Thor Willy Ruud Hansen

• Hansen, Thor Willy Ruud (2025). Andre veier til kunnskap enn gjennom randomiserte studier. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(3). doi: 10.4045/tidsskr.25.0033. Full text in Research Archive
• Ebbesen, Finn; Vreman, Hendrik Jan & Hansen, Thor Willy Ruud (2023). Blue-Green (~480 nm) versus Blue (~460 nm) Light for Newborn Phototherapy—Safety Considerations. International Journal of Molecular Sciences. ISSN 1661-6596. 24(1). doi: 10.3390/ijms24010461. Full text in Research Archive Show summary

  We have previously shown that the phototherapy of hyperbilirubinemic neonates using blue-green LED light with a peak wavelength of ~478 nm is 31% more efficient for removing unconjugated bilirubin from circulation than blue LED light with a peak wavelength of ~452 nm. Based on these results, we recommended that the phototherapy of hyperbilirubinemic newborns be practiced with light of ~480 nm. Aim: Identify and discuss the most prominent potential changes that have been observed in the health effects of phototherapy using either blue fluorescent- or blue LED light and speculate on the expected effects of changing to blue-green LED light phototherapy. Search the phototherapy literature using the terms neonate, hyperbilirubinemia, and phototherapy in the PubMed and Embase databases. Transitioning from blue fluorescent light to blue-green LED light will expose neonates to less light in the 400–450 nm spectral range, potentially leading to less photo-oxidation and geno-/cytotoxicity, reduced risk of cancer, and decreased mortality in extremely low-birthweight neonates. The riboflavin level may decline, and the increased production and retention of bronze pigments may occur in predisposed neonates due to enhanced lumirubin formation. The production of pre-inflammatory cytokines may rise. Hemodynamic responses and transepidermal water loss are less likely to occur. The risk of hyperthermia may decrease with the use of blue-green LED light and the risk of hypothermia may increase. Parent–neonate attachment and breastfeeding will be positively affected because of the shortened duration of phototherapy. The latter may also lead to a significant reduction in the cost of phototherapy procedures as well as the hospitalization process.

• Hansen, Thor Willy Ruud (2021). The epidemiology of neonatal jaundice. Pediatric Medicine. 4(18). doi: 10.21037/pm-21-4. Full text in Research Archive Show summary

  Neonatal jaundice (NJ) is one of the most common causes for medical intervention in the newborn period. While transitory hyperbilirubinemia (HB) is present in almost all newborns, detection of jaundice requires a trained observer and good lighting. Thus, jaundice in the newborn has a reported incidence between 60% to more than 90%. Bilirubin, the molecule that causes the color of jaundice, is the end product of disassembly of heme-containing molecules, primarily hemoglobin. Therefore, conditions that increase hemolysis will increase bilirubin production and cause jaundice. Common conditions in the newborn are blood group incompatibilities and congenital hemolytic anemias. A family history of NJ increases the likelihood of jaundice in the present newborn, and is one of several examples of genetic conditions that contribute. Endocrine and metabolic conditions contribute, the most common being maternal diabetes. An increased incidence is seen in infants of Southeast Asian mothers, while African infants have a lower incidence unless they suffer from G-6-PD-deficiency. Drugs taken by the mother during pregnancy may impact on hepatic metabolism of bilirubin in the newborn, often by reducing the incidence of jaundice, and the same may happen with certain drugs given to the newborn. Birth trauma, through extravasation of blood, will increase bilirubin production and jaundice. Preterm infants have immature bilirubin metabolism and a higher incidence of jaundice. Breast-fed infants have an increased incidence of jaundice, which may also last longer. Extreme NJ, associated with risk of kernicterus spectrum syndrome, has an estimated worldwide incidence of 99/100,000 or more, thus affecting 130,000 or more infants each year and calling for increased vigilance and preparedness for rapid therapeutic intervention.

• Hansen, Thor Willy Ruud; Wong, Ronald J. & Stevenson, David K. (2020). Molecular physiology and pathophysiology of bilirubin handling by the blood, liver, intestine, and brain in the newborn. Physiological Reviews. ISSN 0031-9333. 100(3), p. 1291–1346. doi: 10.1152/physrev.00004.2019. Full text in Research Archive Show summary

  Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.

• Hansen, Thor Willy Ruud (2019). Gulsott hos nyfødte – farligere enn du tror! Sykepleien. ISSN 0039-7628. 107. doi: 10.4220/Sykepleiens.2019.77075. Full text in Research Archive
• Hansen, Thor Willy Ruud; Maisels, M. Jeffrey; Ebbesen, Finn; Vreman, Hendrik J.; Stevenson, David K. & Wong, Ronald J. [Show all 7 contributors for this article] (2019). Sixty years of phototherapy for neonatal jaundice ? from serendipitous observation to standardized treatment and rescue for millions. Journal of Perinatology. ISSN 0743-8346. p. 1–14. doi: 10.1038/s41372-019-0439-1. Full text in Research Archive
• Mreihil, Khalaf; Nakstad, Britt; Stensvold, Hans Jørgen; Benth, Jurate Saltyte & Hansen, Thor Willy Ruud (2018). Uniform national guidelines do not prevent wide variations in the clinical application of phototherapy for neonatal jaundice. Acta Paediatrica. ISSN 0803-5253. 107(4), p. 620–627. doi: 10.1111/apa.14142. Full text in Research Archive Show summary

  AIM: This study compared the use of phototherapy for neonatal jaundice in all 21 Norwegian neonatal intensive care units (NICUs) from 2013-2014 to improve practice. METHODS: Information on all types of phototherapy devices was collected, and irradiance was measured from random units at 20 cm and 50 cm from the light source. We gathered information on local practice rules, including the use of single, double or triple phototherapy, how infants were positioned, the frequency of blood sampling, rules for using reflective surfaces and interrupting phototherapy. In every NICU, we asked one nurse with more than five years of experience and one with less than one year to set up phototherapy equipment, then measured the irradiance and distance. RESULTS: Photodiodes were the most common of the eight types of phototherapy devices used. Rules for the distance from the device to the infant varied from 10 to 40 cm and in practice they varied from 15 to 48 cm, with irradiance ranging from 11.1-56.1 W/m2 . There were significant variations between NICUs with regard to the overall treatment duration and duration in most birthweight categories. CONCLUSION: There were considerable variations in phototherapy practices among Norwegian NICUs. In particular, the significant variations in duration need to be addressed.

• Mreihil, Khalaf; Benth, Jurate Saltyte; Stensvold, Hans Jørgen; Nakstad, Britt & Hansen, Thor Willy Ruud (2018). Phototherapy is commonly used for neonatal jaundice but greater control is needed to avoid toxicity in the most vulnerable infants. Acta Paediatrica. ISSN 0803-5253. 107(4), p. 611–619. doi: 10.1111/apa.14141. Full text in Research Archive Show summary

  AIM: Limited information is available about how guidelines on phototherapy for neonatal jaundice are applied in practice and toxicity is a concern. We studied the use of phototherapy in relation to birthweight and gestational age (GA) in Norwegian neonatal intensive care units (NICUs). METHODS: The study population was all 5382 infants admitted to the 21 NICUs in Norway between September 1, 2013 and August 31, 2014. Data were recorded daily in the Norwegian Neonatal Network database and anonymised data on patient characteristics, diagnoses, duration, the ages at the start and discontinuation of phototherapy were analysed. RESULTS: More than a quarter (26.6%) of all infants admitted to Norwegian NICUs during the study period received phototherapy. The use of phototherapy was inversely related to GA and birthweight. More than 80% of the preterm infants under 28 weeks of GA received phototherapy. The duration was significantly longer in the lowest birthweight and GA groups and decreased with increasing birthweight and GA. CONCLUSION: Phototherapy is proved to be a strong candidate for the most common therapeutic modality in NICU infants. However, in the light of reported toxicity in the smallest, most vulnerable infants, we recommend increased emphasis on quality control.

• Hansen, Thor Willy Ruud & Førde, Reidun (2018). 37 saker om barn og ungdom diskutert i en klinisk etikk-komité. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 138(20), p. 1–6. doi: 10.4045/tidsskr.18.0085. Full text in Research Archive
• Hansen, Thor Willy Ruud; Aasland, Olaf Gjerløw; Janvier, Annie & Førde, Reidun (2018). Physician characteristics influence the trends in resuscitation decisions at different ages. Acta Paediatrica. ISSN 0803-5253. 107(12), p. 2115–2119. doi: 10.1111/apa.14326. Full text in Research Archive Show summary

  Aim: We examined how physicians in different medical specialties would evaluate treatment decisions for vulnerable patients in need of resuscitation. Methods: A survey depicting six acutely ill patients from newborn infant to aged, all in need of resuscitation with similar prognoses, was distributed (in 2009) to a representative sample of 1650 members of the Norwegian Medical Association and 676 members of the Norwegian Pediatric Association. Results: There were 1335 respondents (57% participation rate). The majority of respondents across all specialties thought resuscitation was in the best interest of a 24 weeks’ gestation preterm infant and would resuscitate the patient, but would also accept palliative care on the family's demand. Accepting a family's refusal of resuscitation was more common for the newborn infants. Specialists were overall similar in their answers, but specialty, age and gender were associated with different answers for the patients at both ends of the age spectrum. Conclusion: Resuscitation decisions for the very young do not always seem to follow the best interest principle. Specialty and personal characteristics still have an impact on how we consider important ethical issues. We must be cognisant of our own valuations and how they may influence care.

• Hansen, Thor Willy Ruud (2018). Patient autonomy is a right, but exercising that right may not be an obligation for patients and kin. American Journal of Bioethics. ISSN 1526-5161. 1(18), p. 32–33. doi: 10.1080/15265161.2017.1401164. Full text in Research Archive
• Olusanya, Bolajoko Olubukunola; Kaplan, Michael & Hansen, Thor Willy Ruud (2018). Neonatal hyperbilirubinaemia: a global perspective. The Lancet Child and Adolescent Health. ISSN 2352-4642. 2(8), p. 610–620. doi: 10.1016/S2352-4642(18)30139-1. Full text in Research Archive Show summary

  Hyperbilirubinaemia, presenting as jaundice, is a ubiquitous and frequently benign condition in newborn babies but is a leading cause of hospitalisation in the first week of life. In some infants jaundice can become severe, progressing to acute bilirubin encephalopathy and kernicterus with a substantial risk of neonatal mortality and long-term neurodevelopmental impairments. Severe hyperbilirubinaemia and its sequelae continue to occur in industrialised countries with functioning medical systems and a disproportionately high burden also persists in low-income and middle-income countries due primarily to delays in delivering effective treatments that are routinely available in high-income countries. In this Review we summarise up-to-date evidence on the epidemiology of neonatal jaundice including its global burden based on estimates of its prevalence, and both fatal and non-fatal health outcomes. We also discuss the management of severe hyperbilirubinaemia including the prevention of kernicterus, and highlight future directions for research.

