonagh Ph.D. C.Chem., M.R.S.C. 1938 -2012 University of California San Francisco University of Nevada, Reno J. Donald Ostrow 1930 -2013 Northwestern University Medical School Bilirubin Photo Oxidation in Vitro Bilirubin Light Monopyrroles Polar, colorless oxidation products Dipyrroles McDonagh NICHD Monograph 1976 Maisels and McDonagh, New Engl J Med 2008;358:920-928 Blue light around 460 – 490 most effective Maximal absorption of bilirubin and good skin penetration Maisels and McDonagh, New Engl J Med 2008;358:920-928 Phototherapy Does Not Use Ultraviolet Light  UVB UVA BB LED UVA 200 UVB 300 400 wavelength nanometers 500 600 Phototherapy works quickly Mreihil et al Pediatr Res 2010;67:656-659 A clear dose-response relationship and no saturation point NeoBlue LED 4 groups of 38 infants placed 47,38,29,20 cm from light Vandborg P K et al. Pediatrics 2012;130:e352-e357 Does it prevent kernicterus, improve developmental outcome and is it safe? 2 large NICHD randomized controlled trials 1974-76 and 2002-2005 Pediatrics, February 1985 Infants born 1974-76 1339 Infants, 6 hospitals 672 phototherapy 667 controls Mean Bilirubin Levels in Infants < 2000g PT at 24±12 h X 96h Exchange if TSB 10 -17mg/dL Irradiance ~ 7µW/cm2/nm Brown Pediatrics 1985;75: 393-400 Less Kernicterus at Autopsy 119 deaths, 76 autopsies (64%) Phototherapy Autopsy Kernicterus Control 39 0 37 4* P = 0.033 Fisher exact test *Birth weights 760-1260g Peak TSB 6.5-14.0 mg/dL * One infant assigned to phototherapy group at 21 hours but did not receive phototherapy until 43 hours. After one hour of phototherapy, exchange transfusion performed. If include in phototherapy group P = 0.20 Lipsitz PJ, et al. Pediatrics 1985;75:422-426 But Increased Mortality in Infants <1000g n Died Phototherapy Control 59 38 23 (59%) 15 (40%) Relative risk 1.49 (0.93-2.40) P = 0.112 Lipsitz et al. Pediatrics 1985;75:422-426 Poland Pediatrics 1986;78:179-80 NICHD Neonatal Research Network Trial Born 2002 -2005 in 16 centers 1974 infants < 1000g Aggressive Management n=990 Conservative Management n=984 Birth Weight (g) Phototherapy Phototherapy (mg/dL) 501-750 ASAP after enrollment ≥ 8.0 751-1000 ASAP after enrollment ≥ 10.0 PT Duration (hours) 88±48 35±31 Irradiance 22-23µW/cm2/nm Morris et al NEJM 2008;359:1885-1896 Mortality and Impairment Death or impaired <1000g 501-750g Death* Impaired** Aggressive Conservative RR (95% CI) 52% 55% 0.94 (0.87-1.02) 39 27 34 32 1.13 (0.96-1.34) 0.86 (0.70-1.05) * Only in infants ventilated at 24 hr (Tyson J Perinatol 2012) **Blind, deaf, moderate or severe CP, MDI or PDI <70 In 501-750g 5% ↑ in mortality, 5% ↓ in impaired survivors Morris et al NEJM 2008;359:1885-96 Bayesian Analysis Among infants 501-750 g ventilated at 24 h, • 99% posterior probability of increased mortality despite use of a neutral prior. • 97% posterior probability of decreased NDI • 99% posterior probability of decreased profound NDI • Tyson et al J Perinatol 2012;32:677-684 How has it helped? Maisels. J Perinatol 2001;21:S93 Maisels. J Perinatol 2001;21:S93 How Many Exposed to Phototherapy? • North America and Europe ~ 15,700,00 annual births • Assume 5% receive phototherapy =785,000 infants annually • China and India ~ 45,072,734 annual births • Phototherapy 2,251,386 (?) • Total ~ 3,000,000 per year excluding the rest of Asia, Japan, Indonesia, Africa, Australia • World total >5,000,000 annually • Since 1970 ~ 215 million Safety of Phototherapy • If something bad was happening after 200 million treated we should have heard about it by now • No serious short term clinical side effects observed in infants >1000g But • ↑Mortality < 1000g • Little systematic long term follow-up • Possible long-term consequences Potential Mechanisms for ↑ Mortality in Infants <1000g • • • • DNA damage Decreased cytokine levels Oxidative stress ↓Cardiac output,↑CBF,↓renal blood flow Lymphocyte DNA Damage in Infants Receiving Phototherapy - Comet test* *Single Cell Electrophoresis Assay measures DNA strand breaks in eukaryotic cells Tatli et al Mutation Res 2008;654: 93-95 Dermal CO excretion in Wistar rat pups. Photo oxidation of dermal biomolecules (oxidative stress) Fluorescent 1 BB, 2 cool white Blue LED Vreman et al. Pediatr Res 2009;66:66-69 Can we avoid the downside of phototherapy in ELBW infants? Options: • Lower irradiance (in ‘74-’76 trial only 78µW/cm2/nm) • Shorter duration (’74 96h , ’08 88h aggressive, 35 conventional) • Intermittent phototherapy Phototherapy Light 4Z, 15Z bilirubin molecule Skin 1-3 hrs Serum Unactivated 4Z, 15Z bilirubin nanoseconds isomers 10-15 min isomers Trials of Intermittent Phototherapy “….1 hr on and 1hr off is as effective as continuous PT…” (Niknafs et al, 2008) “…..one in four hours achieved the same treatment effect as continuous PT.” (Lau et al, 1984) “……15 min. on, 60 min. off are as effective as continuous illumination.” (Vogl et al 1978) Potential Long Term Risks of Phototherapy • ↑melanocytic nevi, risk factor for malignant melanoma • Association with – myelocytic leukemia (OR 7.5, 95% CI: 1.8, 31.9) – Juvenile-onset diabetes (OR 3.8, 95% CI: 3.1, 4.6) – Hospitalization for asthma (OR 1.27, 95% CI: 1.08, 1.50) Phototherapy • Discovered in 1956 by Jean Ward, pediatricians and biochemists at the Rochford General Hospital • Simple, cheap and effective tool in the management of the jaundiced newborn • Used on millions of newborns with a significant safety profile • Dramatically ↓ need for exchange transfusion • ↓ neurodevelopmental impairment and kernicterus but ↑ mortality (<750-1000g) • Still need to evaluate short and long term safety to establish a cost/benefit ratio in both term and ELBW infants Thank you, Sister Jean Ward H1024 Section on Perinatal Program: Day 2 Scan this code to submit an evaluation