• Hansen, Thor Willy Ruud; Ebbesen, Finn & Maisels, M.Jeffrey (2017). Update on phototherapy in jaundiced neonates. Current pediatric reviews. ISSN 1573-3963. 13(3), p. 176–180. doi: 10.2174/1573396313666170718150056. Full text in Research Archive Show summary

  Background: Even relatively low serum bilirubin concentrations can cause neurodevelopmental impairment in extremely low birth weight (EBWL) infants, while sequelae from hyperbilirubinemia in late preterm and term infants are rare and occur only at very high serum bilirubin levels. Phototherapy is the current treatment of choice. Objective: To present an update on the most important issues involved in phototherapy for jaundiced infants. Results: Light absorption by bilirubin in the skin transforms the native Z,Zbilirubin to conformational photoisomers Z,E-bilirubin and E,Z-bilirubin and structural photoisomers E,Z-lumirubin and E,E-lumirubin. Formation and excretion of Z,E-bilirubin and E,Z-lumirubin are both important routes of elimination of bilirubin through bile and urine, although the precise contributions of the various photoisomers to the overall elimination of bilirubin are unknown. It appears that the photoisomers of bilirubin are predominantly formed in the plasma, and the rate of formation is affected by the hemoglobin concentration. Phototherapy lights with an emission spectrum of 460-490 nm provide the most efficient bilirubin-reducing light. LEDs should replace fluorescent tubes and halogen spotlights as the preferred light sources. Recent data raise concerns that sick ELBW infants under prolonged phototherapy may have an increased risk of death, though survivors may benefit from reduced rates of neurodevelopmental impairment. Comparison of the efficacy of cycled vs. continuous phototherapy has given divergent results. Changing the infant’s position does not increase the efficacy of phototherapy. Conclusion: During the last decade we have made progress in our understanding of how and where phototherapy works and in its practical applications

• Laventhal, Naomi; Verhagen, Eduard; Hansen, Thor Willy Ruud; Dempsey, Eugene; Davis, Peter Graham & Musante, Gabriel [Show all 9 contributors for this article] (2017). International Variations in Application of the Best Interest Standard Across the Age Spectrum. Journal of Perinatology. ISSN 0743-8346. 37(2), p. 208–213. doi: 10.1038/jp.2016.168. Full text in Research Archive Show summary

  OBJECTIVE: Ethically and legally, assertions that resuscitation is in a patient’s best interest should be inversely correlated with willingness to forego intensive care (and accept comfort care) at the surrogate’s request. Previous single country studies have demonstrated a relative devaluation of neonates when compared with other critically ill patients. STUDY DESIGN: In this international study, physicians in Argentina, Australia, Canada, Ireland, The Netherlands, Norway and the United States were presented with eight hypothetical vignettes of incompetent critically ill patients of different ages. They were asked to make assessments about best interest, respect for surrogate autonomy and to rank the patients in a triage scenario. RESULTS: In total, 2237 physicians responded (average response rate 61%). In all countries and scenarios, participants did not accept to withhold resuscitation if they estimated it was in the patient’s best interest, except for scenarios involving neonates. Young children (other than neonates) were given high priority for resuscitation, regardless of existing disability. For neonates, surrogate autonomy outweighed assessment of best interest. In all countries, a 2-month-old-infant with meningitis and a multiply disabled 7-year old were resuscitated first in the triage scenario, with more variable ranking of the two neonates, which were ranked below patients with considerably worse prognosis. CONCLUSIONS: The value placed on the life of newborns is less than that expected according to predicted clinical outcomes and current legal and ethical theory relative to best interests. Value assessments on the basis of age, disability and prognosis appear to transcend culture, politics and religion in this domain.

• Hansen, Thor Willy Ruud (2016). Biology of Bilirubin Photoisomers. Clinics in Perinatology. ISSN 0095-5108. 43(2), p. 277–290. doi: 10.1016/j.clp.2016.01.011. Full text in Research Archive
• Hansen, Thor Willy Ruud (2016). Patient autonomy – what does it mean for clinical decision-making in children and adolescents. International e-Journal of Science, Medicine & Education. 10, p. 3–9. Full text in Research Archive
• Fredheim, Olav Magnus; Hansen, Thor Willy Ruud; Haugen, Guttorm & Magelssen, Morten (2016). Bør man kunne tilby keisersnitt ved trisomi 13 og 18? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(7), p. 630–632. doi: 10.4045/tidsskr.15.0037. Full text in Research Archive
• Solberg, Marianne Trygg; Hansen, Thor Willy Ruud & Bjørk, Ida Torunn (2015). The need for predictability in coordination of ventilator treatment of newborn infants - A qualitative study. Intensive and Critical Care Nursing. ISSN 0964-3397. 31(4), p. 205–212. doi: 10.1016/j.iccn.2014.12.003. Full text in Research Archive
• Smerud, Ole-Jørgen; Solevåg, Anne Lee; Hansen, Thor Willy Ruud & Grønn, Morten (2015). 14 dager gammel gutt med gulsott og apnéanfall. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 135(23-24), p. 2167–2170. doi: 10.4045/tidsskr.15.0519. Full text in Research Archive
• Guillén, Úrsula; Weiss, Elliott M.; Munson, David; Maton, Pierre; Jefferies, Ann & Norman, Mikael [Show all 20 contributors for this article] (2015). Guidelines for the management of extremely premature deliveries: A systematic review. Pediatrics. ISSN 0031-4005. 136(2), p. 343–350. doi: 10.1542/peds.2015-0542. Full text in Research Archive
• Mreihil, Khalaf; Madsen, Poul; Nakstad, Britt; Benth, Jurate Saltyte; Ebbesen, Finn & Hansen, Thor Willy Ruud (2015). Early formation of bilirubin isomers during phototherapy for neonatal jaundice: Effects of single vs. double fluorescent lamps vs. photodiodes. Pediatric Research. ISSN 0031-3998. 78(1), p. 56–62. doi: 10.1038/pr.2015.61. Full text in Research Archive
• Førde, Reidun & Hansen, Thor Willy Ruud (2014). Do organizational and clinical ethics in a hospital setting need different venues? HEC Forum. ISSN 0956-2737. 26(2), p. 147–158. doi: 10.1007/s10730-014-9237-5. Full text in Research Archive
• Solberg, Marianne Trygg; Hansen, Thor Willy Ruud & Bjørk, Ida Torunn (2014). Oxygen and ventilator treatment: perspectives on interprofessional collaboration in a neonatal intensive care unit. Journal of Research in Interprofessional Practice and Education. 4(1). doi: 10.22230/jripe.2014v4n1a172. Full text in Research Archive Show summary

  Abstract Background: The aim of this study was to explore perspectives on the collaboration between physicians and nurses managing oxygen and ventilator treatment of sick infants in a Norwegian neonatal intensive care unit. Methods and Findings: We performed a qualitative study using focus groups. We found that interprofessional collaboration concerning newborns on mechanical ventilation lacked co-ordination and was unsystematic. This led to inadequate utilization of the medical and clinical competency of the nursing staff. Nurses and physicians approached decision-making differently, and there was limited flexibility and dynamics in the allocation of responsibility between the professionals. Conclusion: Findings from this study indicate that nurses and physicians have the opportunity to improve the quality of care by developing high-quality communication, formulating plans together, and improving the co-ordination of the ventilator treatment. Further studies should develop and test interventions based on the professionals’ perception of relevant co-ordination strategies to improve mechanical ventilation and oxygen treatment to premature and sick newborn infants. Keywords: Quality of care; Collaboration; Oxygen treatment; Mechanical ventilation; Neonatal intensive care unit

• Barrington, Keith; Janvier, Annie; Aziz, Khalid; Bancalari, Eduardo; Batton, D & Bellieni, C [Show all 21 contributors for this article] (2014). Commentary: CPS policy statement for prenatal counselling before a premature birth: Simple rules for complicated decisions. Journal of Paediatrics and Child Health. ISSN 1034-4810. 19, p. 22–24. Full text in Research Archive
• Fanaroff, Jonathan M.; Hascoet, Jean-Michel; Hansen, Thor Willy Ruud; Levene, Malcolm; Norman, Mikael & Papageorgiou, Apostolos [Show all 9 contributors for this article] (2014). The ethics and practice of neonatal resuscitation at the limits of viability: An international perspective. Acta Paediatrica. ISSN 0803-5253. 103(7), p. 701–708. doi: 10.1111/apa.12633. Full text in Research Archive
• Leerberg, Maria Nemat; Alme, Tomas Nordheim & Hansen, Thor Willy Ruud (2014). Metyrapone, an inhibitor of cytochrome oxidases, does not affect viability in a neuroblastoma cell model of bilirubin toxicity. Molecular Genetics and Metabolism Reports. ISSN 2214-4269. 1, p. 197–202. doi: 10.1016/j.ymgmr.2014.04.002. Full text in Research Archive
• Hansen, Thor Willy Ruud; Janvier, Annie; Aasland, Olaf Gjerløw & Førde, Reidun (2013). Ethics, Choices, and Decisions in Acute Medicine: A National Survey of Norwegian Physicians' Attitudes. Pediatric Critical Care Medicine. ISSN 1529-7535. 14(2), p. E63–E69. doi: 10.1097/PCC.0b013e31826e73f1. Full text in Research Archive
• Hansen, Thor Willy Ruud (2013). Curing neonatal jaundice with language of friendship and rays of hope' in the 18th century. Acta Paediatrica. ISSN 0803-5253. 102(2), p. 119–122. doi: 10.1111/apa.12068. Full text in Research Archive
• Solberg, Marianne Trygg; Bjørk, Ida Torunn & Hansen, Thor Willy Ruud (2013). Adherence to oxygenation and ventilation targets in mechanically ventilated premature and sick newborns: a retrospective study. BMC Pediatrics. 13(126). doi: 10.1186/1471-2431-13-126. Full text in Research Archive Show summary

  Background Ventilator treatment exposes newborns to both hyperoxemia and hyperventilation. It is not known how common hyperoxemia and hyperventilation are in neonatal intensive care units in Norway. The purpose of this study was to assess the quality of current care by studying deviations from the target range of charted oxygenation and ventilation parameters in newborns receiving mechanical ventilation. Methods Single centre, retrospective chart review that focused on oxygen and ventilator treatment practices. Results The bedside intensive care charts of 138 newborns reflected 4978 hours of ventilator time. Arterial blood gases were charted in 1170 samples. In oxygen-supplemented newborns, high arterial pressure of oxygen (PaO2) values were observed in 87/609 (14%) samples. In extremely premature newborns only 5% of the recorded PaO2 values were high. Low arterial pressure of CO2 (PaCO2) values were recorded in 187/1170 (16%) samples, and 64 (34%) of these were < 4 kPa. Half of all low values were measured in extremely premature newborns. Tidal volumes above the target range were noted in 22% of premature and 20% of full-term newborns. Conclusions There was a low prevalence of high PaO2 values in premature newborns, which increased significantly with gestational age (GA). The prevalence of low PaCO2 values was highest among extremely premature newborns and decreased with increasing GA. Further studies are needed to identify whether adherence to oxygenation and ventilation targets can be improved by clearer communication and allocation of responsibilities between nurses and physicians.

• Hansen, Thor Willy Ruud & Saugstad, Ola Didrik (2013). Management of periviable newborns in Nordic countries. Current pediatric reviews. ISSN 1573-3963. 9, p. 19–24. doi: 10.2174/157339613805289415. Full text in Research Archive
• Hansen, Thor Willy Ruud (2012). Advanced clinical medicine requires advanced clinical ethics. Neonatology. ISSN 1661-7800. 101(1), p. 8–12. doi: 10.1159/000325162. Full text in Research Archive
• Hagen, Eirik; Therkelsen, Øystein Buerødgård; Førde, Reidun; Aasland, Olaf Gjerløw; Janvier, Annie & Hansen, Thor Willy Ruud (2012). Challenges in Reconciling Best Interest and Parental Exercise of Autonomy in Pediatric Life-or-Death Situations. Journal of Pediatrics. ISSN 0022-3476. 161(1), p. 146–151. doi: 10.1016/j.jpeds.2012.01.017. Full text in Research Archive
• Hansen, Thor Willy Ruud (2011). Neonatal jaundice. In Oh, William (Eds.), Evidence-based handbook of neonatology. World Scientific. ISSN 9789814313469. p. 339–371. Full text in Research Archive
• Hansen, Thor Willy Ruud (2011). The Role of Phototherapy in the Crash-Cart Approach to Extreme Neonatal Jaundice. Seminars in Perinatology. ISSN 0146-0005. 35(3), p. 171–174. doi: 10.1053/j.semperi.2011.02.012. Full text in Research Archive
• Meberg, Alf & Hansen, Thor Willy Ruud (2011). Neonatal transports - risks and oppurtunities. Open Journal of Pediatrics. ISSN 2160-8741. 1(4). doi: 10.4236/ojped.2011.14013. Full text in Research Archive
• Hansen, Thor Willy Ruud (2011). Prevention of neurodevelopmental sequelae of jaundice in the newborn. Developmental Medicine & Child Neurology. ISSN 0012-1622. 53, p. 24–28. doi: 10.1111/j.1469-8749.2011.04059.x. Full text in Research Archive
• Solberg, Marianne Trygg; Hansen, Thor Willy Ruud & Bjørk, Ida Torunn (2011). Nursing assessment during oxygen administration in ventilated preterm infants. Acta Paediatrica. ISSN 0803-5253. 100(2), p. 193–197. doi: 10.1111/j.1651-2227.2010.02094.x. Full text in Research Archive
• Bratlid, Dag; Nakstad, Britt & Hansen, Thor Willy (2011). National guidelines for treatment of jaundice in the newborn. Acta Paediatrica. ISSN 0803-5253. 100(4), p. 499–505. doi: 10.1111/j.1651-2227.2010.02104.x. Full text in Research Archive
• Hansen, Thor Willy (2010). Bilirubin metabolism. NeoReviews. ISSN 1526-9906. 11, p. e316–e322. Full text in Research Archive
• Hansen, Thor Willy (2010). Phototherapy for neonatal jaundice - therapeutic effects on more than one level? Seminars in Perinatology. ISSN 0146-0005. 34(3), p. 231–234. doi: 10.1053/j.semperi.2010.02.008. Full text in Research Archive
• Erlandsen, Marie & Hansen, Thor Willy (2010). Treatment of neonatal jaundice - more than phototherapy and exchange transfusions. Eastern Journal of Medicine. ISSN 1301-0883. 15, p. 175–185. Full text in Research Archive
• Kalikstad, Betty; Skjerdal, Åse Sofie & Hansen, Thor Willy (2010). Compatibility of drug infusions in the NICU. Archives of Disease in Childhood. ISSN 0003-9888. 95(9), p. 745–748. doi: 10.1136/adc.2009.174268. Full text in Research Archive
• Mreihil, Khalaf; McDonagh, Antony F.; Nakstad, Britt & Hansen, Thor Willy (2010). Early Isomerization of Bilirubin in Phototherapy of Neonatal Jaundice. Pediatric Research. ISSN 0031-3998. 67(6), p. 656–659. doi: 10.1203/PDR.0b013e3181dcedc0. Full text in Research Archive
• Hansen, Thor Willy Ruud; Nietsch, Lutz; Norman, Elisabeth; Bjerre, Jesper; Hascoet, Jean-Michel & Mreihil, Khalaf [Show all 7 contributors for this article] (2009). Reversibility of acute intermediate phase bilirubin encephalopathy. Acta Paediatrica. ISSN 0803-5253. 98(10), p. 1689–1694. doi: 10.1111/j.1651-2227.2009.01409.x. Full text in Research Archive Show summary

  Aim To show the potential for reversing acute intermediate to advanced phase bilirubin encephalopathy. Methods Case studies. Results Six extremely jaundiced infants had symptoms of intermediate to advanced phase acute bilirubin encephalopathy. The infants were treated aggressively. Two patients had brain MRIs showing increased signals in the globus pallidus. On follow-up all infants are neurologically normal. Conclusions Intermediate to advanced stage acute bilirubin encephalopathy may occasionally be reversible. These cases provide a strong argument in favor of rapid and aggressive intervention in infants presenting with extreme jaundice and neurological symptoms.

• Førde, Reidun & Hansen, Thor Willy (2009). Involving patients in a Norwegian Clinical Ethics committee - what have we learned? Clinical Ethics. ISSN 1477-7509. 4, p. 125–130. Full text in Research Archive Show summary

  To date, few Norwegian clinical ethics committees (CECs) have included patients or next of kin in case discussions. In 2008, Rikshospitalet’s (The National Hospital’s) CEC began to routinely invite patients and relatives into case discussions. In this paper, we describe seven cases discussed by this committee in 2008. Six involved life and death decision-making in collaboration with the next of kin; while one related case did not include relatives. In our opinion representing the patient’s perspective was advantageous to the discussion itself, to the decision made and to the next of kin’s acceptance of the resolution. We believe that if the patient had been represented in the last case, the outcome might have been different. We conclude that successful patient involvement will rely on well structured case discussions, an open atmosphere and good preparation and follow-up.

• Hansen, Thor Willy (2009). Vanlige problemer i nyfødtperioden. In Tandberg, Bente Silnes & Steinnes, Solfrid (Ed.), Nyfødtsykepleie, bind I. Cappelen Damm AS. ISSN 9788202253929. Full text in Research Archive
• Finne, Per Haavardsholm; Dalen, Ingvild; Ikonomou, N; Ulimoen, G & Hansen, Thor Willy (2008). Diagnosis of congenital hip dysplasia in the newborn. Acta Orthopaedica. ISSN 1745-3674. 79, p. 313–320. doi: 10.1080/17453670710015193. Full text in Research Archive
• Huizing, Kirsten; Røislien, Jo & Hansen, Thor Willy (2008). Intravenous immune globulin reduces the need for exchange transfusions in Rhesus and AB0 incompatibility. Acta Paediatrica. ISSN 0803-5253. 97, p. 1362–1365. doi: 10.1111/j.1651-2227.2008.00915.x. Full text in Research Archive
• Saugstad, Ola Didrik; Hansen, Thor Willy; Rønnestad, Arild Erlend; Nakstad, Britt; Tølløfsrud, Per Arne & Reinholt, Finn P. [Show all 12 contributors for this article] (2007). Novel mutations in the gene encoding ATP binding cassette protein member A3 (ABCA3) resulting in fatal neonatal lung disease. Acta Paediatrica. ISSN 0803-5253. 96, p. 185–190. doi: 10.1111/j.1651-2227.2007.00016.x. Full text in Research Archive Show summary

  Aim: To investigate whether intractable respiratory distress syndrome in three Norwegian term infants was due to mutations in the ABCA3 gene. Methods: The genes encoding SP-B (SFTPB), SP-C (SFTPC), and ABCA3 (ABCA3) were sequenced from the parents of one infant and two unrelated infants with fatal neonatal lung disease. Lung tissue was examined by histology, immunohistochemistry and electron microscopy. Results: Novel ABCA3 mutations were identified in each family. One patient had a phenotype differing from previous descriptions of this disease with an initial uneventful period. The diagnosis was established 19 years after death by analysing DNA material from the parents, with an ABCA3 mutation identified on one allele in each parent. The other two infants had more typical clinical courses with the onset of respiratory symptoms immediately after birth. ABCA3 mutations were identified on both alleles from these two infants, and electron microscopy of alveolar type 2 cells demonstrated abnormal lamellar body formation characteristic of this disorder. Conclusion: ABCA3 mutations were the basis for lung disease in all three patients. Children with lung disease due to ABCA3 deficiency may not have symptoms at birth. The finding of five novel mutations indicates allelic heterogeneity for ABCA3 mutations within the Norwegian population

• Hansen, Thor Willy (2007). Nevrologisk undersøkelse av nyfødte. In Gjerstad, Leif; Skjeldal, Ola & Helseth, Eirik (Ed.), Nevrologi og nevrokirurgi (4. utg). Forlaget Vett & Viten AS. ISSN 9788241206283. p. 31–48. Full text in Research Archive
• Hansen, Thor Willy (2006). A Quisling on neonatal jaundice. Acta Paediatrica. ISSN 0803-5253. 95(1), p. 108–112. Full text in Research Archive Show summary

  Nils Andreas Quisling was born in Telemark, Norway, in 1854 and became an obstetrician. In 1893 he published a monograph on neonatal jaundice. This monograph was studied and compared with other published sources from the same time period. Results: Quisling discussed four theories on the cause of neonatal jaundice. "Suppression jaundice" held that jaundice was the result of suppressed liver function. "Haematogenous jaundice" claimed that bilirubin was formed from haemoglobin outside the liver, and had nothing to do with the liver. "Polycholia" held that neonatal jaundice was due to an increased secretion of all the constituents of bile. Quisling rejected these and supported the "hepatogenous" theory-jaundice was always a liver-related phenomenon. He described 50 cases of neonatal jaundice. The incidence of neonatal jaundice at the Kristiania Maternity Foundation was 26%. In Quisling's cases, gastrointestinal disturbances were common, and he felt this to be an under-reported complication of neonatal jaundice. He found that neonatal jaundice was often accompanied by fever.Conclusion: Gastrointestinal disturbances were causally involved in neonatal jaundice, resulting in impeded bile drainage. At the time of Quisling's study (1887), this "hepatogenous" theory of neonatal jaundice probably still had majority support in the European literature.

• Djokomuljanto, Stanislaus; Quah, Ban-Seng; Yusoff, Surini; Ramli, Noraida; Ismail, Nik Zainal Abidin Nik & Hansen, Thor Willy [Show all 7 contributors for this article] (2006). The efficacy of phototherapy for neonatal jaundice is increased by the use of low-cost white reflecting curtains. Archives of Disease in Childhood: Fetal and Neonatal Edition. ISSN 1359-2998. 91(6), p. F439–F442. doi: 10.1136/adc.2006.095687. Full text in Research Archive Show summary

  Objective: To determine whether the addition of low-cost reflecting curtains to a standard phototherapy unit could increase effectiveness of phototherapy for neonatal jaundice. Design: Randomised controlled clinical trial. Setting: Level one nursery of a tertiary University Hospital in Malaysia. Patients: Term newborns with uncomplicated neonatal jaundice presenting in the first week of life. Interventions: Phototherapy with white curtains hanging from the sides of the phototherapy unit (study group) was compared to single phototherapy without curtains (control group). Main outcome measures: The primary outcome was the mean difference in total serum bilirubin measured at baseline and after four hours of phototherapy. The secondary outcome was the duration of phototherapy. Results:There were 50 babies in the study group and 47 babies in the control group. The mean decrease in total serum bilirubin levels after 4 hours of phototherapy was significantly (p<0.001) greater in the study group (27.62 µmol/L, SD 25.24) compared to that of the control group (4.04 µmol/L, SD 24.27). Cox proportional hazards regression analysis indicated that the median duration of phototherapy was significantly shorter in the study group (10 hours) than in the control group (34 hours) (chi-square-change = 38.93; p<0.001; hazards ratio: 0.21; 95% confidence interval, 0.13 to 0.35). No difference in adverse events was noted in terms of hyper- or hypothermia, weight loss, skin rash, loose stools, or feeding intolerance. Conclusion:Hanging white curtains around phototherapy units significantly increases the efficacy in the treatment of neonatal jaundice without evidence of increased adverse effects.

• Hankø, Erik; Hansen, Thor Willy; Almaas, Runar & Rootwelt, Terje (2006). Recovery after short-term bilirubin exposure in human NT2-N neurons. Brain Research. ISSN 0006-8993. 1103(1), p. 56–64. doi: 10.1016/j.brainres.2006.05.083. Full text in Research Archive Show summary

  We used human NT2-N neurons to investigate delayed effects of short-term exposure to unconjugated bilirubin (UCB). Cell viability was evaluated with MTT reduction assays and nuclear morphology. A 6-h exposure to 1, 5, or 25 μM UCB and serum deprivation (SED) significantly diminished MTT reduction. 96 h after rescue of neurons with removal of UCB and re-incubation in the original serum-containing medium, delayed effects were evident as recovery (1 μM UCB), intermediate cell death (5 μM UCB), or near complete cell death (25 μM UCB). The impact of 6 h of SED alone appeared to be modest in rescued neurons. In this model, co-treatment with the specific caspase-3 inhibitor, zDEVD.FMK (100 μM), or the pancaspase inhibitor zVAD.FMK (100 μM) did not improve viability in rescued neurons exposed to 5 μM UCB, while treatment with the NMDA receptor antagonist MK-801 (1 μM) enhanced the number of undamaged nuclei (86 ± 14% versus 50 ± 12%, P = 0.001). MK-801 had, however, no impact on MTT reduction. In a different model with a 102-h continuous exposure to UCB and SED, we found a significant additional toxic impact of serum deprivation. Separate experiments suggested that this was a result of late caspase-mediated toxicity. We conclude that UCB-mediated effects may be reversible in this model. Blockade of excitotoxic mechanisms, but not caspase activity may prevent delayed cell death.

• Hankø, Erik; Hansen, Thor Willy; Almaas, Runar; Paulsen, Ragnhild Elisabeth & Rootwelt, Terje (2006). Synergistic Protection of a General Caspase Inhibitor and MK-801 in Bilirubin-Induced Cell Death in Human NT2-N Neurons. Pediatric Research. ISSN 0031-3998. 59(1), p. 72–77. doi: 10.1203/01.pdr.0000191135.6358. Full text in Research Archive Show summary

  Unconjugated bilirubin (UCB) induces both apoptosis and necrosis in neurons. To investigate the role of caspases and excitotoxicity in UCB-induced cell death, we exposed NT2-N neurons to 5 µM UCB (a concentration known to induce apoptosis) or 2 µM staurosporine (positive apoptosis control) and investigated the effects of treatments with the specific caspase-3 inhibitor, zDEVD.FMK (20 and 100 µM), or the general caspase inhibitor, zVAD.FMK (20 and 100 µM), and/or the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (10 µM) during a 24- or 48-h exposure. UCB increased caspase-3 activity 2.3-fold after 6 h. Despite this, treatment with zDEVD.FMK did not prevent cell death. zVAD.FMK (100 µM only) reduced apoptotic morphologies induced by UCB after 48 h, however, this effect was not reflected in MTT assays. MK-801 attenuated UCB-induced cell death after 24 h, but not significantly after 48 h. Similar effects were seen in the MTT assay. Combined treatment with MK-801 and zVAD.FMK synergistically reduced apoptotic morphologies after 24 and 48 h. MTT assays showed comparable effects after 24 h but did not show significant differences after 48 h. We conclude that NMDA receptor-mediated pathways and caspase-mediated pathways are involved in UCB-induced cell death in human NT2-N neurons. Concomitant inhibition of both pathways results in synergistic protection

• Djokomuljanto, S; Quah, BS; Surini, Y; Noraida, R; Ismail, NZN & Hansen, Thor Willy [Show all 7 contributors for this article] (2006). Efficacy of phototherapy for neonatal jaundice is increased by the use of low-cost white reflecting curtains. Archives of Disease in Childhood: Fetal and Neonatal Edition. ISSN 1359-2998. 91, p. 439–442. doi: 10.1136/adc.2006.095687. Full text in Research Archive Show summary

  Objective: To determine whether the addition of low-cost reflecting curtains to a standard phototherapy unit could increase effectiveness of phototherapy for neonatal jaundice. Design: Randomised controlled clinical trial. Setting: Level-one nursery of the Hospital Universiti Sains Malaysia, Kelantan, Malayasia. Patients: Term newborns with uncomplicated neonatal jaundice presenting in the first week of life. Interventions: Phototherapy with white curtains hanging from the sides of the phototherapy unit (study group, n = 50) was compared with single phototherapy without curtains (control group, n = 47). Main outcome measures: The primary outcome was the mean difference in total serum bilirubin measured at baseline and after 4 h of phototherapy. The secondary outcome was the duration of phototherapy. Results: The mean (standard deviation) decrease in total serum bilirubin levels after 4 h of phototherapy was significantly (p<0.001) higher in the study group (27.62 (25.24) µmol/l) than in the control group (4.04 (24.27) µmol/l). Cox proportional hazards regression analysis indicated that the median duration of phototherapy was significantly shorter in the study group (12 h) than in the control group (34 h; 2 change 45.2; p<0.001; hazards ratio 0.20; 95% confidence interval 0.12 to 0.32). No difference in adverse events was noted in terms of hyperthermia or hypothermia, weight loss, rash, loose stools or feeding intolerance. Conclusion: Hanging white curtains around phototherapy units significantly increases efficacy of phototherapy in the treatment of neonatal jaundice without evidence of increased adverse effects

• Meberg, Alf & Hansen, Thor Willy Ruud (2005). Kvalitetsvurdering av transport av syke nyfødte. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 125. Full text in Research Archive
• Hansen, Thor Willy (2005). Behandling av gulsott hos nyfødte. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 125(5), p. 594–598. Full text in Research Archive Show summary

  Bakgrunn. Undersøkelse og behandling av gulsott er blant de vanligste tiltakene i nyfødtmedisinen. Tilstanden er fysiologisk, men graden av gulsott kan forsterkes av en rekke faktorer. Behandling iverksettes fordi sterk gulsott innebærer fare for hjerneskade (kjerneicterus). Grensene for behandling er uklare, fordi det vitenskapelige grunnlaget for å definere grensene har klare svakheter. Materiale og metode. Det amerikanske barnelegeakademiet publiserte i juli 2004 nye retningslinjer for undersøkelse og behandling av ikteriske nyfødte. Disse retningslinjene skiller seg på flere felter fra dem som ble publisert i 1994. En rekke av de nye momentene har interesse for norske leger som behandler nyfødte med gulsott. Resultater. Målsettingen for de nye retningslinjene er å redusere forekomsten av alvorlig gulsott og kjerneicterus hos nyfødte. I motsetning til retningslinjene fra 1994 gir de nye retningslinjene spesifikk veiledning om lett premature barn, barn med hemolyse, og barn som er syke. Det legges vekt på tidlig risikovurdering av det enkelte barnet, samt på en gradering av oppfølgingsbehovet etter utskrivning fra fødeklinikken. Fortolkning. Det amerikanske barnelegeakademiets nye retningslinjer tilfører viktige momenter i forhold til tidligere, og bør kunne bidra til en tryggere behandling av ikteriske nyfødte. Norske barneleger bør kunne ha nytte av å sette seg inn i anbefalingene.

• Kalikstad, Betty & Hansen, Thor Willy (2005). Medikamentell behandling av nyfødte - et sjansespill? Tidsskrift for Norsk anestesiologisk forening (NAForum). 18(1), p. 4–6. Full text in Research Archive Show summary

  To av tre barn får ikke-godkjent legemiddelbehandling og omkring 90 % av nyfødte som intensivbehandles, får et ikke-dokumentert legemiddel eller et legemiddel som administreres på en ikke-godkjent måte. Manglende forskning på farmakoterapi for nyfødte begrenser mulighetene for optimal legemiddelbehandling. I stedet brukes medikamenter laget for voksne og på andre indikasjoner. Kunnskapen om medikamenters metabolisme og virkning hos barn er heller ikke tilstrekkelig kjent. Informasjon om medikamenter bør legges til rette for praktisk bruk i den kliniske hverdagen med tanke på barn med ulik modning, ulik grad av sykdom og ulik alder.

• Hansen, Thor Willy (2005). Changes in the utilization of diagnostic codes in neonatology following the introduction of activity-based financing. Health Policy. ISSN 0168-8510. 74(2), p. 218–223. doi: 10.1016/j.healthpol.2005.0. Full text in Research Archive Show summary

  Activity-based financing was introduced in public hospitals in Norway in 1997. Following this, hospitals have been financed in part by block grants, in part by grants based on productivity as measured through weighted diagnosis-related groups (DRGs). Insufficient national data were available to allow for proper calculation of DRG weights for neonatology. Thus, data from other countries were used to estimate weights. It seemed of interest to examine whether the use of diagnostic codes in neonatal medicine was changed following the introduction of activity-based financing and DRGs. Data from 1994, 1996, 1998, and 2000 were obtained from the proprietary database of the NICU at Rikshospitalet, University of Oslo, as well as from the hospital Patient Information Management System. Diagnoses were organized into 39 categories, counted for each of the 4 years, and analyzed by non-parametric ANOVA. There were significant changes in the use of diagnostic categories during the 1994�2000 time period. Some diagnoses which previously have been only rarely used, became more frequent. The use of other diagnoses varied in ways that could only be understood in terms of tactical usage. It is concluded that the use of DRGs as a basis for activity-based financing may result in changes in the use of certain diagnostic categories which are not related to biological changes in the patient population. This may complicate epidemiological research. On the other hand, activity-based financing may result in increased attention to the diagnostic process, leading to increased use of secondary diagnoses and thus more complete diagnostic coding

• Meberg, Alf & Hansen, Thor Willy (2005). Kvalitetsvurdering av transport av syke nyfødte. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 18(125), p. 2474–2476. Full text in Research Archive Show summary

  Bakgrunn. Transport av syke nyfødte representerer risiko for komplikasjoner og for svikt i teknisk utstyr. Materiale og metode. Arbeidet er en prospektiv observasjonsstudie av barn transportert fra nyfødt-intensivenheten, Sykehuset i Vestfold, Tønsberg til regionsykehus eller annet sykehus i 23-årsperioden 1982 - 2004. Resultater. 396 transporter (359 pasienter; 0,7 % av levende fødte) ble foretatt. Indikasjonene var prematuritet/neonatalt åndenødssyndrom (respiratory distress syndrome, RDS) ved 84 transporter (21 %), medfødte misdannelser ved 188 (47 %), og andre tilstander ved 124 (31 %). Etter etablering av et lokalt respiratorprogram for nyfødte med alvorlig respirasjonsvikt 1989 falt behovet for overflyttinger pga. prematuritet/neonatalt åndenødssyndrom fra 3,4 per 1 000 levende fødte i perioden 1982 - 88 til 1,0 per 1 000 1989 - 2004 (p < 0,0001). Transporter om natten ble redusert med 55 %. Signifikant flere barn var hypokapniske (pCO2 < 4,0 kPa) og hadde baseunderskudd (BD) > 10 mmol/l ved ankomst i forhold til ved avreise (p < 0,05). 7 % av barna koblet til respirator fikk tubekomplikasjoner under transporten. Fortolkning. Undersøkelsen dokumenterer at neonatale transporter medfører risiko for klinisk og laboratoriemessig forverring. Et lokalt respiratorprogram reduserer transporter for prematuritet/neonatalt åndenødssyndrom og transporter om natten.

• Hansen, Thor Willy (2005). Views on breast milk and neonatal jaundice from the 15th-19th century. Pediatric Research. ISSN 0031-3998. 55, p. 312–312. Full text in Research Archive Show summary

  BACKGROUND: Current thinking is that an unknown factor in breast milk may in some mother-infants dyads contribute to excessive and/or prolonged NJ. In an era when almost all Norwegian infants leaving their birth hospital are breast-fed, the phenomenon of prolonged NJ is frequently encountered. It seemed of interest to study how the question of BM and NJ had been viewed in earlier times. OBJECTIVE: To examine historic medical texts with particular reference to discussions about BM and NJ, both as it refers to the possible influence of nutrition on the occurrence of NJ, and to any mention of prolonged NJ. DESIGN/METHODS: Chapters or sections dealing with jaundice in pediatric or obstetric texts from 1473 through the end of the 19th century were examined. Included were textbooks, manuals, pamphlets/monographs, and theses in English, French, German, Latin, and the Scandinavian languages. RESULTS: In the oldest text studied, Bartolomaeus Metlinger’s "Ein Regiment der jungen Kinder" from 1473, NJ is said to be due to blockage of the bile duct by the coarse and thick milk from a wet-nurse. These two ideas: i) that coarse and/or thick milk was causally related to the occurrence of NJ, and ii) that the milk from wet-nurses had undesirable qualities in this context, were recurrent themes in the medical literature on NJ during the following four centuries. As for the mother’s own milk, most of the writers during this period were strong believers in the utility of colostrum to expel meconium. Thus, Baumes (1788) writes: "the art of medicine has nothing to compare to colostrum" in cases where NJ was due to meconium retention. Expulsion of meconium was thought to be very important, and a plethora of laxatives and/or enemas was otherwise employed to achieve this end. Regarding wet-nurses, unless these had very recently given birth to their own baby, their milk was seen as a frequent cause of NJ. Infants nourished by their own mother’s milk were thought to be at very low risk of NJ. Protracted NJ (beyond the first 2 weeks of life) is only referred to a couple of times in the literature reviewed for this study, and the concept that BM should in some way be responsible for this phenomenon was not entertained. CONCLUSIONS: BM from the infant’s own mother was largely regarded as curative and preventive as far as NJ in medical literature from the 15th-19th century. BM from wet-nurses, however, was not a good thing. The concept of BM-associated NJ in the modern-day sense of excessive and/or prolonged jaundice was not discussed.

• Hansen, Thor Willy (2005). Nils Rosen von Rosenstein and neonatal jaundice in the 18th century. Acta Paediatrica. ISSN 0803-5253. 94(12), p. 1834–1836. Full text in Research Archive Show summary

  Background: Nils Rosen von Rosenstein (1706-1773) was a Swedish nobleman and a professor at Uppsala University. His series of lectures on children's diseases and their treatment was published in 1764 under the title Underrattelser om Barn-Sjukdomar och Deras Bote-Medel. Materials and methods: Rosen von Rosenstein's book was translated into several languages. The present paper deals with the opinions and advice proffered on the jaundiced neonate in chapter 25 of the Danish edition from 1769. Results: The distinction between jaundice in the neonate and jaundice in older children is not clear everywhere in the chapter, and much of Rosen von Rosenstein's advice on therapy appears to be intended for all age groups. Rosen von Rosenstein believed that neonatal jaundice was less common in Sweden than elsewhere, and ascribed this to the common practice of purging newborns with a manna sugar laxative. The principal cause of jaundice, according to Rosen von Rosenstein, was bile stasis. When milk curdled in the stomach, the curds could plug the common bile duct, and bile would be forced into the lymphatics and from there into the blood. Thus, the bile was carried around the body and caused the skin and the sclera, as well as other organs, to become yellow. Cure was usually easy-a laxative in the form of pureed manna with powdered rhubarb was what Rosen von Rosenstein recommended.Conclusion: Rosen von Rosenstein's opinions and advice concerning neonatal jaundice were not original, and did not differ from those found in other medical texts from the 18th and 19th centuries. The bile stasis explanation for all kinds of jaundice, including neonatal jaundice, was widely held in the 18th century, and continued to predominate in paediatric texts until the end of the 19th century. Similarly, laxatives and enemas as the cure-all for many ailments held sway until the late 1800s

• Hankø, Erik; Hansen, Thor Willy Ruud; Hansen, R; Almaas, Runar; Lindstad, Julie K. & Rootwelt, Terje (2005). Bilirubin induces apoptosis and necrosis in human NT2-N neurons. Pediatric Research. ISSN 0031-3998. 57. Full text in Research Archive
• Hagen, C. & Hansen, Thor Willy (2004). Deaths in a neonatal intensive care unit: A 10-year perspective. Pediatric Critical Care Medicine. ISSN 1529-7535. 5(5), p. 463–468. Full text in Research Archive Show summary

  OBJECTIVE: To examine changes in the characteristics and management of infants dying in a regional neonatal intensive care unit in 1987-1988 vs. 1997-1998. SETTING: The level III Neonatal Intensive Care Unit (NICU) at Rikshospitalet, Oslo, Norway, handles both regional and national referrals. Design/Methods: The study was retrospective and observational. Patients who died in the neonatal intensive care unit were identified using our own and the hospital's data records. Charts were reviewed by the principal author. RESULTS: The mortality rate relative to admissions decreased significantly from 1987-1988 to 1997-1998 (6.9% vs. 3.4%, p <.0001). Infants who died in 1997-1998 were more mature and had higher birth weights than those who died in 1987-1988 (34.0 +/- 5.5 vs. 32 +/- 6.0 wks gestational age [mean +/- sd], p <.05; and 2186 +/- 1207 vs. 1699 +/- 1038 g, p <.05). There was a significantly higher proportion of infants with complex congenital malformations among those who died in 1997-1998 (54% vs. 28%, p <.005). Forgoing intensive care treatment was more commonly associated with the process of dying in 1997-1998 than 10 yrs earlier (63.5% vs. 22.8%, p <.0001). Parental involvement in the process leading to a decision to forgo life support was more frequently described in the charts from 1997-1998 (72.7% vs. 23.8%, p <.001). During the last time period, parents were also present at the time of death significantly more often. CONCLUSIONS: The mortality rate of sick infants decreased significantly between 1987-1988 and 1997-1998, showing the improvements in neonatal intensive care during that decade. In 1997-1998, congenital malformations had become the leading cause of death. Parental involvement in life-and-death questions seems to have become the rule, and almost two thirds of neonatal intensive care unit deaths followed a decision to forgo life support.

• Hansen, Thor Willy (2004). Tratamento da Icterícia Neonatal. AVANÇOS EM PERINATOLOGIA. p. 111–119. Full text in Research Archive Show summary

  Editores Alves Filho & Trindade Editores Convidados: Manoel de Carvalho - Lopes, José Maria de Andrade. (Guanabara Koogan)

• Hankø, Erik; Hansen, Thor Willy; Almaas, R.; Lindstad, J & Rootwelt, Terje (2004). Additional protection of the NMDA-receptor blocker MK-801 and pan-caspase inhibitors in bilirubin-induced apoptosis in NT2-N neurons. Pediatric Research. ISSN 0031-3998. 56, p. 464–464. Full text in Research Archive Show summary

  ESPR EUROPEAN SOCIETY FOR PEDIATRIC RESEARCH: Stockholm, Sweden September 19-22, 2004 Pediatr Res 2004 56: 464

• Hansen, Thor Willy Ruud (2003). Nevrologisk undersøkelse av nyfødte, Nevrologi og nevrokirurgi (3.utg)fra barn til voksen;undersøkelse, diagnose, behandling. Forlaget Vett & Viten AS. p. 31–48. Full text in Research Archive Show summary

  Omtale fra Forlagsentralen Boken er både en lærebok for medisinstudenter og en fagbok for allmennpraktiserende leger. Den dekker alle områder av nevrologien, den åpner med kapitler om klinisk-nevrologiske undersøkelser, og tar så for seg sykdomstilstander i detalj. Har ordlister og stikkordregister. © FS Informasjonstjenester ISBN: 8241205562

• Hansen, Thor Willy Ruud (2003). Recent advances in the pharmacotherapy for hyperbilirubinaemia in the neonate. Expert Opinion on Pharmacotherapy. ISSN 1465-6566. 4(11), p. 1939–1948. Full text in Research Archive Show summary

  Recent advances in the pharmacotherapy for hyperbilirubinaemia in the neonate. Hansen TW. Department of Pediatrics, Rikshospitalet, NO-0027, Oslo, Norway. thor.willy.ruud.hansen@rikshospitalet.no Jaundice is a common cause for diagnostic works-up and therapeutic intervention in neonates. This is motivated by the risk for severe neurological sequelae (kernicterus). The mainstays of treatment for the past decades have been exchange transfusion and phototherapy. Exchange transfusion is now becoming rare due to immune prophylaxis in Rhesus-negative women, and treatment of sensitised infants with intravenous immunoglobulin. Several different pharmacological approaches have been studied as far as the treatment of neonatal jaundice. Of these, the focus of attention in recent years has been on the haem oxygenase inhibitors (metal meso- and protoporphyrins). These are effective inhibitors of bilirubin production and have been shown to significantly reduce peak serum bilirubin levels in several clinical trials, both when used prophylactically and therapeutically. However, questions remain regarding long-term safety, as well as the advisability of whole-scale inhibition of bilirubin production. Nevertheless, in selected infants with a high risk of severe jaundice, the use of haem oxygenase inhibitors may be acceptable. Pharmacotherapy in jaundiced infants is fraught with risks, as many drugs may increase the entry of bilirubin into the brain and presumably, the risk for neurotoxicity. Both the displacement of bilirubin from its albumin binding and interference with the function of phosphoglycoprotein in the blood-brain barrier are documented mechanisms in this respect. Publication Types: Review Review, Tutorial PMID: 14596647 [PubMed - indexed for MEDLINE]

• Hankø, Erik; Tommarello, Steve; Watchko, Jon F. & Hansen, Thor Willy Ruud (2003). Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain. Pediatric Research. ISSN 0031-3998. 54(4), p. 441–445. Full text in Research Archive Show summary

  Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain. Hanko E, Tommarello S, Watchko JF, Hansen TW. Department of Pediatrics, Rikshospitalet, N-0027 Oslo, Norway. P-glycoprotein (P-gp) is an ATP-dependent integral plasma membrane efflux pump, expressed in abundance in brain capillary endothelial cells and astrocytes. P-gp contributes to the blood-brain barrier in limiting the influx and retention of a variety of lipophilic compounds, including unconjugated bilirubin. Several drugs block P-gp function and thereby enhance intracellular accumulation of P-gp substrates. In this study we proposed that pretreatment with drugs known to inhibit P-gp function in clinically relevant doses would alter the uptake of bilirubin in the brain of 32- to 36-d-old rats. In the first arm of the study, the animals received pretreatment with an i.v. infusion of either propanolol, erythromycin, verapamil, ceftriaxone, rifampin, or saline, 10 min before an i.v. bolus of 50 mg/kg bilirubin was given. Except for the erythromycin-treated rats, all treatment groups had significantly higher brain-to-serum bilirubin ratios than control animals (p < 0.05, Welch's t test). In the second arm of the study, treatment with either ceftriaxone or rifampin or saline i.v. preceded a 50 mg/kg i.v. bolus of radioactive bilirubin. Analysis of seven different brain regions by scintillation counting showed that the distribution patterns differed significantly between the study groups (p < 0.001, ANOVA), however, not in accordance with a kernicteric staining pattern. Because of limited knowledge of expression and function of P-gp and other membrane transport proteins in the newborn, the implications of this study remain to be seen. We speculate that drugs known to inhibit P-gp function may increase the risk of bilirubin encephalopathy in the hyperbilirubinemic infant. PMID: 12904601 [PubMed - in process]

• Kalikstad, Betty & Hansen, Thor Willy Ruud (2003). Medikamentell behandling av nyfødte - et sjansespill. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 123(19), p. 2738–2740. Full text in Research Archive Show summary

  Medikamentell behandling av nyfødte - et sjansespill? [Drug treatment of newborn infants--a chance taking?] To av tre barn får ikke-godkjent legemiddelbehandling og omkring 90 % av nyfødte som intensivbehandles, får et ikke-dokumentert legemiddel eller et legemiddel som administreres på en ikke-godkjent måte. Manglende forskning på farmakoterapi for nyfødte begrenser mulighetene for optimal legemiddelbehandling. I stedet brukes medikamenter laget for voksne og på andre indikasjoner. Kunnskapen om medikamenters metabolisme og virkning hos barn er heller ikke tilstrekkelig kjent. Informasjon om medikamenter bør legges til rette for praktisk bruk i den kliniske hverdagen med tanke på barn med ulik modning, ulik grad av sykdom og ulik alder.

• Hansen, Thor Willy Ruud (2002). Fiberoptisk fototerapi ved neonatal icterus - kommentar til en Cochrane-rapport. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 122, p. 45–47. Full text in Research Archive Show summary

  24 studier tilfredsstilte inklusjonskriteriene for denne Cochrane-rapporten om bruk av fiberoptisk fototerapi ved gulsott hos nyfødte. Fiberoptisk fototerapi har effekt på gulsott, og kan ha en plass i behandlingen av neonatal ikterus. Hos barn født nær termin er fiberoptisk behandling dårligere enn konvensjonell fototerapi, mens den hos premature barn er jevngod. Når fiberoptisk behandling kombineres med konvensjonell behandling, oppnås bedre effekt enn med konvensjonell behandling alene. Fiberoptisk behandling er ikke dokumentert å være mindre forstyrrende enn konvensjonell fototerapi når det gjelder foreldrenes opplevelse av og tilknytning til barnet. Det er fortsatt stort behov for forskning vedrørende fototerapi av nyfødte med gulsott.

• Hansen, Thor Willy Ruud (2002). Kernicterus: an international perspective. Seminars in Neonatology. ISSN 1084-2756. 7(2), p. 103–109. Full text in Research Archive Show summary

  Kernicterus occurs in all parts of the world. The risk is increased in countries where glucose-6-phosphate dehydrogenase-deficiency is common. In the 1990's more case reports of infants who developed kernicterus were published than in the previous decades. A combination of reduced concern for jaundice in newborns, early discharge with inadequate follow-up and a decreased awareness of the signs that may herald serious toxicity may have contributed to the apparent increase in the incidence of kernicterus. Although most jaundiced newborns do not need aggressive evaluation or treatment, physicians who deal with such infants still need to be vigilant. We lack the necessary tools to distinguish infants who may be particularly vulnerable to the effects of bilirubin on the brain from those who may tolerate high serum bilirubin levels without harm. Therefore it is imperative that each infant with significant jaundice be conscientiously evaluated and a plan for testing and, if necessary, therapy be formulated. Transcutaneous measurement of bilirubin is a simple tool that significantly reduces the need for invasive tests. Signs of possible neurotoxicity must never be disregarded or neglected. Any jaundiced infant who shows signs of possible neurotoxicity should receive intensive phototherapy as an emergency procedure while further evaluation continues. Further studies regarding bilirubin toxicity and neonatal jaundice are needed, both in the basic science as well as in the clinical arena.

• Kaldestad, Runa Helen; Wingaard, Lisbeth & Hansen, Thor Willy Ruud (2002). Screening for medfødt hørselstap - en pilotstudie. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 122(22), p. 2190–2193. Full text in Research Archive Show summary

  Bakgrunn. I Norge har inntil nylig medfødt hørselstap vært diagnostisert gjennomsnittlig ved 2,8 års alder. Sen diagnostikk medfører at verdifull tid tapes i hørselshabilitering og taleutvikling. Materiale og metode. Ved Barneklinikken, Rikshospitalet har vi fra september 1999 gjennomført universell screening på medfødt hørselstap både hos friske og syke nyfødte. I den første delen av perioden ble alle barna screenet med automatisert hjernestammeresponsaudiometri (AABR), deretter ble friske barn primært screenet med otoakustiske emisjoner (OAE) mens automatisert hjernestammeresponsaudiometri ble brukt som annen linjes screening. Prosjektet, som er finansiert av Stiftelsen Helse og Rehabilitering, screenet fra starten til og med desember 2001 3 996 barn. Resultater. Det ble bekreftet hørselstap hos 25 barn (11 ensidig og 14 dobbeltsidig). I tillegg ble det henvist to barn til undersøkelse som viste seg å ha normal hørsel. Insidensen av medfødt hørselstap var 0,16% hos nyfødte på barselposten, og 2,2% hos barn innlagt i nyfødtseksjonen. Fortolkning. Screening for medfødt hørselstap kan gjøres med en meget lav rate for henvisning og falskt positive undersøkelser, særlig når man har tilgang til både otoakustiske emisjoner og automatisert hjernestammeresponsaudiometri. Det er vår oppfatning at vi i Norge snarest må lovfeste universell screening i nyfødtperioden for dette funksjonstapet. Samtidig må våre hørselssentraler settes i stand til å tilby korrekt tilpassede hørselshabiliterende tiltak for denne nye pasientgruppen.

• Hansen, Thor Willy Ruud (2002). Neonatal jaundice and scientific fraud in 1804. Acta Paediatrica. ISSN 0803-5253. 91, p. 1135–1138. Full text in Research Archive Show summary

  In 1785 the University of Paris issued a prize challenge: "Describe neonatal jaundice and distinguish between those circumstances in which jaundice needs professional help and those in which one only needs to await the course of nature." The prize was awarded to Jean Baptiste Timothée Baumes for a paper, published as a pamphlet in 1788, in which he described 10 jaundiced neonates and discussed his theories on the causes and mechanisms. In a revised edition published in 1806 Baumes accused François Bidault of plagiarism in his 1804 thesis submitted for the MD degree at the University of Paris. Herein I have compared Baumes' 1788 original with Bidault's thesis as well as Baumes 1806 revision. It is clear beyond doubt that the 10 cases discussed by Bidault were the same as those Baumes had published 16 years earlier. Parts of Bidault's descriptions and discussions were verbatim transcripts of Baumes' original. However, Bidault had economized with paper, ink, and effort by significantly reducing the overall length of Baumes' original. In his second edition Baumes denounced Bidault in strong terms and suggested that the University of Paris take strong action to punish him for his dishonesty. Unfortunately university records from that period are incomplete, and it is not clear what, if anything, was done about the matter. Baumes had a very distinguished career and achieved a great reputation both as a teacher and clinician.

• Hansen, Thor Willy Ruud (2002). Guidelines for treatment of neonatal jaundice. Is there a place for evidence-based medicine? Neonatal intensive care. ISSN 1062-2454. 15(2), p. 47–49. Full text in Research Archive
• Hansen, Thor Willy Ruud (2002). Mechanisms of bilirubin toxicity: clinical implications. Clinics in Perinatology. ISSN 0095-5108. 29, p. 765–778. Full text in Research Archive Show summary

  The basic mechanism of kernicterus and bilirubin encephalopathy has not been unequivocally determined. However, much knowledge has been gained about phenomena that contribute to bilirubin neurotoxicity, and this knowledge has implications for clinical practice. Conditions that impact on blood-brain barrier function, increase brain blood flow, or impact on bilirubin metabolism including its transport in serum should if possible be avoided, and if not avoidable should result in a more aggressive approach to treatment of hyperbilirubinemia. Such conditions include drugs and drug stabilizers that compete with bilirubin binding to albumin, or that inhibit P-glycoprotein in the blood-brain barrier; prematurity/immaturity; and clinically significant illness in the infant involving hemolysis, respiratory and metabolic acidosis, infection, asphyxia, hypoxia and (perhaps) hyperoxia, and hyperosmolality. The limits of tolerance for hyperbilirubinemia varies between neonates and there are at present no tools to determine with certainty when a particular infant is approaching the danger zone. However, neurological symptoms in a jaundiced infant requires extreme vigilance and, in most cases, immediate intervention.

• Tsai, Cathy; Daood, Monica J.; Lane, R.H.; Hansen, Thor Willy Ruud; Gruetzmacher, E.M. & Watchko, Jon F. (2002). P-glycoprotein expression in mouse brain increases with maturation. Biology of the Neonate. ISSN 0006-3126. 81(1), p. 58–64. Full text in Research Archive
• Hansen, Thor Willy Ruud; Tommarello, Steve & Allen, Jeffrey Wray (2001). Subcellular localization of bilirubin in rat brain after in vivo i.v. administration of [3H]bilirubin. Pediatric Research. ISSN 0031-3998. 49, p. 203–207. Full text in Research Archive Show summary

  Bilirubin appears to be toxic in vitro to several cellular functions localized to different subcellular compartments. It would therefore be useful to know what concentrations of bilirubin might be found in cell organelles in vivo. Rats were anesthetized and allocated to one of three groups: control, hypercarbia, and hyperosmolality. Each rat received a 5-min bolus dose of bilirubin 50 mg/kg IV (containing &#8776;200 &#956;Ci 3H-bilirubin). Rats were sacrificed 10 or 30 min after the start of the bilirubin infusion. Each brain was homogenized and subcellular fractions were isolated by high-speed gradient centrifugation in sucrose media. The gradients were separated into aliquots of 2 mL, and the protein content was determined in each aliquot. Radioactivity was determined by scintillation counting and the content of bilirubin per mg of protein calculated. Statistical comparisons were performed with Kruskal-Wallis non-parametric ANOVA. There were highly significant differences in bilirubin content per mg protein between subcellular compartments in all groups and at both time points. In all groups there were relatively high concentrations of bilirubin in the myelin fraction, an interesting observation in light of the theory that membranes are the primary target of bilirubin toxicity. The very high concentration of bilirubin relative to protein in cytoplasm, ribosomes, and mitochondria in the hyperosmolar group are also notable in light of data from hyperbilirubinemic animals where changes in electrophysiology or energy metabolism only appeared after hyperosmolar opening of the blood-brain barrier. The present data may be useful in planning in vitro studies of bilirubin toxicity in cell organelles.

• Hansen, Thor Willy Ruud (2001). Bilirubin production, breast-feeding and neonatal jaundice. Acta Paediatrica. ISSN 0803-5253. 90(7), p. 716–717. Full text in Research Archive Show summary

  The risk for significant neonatal jaundice varies considerably between individuals. A number of factors appear to influence the incidence of jaundice in neonates, including race, genetics and family history, maternal, pregnancy, and delivery history, drugs given to mother or infant, low birth weight, prematurity, gender, breast feeding, and post-natal weight loss. The mechanisms underlying breast milk jaundice are primarily believed to include decreased caloric intake and increased enterohepatic bilirubin circulation, while the role of inhibitory substances in breast milk is more conflicting. The steps involved in the production of bilirubin are well described, and a proxy for production rate can be obtained through measurement of carbon monoxide in exhaled breath. The role of bilirubin production in breast milk jaundice has not been established. A priori there seems little reason to suppose that the rate of bilirubin production should differ between breast-fed and formula-fed infants prior to having received significant amounts of their respective foods. Indeed, no such difference was found by Hintz et al in an NIHCD Research Network study published in the present issue of Acta Paediatrica. Conclusion: The precise mechanism (or mechanisms) for the increased incidence, severity, and duration of neonatal jaundice in breast milk nourished infants has not been unequivocally determined. The influence of breast milk nutrition on bilirubin production in the neonate will require further studies.

• Hankø, Erik; Lindeman, Rolf & Hansen, Thor Willy Ruud (2001). Spectrum of outcome in infants with extreme neonatal jaundice. Acta Paediatrica. ISSN 0803-5253. 90(7), p. 782–785. Full text in Research Archive Show summary

  The increasing number of case reports on neurologic sequela related to hyperbilirubinemia may represent a re-emergence of kernicterus in the industrialized world. However, not much has been written about infants who survived extreme levels of serum bilirubin without neurologic damage. We present three cases of extreme neonatal hyperbilirubinemia, all with peak serum bilirubin levels > 600 µmol/L. Two of the infants developed neurologic sequelae, but the third infant did not. In contrast to the two with sequelae, the infant without sequelae was female, had a positive Coombs' test, less clinical signs compatible with bilirubin encephalopathy, and a shorter exposure to serum bilirubin values > 400 µmol/L. Conclusion: The basic mechanism of bilirubin neurotoxicity remains unknown, and it is not clear why some infants do not develop neurologic injury at serum bilirubin levels where others do. We speculate that important information may be found by contrasting patients with sequela to those without.

• Hansen, Thor Willy Ruud (2001). Fiberoptisk fototerapi ved neonatal ikterus. Kommentar til en Chochrane-rapport. Läkartidningen. ISSN 0023-7205. 45, p. 4964–4969. Full text in Research Archive Show summary

  Sammendrag ¿ Tjuefire studier tilfredsstilte inklusjonskriteriene for denne Cochrane-rapporten om bruk av fiberoptisk fototerapi ved gulsott hos nyfødte ¿ Fiberoptisk fototerapi har effekt på gulsott, og kan ha en plass i behandlingen av neonatal ikterus. ¿ Hos barn født nær termin er fiberoptisk behandling dårligere enn konvensjonell fototerapi, mens den hos premature barn er jevngod. ¿ Når fiberoptisk behandling kombineres med konvensjonell behandling, oppnås bedre effekt enn med konvensjonell behandling alene. ¿ Fiberoptisk behandling er ikke dokumentert å være mindre forstyrrende enn konvensjonell fototerapi når det gjelder foreldrenes opplevelse av og tilknytning til barnet. ¿ Det er fortsatt stort behov for forskning vedrørende fototerapi av nyfødte med gulsott.

• Hankø, Erik; Lindeman, Rolf & Hansen, Thor Willy Ruud (2001). Spectrum of outcome in infants with extreme neonatal jaundice. Acta Paediatrica. ISSN 0803-5253. 90, p. 782–785. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Bilirubin brain toxicity. Journal of Perinatology. ISSN 0743-8346. 21, p. S48–S51. Full text in Research Archive Show summary

  1. Bilirubin is toxic in most biological systems tested. Several mechanisms have been suggested for this toxic effect, including inhibition of the respiratory cycle, perturbation of membrane function, inhibition of enzyme systems, and inhibition of cell regulatory reactions (protein/peptide phosphorylation). The identity of the basic mechanism (or mechanisms) has not been conclusively proven, but inhibition of peptide phosphorylation, perhaps mediated or modulated by lysine at the active site(s), appears to be compatible with many of the observations currently found in the literature. 2. Bilirubin entry into brain is facilitated by e.g. drug displacement of bilirubin from its albumin binding, reduced albumin binding capacity, increased brain blood flow, and increased permeability of the blood-brain barrier. The rate of bilirubin entry into brain, as well as the degree of retention and rate of clearance from brain depend on which of the above circumstances are operative. It is as yet unclear whether the mechanism responsible for increased brain bilirubin is important for toxicity. The mechanism for preferential localization of bilirubin to the basal ganglia in kernicterus is not yet known. Bilirubin appears to distribute differentially to brain subcellular compartments. 3. Bilirubin is oxidized in brain by an enzyme localized on the inner mitochondrial membrane. This enzyme is found both in neurons and in glia, but appears to be more active in the latter. The activity increases with postnatal age, and is subject to genetic variability in animals. The enzyme is cytochrome-c-dependent. It is as yet not clear whether the activity of this enzyme serves a brain protective effect in severe hyperbilirubinemia.

• Hansen, Thor Willy Ruud (2001). Guidelines for treatment of neonatal jaundice - is there a place for evidence based medicine? Acta Paediatrica. ISSN 0803-5253. 90, p. 239–241. Full text in Research Archive Show summary

  Treatment of neonatal jaundice continues to be a controversial issue. Arguments that traditional practice results in over-treatment have led to the adoption of more liberal guidelines in some countries. The importation of liberal guidelines from one country to another is fraught with danger. Differences in epidemiology, sociology, and health care delivery systems between countries may not be adequately reflected. The unreflected extension of liberalization to non-target groups of patients may expose the latter to significant risk. It is not clear that the evidence on which guidelines for treatment of neonatal jaundice are based, satisfy the requirements for evidence-based medicine. Evidence of adequate quality may be hard to obtain. Conclusion: Introduction of more liberal guidelines for the treatment of neonatal jaundice, if it is at all to be contemplated, must be adapted to local circumstances, and any available evidence pertaining to local epidemiology, sociology, and health care organization needs to be carefully weighed and incorporated. The time is ripe for a joint international effort to secure adequate funding for basic and applied research into the mechanisms of bilirubin encephalopathy in the newborn

• Hansen, Thor Willy Ruud (2001). Neonatal jaundice. In Altschuler, Steven; Arceci, Robert J; Ballow, Mark; Berger, Stuart & Buehler, Bruce (Ed.), eMedicine: Pediatrics. An On-line Medical Reference (http://www.emedicine.com/PED/topic1061.htm). eMedicine Online Textbooks. St.Petersburg, FL, U.S.A.. Full text in Research Archive
• Mahmood, Burhan; Daood, Monica J.; Hart, Claudia; Hansen, Thor Willy Ruud & Watchko, Jon F. (2001). Ontogeny of P-glycoprotein in mouse intestine, liver, and kidney. Journal of Investigative Medicine. ISSN 1081-5589. 49(3), p. 250–257. Full text in Research Archive
• Hansen, Thor Willy Ruud (2000). Phototherapy for neonatal jaundice - still in need of fine tuning. Acta Paediatrica. ISSN 0803-5253. 89, p. 770–772. Full text in Research Archive
• Hansen, Thor Willy Ruud & Whilelaw, Andrew (2000). Nevrologisk undersøkelse av nyfødte. In Gjerstad, Leif & Skjeldal, Ola (Ed.), Nevrologi. Fra barn til voksen. Forlaget Vett & Viten AS. p. 27–44. Full text in Research Archive
• Hansen, Thor Willy Ruud & Allen, Jeffrey Wray (2000). Bilirubin oxidation by brain mitochondrial membranes is not affected by hyperosmolality. Biology of the Neonate. ISSN 0006-3126. 78, p. 68–69. Full text in Research Archive Show summary

  Brain mitochondrial membranes oxidize bilirubin at a rate that may be biologically significant. Hyperosmolality delays clearance of bilirubin from rat brain. We hypothesized that this might be due to a decrease in brain bilirubin metabolism. Rats were anesthetized and infused with 75 mM/kg urea iv over 5 min (n=7) and sacrificed at 1 hr, control rats (n=7) had no treatment. Crude mitochondrial membrane fractions (¿P2¿) were produced by homogenization and differential centrifugation in sucrose. The change in optical density at 440nM of a 10ìmol/L bilirubin solution was measured after 60 min incubation with mitochondrial membranes. Hyperosmolality did not affect bilirubin oxidation by brain mitochondrial membranes (t=1.27, p=0.23 by unpaired t-test). The lack of effect of hyperosmolality on bilirubin oxidation by brain mitochondrial membranes suggests that decreased clearance of bilirubin from brain in hyperosmolality may be related to changes in transfer of bilirubin across the blood-brain barrier.

• Høgåsen, Anne Kirsti Myrvang; Øverlie, Inger; Hansen, Thor Willy Ruud; Abrahamsen, Tore G; Finne, Per Haavardsholm & Høgåsen, Kolbjørn (2000). The analysis of the complement activation product SC5b-9 is applicable in neonates in spite of their profound C9 deficiency. Journal of Perinatal Medicine. ISSN 0300-5577. 28, p. 39–48. Full text in Research Archive
• Hansen, Thor Willy Ruud (2000). Kernicterus in term and near-term infants - the specter walks again. Acta Paediatrica. ISSN 0803-5253. 89, p. 1155–1157. Full text in Research Archive Show summary

  Neonatal jaundice is a very common cause for diagnostic and therapeutic intervention in newborns. This is motivated by the fear of bilirubin-associated brain damage, kernicterus. In recent years a resurgence of kernicterus has been noted in countries in which this complication had essentially disappeared. Both early postnatal discharge and relaxation of attitudes towards neonatal jaundice have been implicated. Guidelines for the management of neonatal jaundice show significant disparity, attesting to our inadequate understanding of the underlying biology. Aggressive guidelines expose infants to unnecessary risks which are quite significant when it comes to exchange transfusion, and may also involve improper use of limited resources. Relaxed guidelines, on the other hand, may expose infants to increased risk of brain toxicity. At present we have no tools that would permit certain identification of individuals with increased vulnerability to bilirubin toxicity. Therefore, relaxation of guidelines which have been proven safe through prolonged use, should only be undertaken in an atmosphere of increased vigilance. Guidelines which allow for a range of therapeutic and diagnostic options underline the need for careful assessment of each case on its individual merits.

• Hansen, Thor Willy Ruud (2000). Pioneers in the scientific study of neonatal jaundice and kernicterus. Pediatrics. ISSN 0031-4005. 106, p. e15–e15. Full text in Research Archive Show summary

  Neonatal jaundice must have been noticed by caregivers through the centuries, but the scientific description and study of this phenomenon seems to start in the last half of the eighteenth century. In 1785 Jean Baptiste Thimotée Baumes was awarded a prize from the University of Paris for his work describing the clinical course in ten jaundiced infants. The work by Jaques Hervieux, which he defended for his M.D. degree in 1847, was in many respects a landmark. He had autopsied 44 jaundiced infants, and apparently had clinical observations on many others. His descriptions of pathoanatomical findings were very detailed and systematic. A number of his clinical observations are still thought to be accurate today, such as the essentially benign nature of neonatal jaundice in most cases, its appearance during the first 2-4 days of life as well as its disappearance within 1-2 weeks, and the cephalocaudal progression of jaundice. He described jaundice of the brain in 31 of his 44 autopsied cases, with variable intensity of staining. Johannes Orth was an assistant to the famous Virchow in Berlin when in 1875 he published the results of an autopsy of a jaundiced term infant. The brain was notable for an intense yellow staining of the basal ganglia, the wall of the third ventricle, the hippocampus, and the central parts of the cerebellum. While Orth¿s contribution was limited to this single case report, Christian Schmorl in 1903 presented to the German Society for Pathology the results of his autopsies of 120 jaundiced infants. All of these infants¿ brains were jaundiced, but only six cases demonstrated a staining phenomenon similar to that previously described by Orth. For this staining pattern Schmorl coined the term kernicterus (¿jaundice of the basal ganglia¿). While the following century of scientific study has added an enormous amount of information about the epidemiology and pathophysiology of neonatal jaundice and kernicterus, the contributions of Hervieux, Orth, and Schmorl will undoubtedly continue to be seen as historical landmarks in our quest for understanding of these phenomena.

• Hansen, Thor Willy Ruud (2000). Neonatal jaundice and scientific plagiarism - two hundred years ago. Perinatal Section News: AAP. 26(2), p. 11–12. Full text in Research Archive
• Hansen, Thor Willy Ruud (2000). Bilirubin oxidation in brain. Molecular Genetics and Metabolism. ISSN 1096-7192. 71, p. 411–417. Full text in Research Archive Show summary

  Bilirubin is a product of heme catabolism which by virtue of its lipid solubility can cross the blood-brain barrier and enter the brain. Neonatal jaundice is a common transitional phenomenon which is due to the combination of increased heme catabolism and rate limitations as far as hepatic conjugation and biliary excretion of bilirubin. In the great majority of cases this is an innocuous condition, which is even posited to have some beneficial effects due to the ability of bilirubin to quench free oxygen radicals. However, because bilirubin is neurotoxic hyperbilirubinemia in the newborn may exceptionally result in death in the neonatal period, or survival with severe neurological sequelae (kernicterus). Bilirubin enters the brain through an intact blood-brain barrier. Clearance of bilirubin from brain partly involves retro-transfer through the blood-brain barrier, and possibly also through the brain-CSF-barrier into CSF. Work in our lab during the past five years has substantiated earlier work which had suggested that bilirubin may also be metabolized in brain. The responsible enzyme is found on the inner mitochondrial membrane, and oxidizes bilirubin at at rate of 100-300 pmol bilirubin per mg protein per minute. The enzyme activity is lower in the newborn vs the mature animal, and is also lower in neurons vs glia. Studies of different rat strains have documented genetic variability. The enzyme is cytochrome-c-dependent, but has as yet not been unequivocally identified. The rate of oxidation of bilirubin is such that this enzyme probably contributes meaningfully to the clearance of bilirubin from brain

• Hansen, Thor Willy Ruud (2000). The pathophysiology of bilirubin toxicity. In Maisels, M.Jeffrey & Watchko, Jon F. (Ed.), Neonatal Jaundice. Harwood Academic Publishers, London. ISSN 9789057026263. p. 89–104. Full text in Research Archive Show summary

  Bilirubin is toxic to brain as well as to many other tissues. It probably enters the brain mainly as an unbound (¿free¿) molecule as long as the blood-brain barrier is intact, but may enter bound to albumin when the blood-brain barrier is opened. The evidence suggests that it is toxic when unbound, but the data are more controversial with regard to the effects of albumin-bound bilirubin in brain. Bilirubin entry into brain is facilitated by the presence of endogenous or exogenous compounds that compete for the binding site to albumin, by increased brain blood flow, and by opening of the blood-brain barrier. Bilirubin itself may increase the permeability of the blood-brain barrier and thus facilitate its own entry, but we still do not know why bilirubin preferentially localizes to the basal ganglia and cerebellum to produce kernicterus. Bilirubin is cleared from brain partly through retro-transfer to blood through the blood-brain barrier and possibly through the CSF. Evidence is also accumulating that bilirubin may be metabolized locally in the brain by a mitochondrial enzyme. Our understanding of the basic mechanism for bilirubin toxicity is as yet incomplete. However, the many points of action within the cell point to interference with a fairly ubiquitous regulatory mechanism as a possible common cause. Inhibition of protein phosphorylation, possibly through binding to lysine residues, appears to be compatible with much of the available data.

• Hansen, Thor Willy Ruud (2000). Fetal and neonatal bilirubin metabolism. In Maisels, M.Jeffrey & Watchko, Jon F. (Ed.), Neonatal Jaundice. Harwood Academic Publishers, London. ISSN 9789057026263. p. 3–20. Full text in Research Archive Show summary

  Bilirubin metabolism undergoes significant changes during fetal and neonatal life. This applies both to the isomers that predominate and to the processes involved in uptake into the hepatocyte, binding and conjugation inside the hepatocyte, and excretion into the bile. Several steps in the process that causes neonatal jaundice can be modulated both by endogenous (e.g. hormones) and exogenous (e.g. drugs) compounds. Drugs that increase the concentration of ligandin or the activity of bilirubin UDP-glucuronyl transferase are well documented, but appear not to be widely used. Drugs that limit bilirubin production by inhibiting heme oxygenase are undergoing trials, but their eventual place in the routine management of neonatal jaundice remains to be determined. Natural compounds that stimulate alternate pathways for hepatic bilirubin metabolism may provide a therapeutic option for patients with Crigler-Najjar type I, but much work will be required to bring this beyond the experimental stage. Enterohepatic circulation contributes to neonatal jaundice, and is also amenable to therapeutic intervention by formula feeds or other bilirubin binding or degrading agents.

• Hansen, Thor Willy Ruud (2000). Amishene og det enkle liv - glimt fra historie, samfunn og helse i en religiøs minoritet. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. p. 3789–3792. Full text in Research Archive Show summary

  Amisher, mennonitter og hutteritter er nær beslektede religiøse grupper som har sin opprinnelse i Sentral-Europa. Amisher og hutteritter finnes nå bare i Nord-Amerika. Fordi deres klesdrakt, gårdsbruk og kjøretøyer reflekterer deres forsakelse av det moderne, er de lett gjenkjennelige. I områder av USA er disse gruppene nærmest blitt en turistattraksjon. Men hvis man reiser gjennom amishområder bare for å se på disse menneskene som rariteter i et titteskap, har man berøvet seg selv muligheten av å reflektere over hvem disse menneskene er, og hvorfor de har valgt å leve sitt liv uten de tekniske og mekaniske hjelpemidlene som vi betrakter som fremskritt. Amishene velger fortsatt i det 21. århundre å leve nær hjem, familie og kirke. Ved å underkaste seg gruppens regler uttrykker de sin tro på at lydighet, ydmykhet, sparsomhet og en enkel livsførsel vil holde dem nær Gud. Det å eie en bil eller et fjernsynsapparat er eksempler på noe negativt fordi det vil trekke oppmerksomheten bort fra det sentrale. De som holder seg tettest opp til de opprinnelige, strenge reglene, kalles "Old Order". Fordi anabaptistene i USA opprinnelig kommer fra en liten gruppe innvandrere, har de et begrenset genmateriale. Det er derfor ikke overraskende at enkelte arvelige sykdommer er vanlige blant dem. Til tross for at de avstår fra det meste av moderne teknologi, aksepterer de i stor grad moderne medisinsk behandling hvis denne oppfattes som livreddende.

• Hansen, Thor Willy Ruud (1999). Neonatal hyperbilirubinemia and kernicterus - A 1998 update. Journal of Medical Libanaise. 47(1), p. 22–27. Full text in Research Archive Show summary

  Neonatal jaundice is a very common clinical phenomenon. Its clinical presentation as well as its rare, but devastating sequelae: kernicterus, have been studied for more than a century. In classical kernicterus intense yellow staining of the basal ganglia with evidence of neuronal death was seen at autopsy, while choreoathetosis, gaze paresis, nerve deafness, and mental retardation were seen in the survivors. Most of the cases of kernicterus described in the early literature were probably the result of Rhesus immunization. Subsequently bilirubin-induced brain damage was also seen in non-hemolytic jaundice. Kernicterus had virtually disappeared in many countries, but has recently reappeared in the wake of early postnatal discharge with inadequate follow-up. Kernicterus seen today appears to have the same characteristics as those described in times past. The basic mechanism of bilirubin-induced brain damage is not known with certainty in spite of many interesting theories and hypotheses and a multitude of fascinating findings. Early studies showed inhibition of cell respiration and uncoupling of oxidative phosphorylation. However, bilirubin appears able to inhibit most of the biological systems and reactions in which it has been tested. Current theories being pursued in various laboratories include interference with cell membrane function, and inhibition of cell regulatory mechanisms through inhibition of protein/peptide phosphorylation. The role of specific blood-brain barrier proteins in modulating bilirubin entry into brain is also an active research field. In the past few years we have seen a drive towards a more lenient approach to jaundice in healthy, term infants. These infants, it is argued, are not as vulnerable to bilirubin brain toxicity, and hence do not need to be treated as aggressively when jaundice occurs. While true for most such infants, our lack of ability to identify the exceptional infant who may be less tolerant may be partly responsible for the increased number of kernicterus cases seen in recent years. My advice for now is to stick with proven guidelines until a more scientifically sound basis for changes in therapy can be found.

• Hansen, Thor Willy Ruud (1999). Early discharge from the nursery: Implications for the care of healthy and sick neonates. Journal of Medical Libanaise. 47(1), p. 28–33. Full text in Research Archive Show summary

  Early discharge of mother and infant from maternity hospitals is increasing in frequency and (perhaps) popularity. Several driving forces may be operative behind this development. While financial pressure is often seen as the most important influence, logistics, history, and ideology may also be important. Several problems have surfaced in the wake of a wider implementation of early post-partum discharge policies, particularly when early discharge has occurred in the absence of changes in the previously established follow-up programs. These include i.a. inadequate instruction of parents, missed screening for metabolic disorders, severe dehydration, and significant jaundice. Thus, a program of early post-partum discharge, if implemented, needs to be accompanied by a program of early follow-up. Early discharge from the neonatal intensive care nursery was first implemented in countries where the supply of medical resources was limited. Using criteria for pre-screening, it appears well documented that premature infants may be discharged safely at weights much lower than those found in traditional guidelines. Technology-dependent infants are also being discharged home, but require a well organized system for parental instruction and home health care. Each hospital must, if implementing such early discharge, establish a set of criteria that is specifically tailored to the socioeconomic realities of the community and the families involved. In conclusion, early discharge of infants from hospitals can probably be accomplished safely assuming each family is properly evaluated for suitability, and assuming an adequate follow-up system is in place. Under such circumstances, transfer of responsibility to the family may result in empowerment. On the other hand, a blanket policy of early discharge without due consideration for the factors mentioned above may well be a recipe for disaster.

• Hansen, Thor Willy Ruud; Mathiesen, Siri B. W.; Sefland, Iren & Walaas, Sven Ivar (1999). Bilirubin inhibits Ca2+-dependent release of norepinephrine from permeabilized nerve terminals. Neurochemical Research. ISSN 0364-3190. 24(6), p. 733–738. Full text in Research Archive Show summary

  Although the well-known neurotoxic agent bilirubin can induce alterations in neuronal signaling, direct effects on neurotransmitter release have been difficult to demonstrate. In the present study we have used permeabilized nerve terminals (synaptosomes) from rat brain labeled with [3H]norepinephrine to examine the effects of bilirubin on transmitter release. Rat cerebrocortical synaptosomes were permeabilized with streptolysin-O (2 U/ml) in the absence or presence of bilirubin (10 microM-320 microM) and Ca2+ (100 microM), and the amount of radiolabeled transmitter released during 5 min to the medium was analysed. Low levels of bilirubin decreased Ca2+-evoked release in a dose-dependent manner, with half-maximal effect at approx 25 microM bilirubin. Higher levels of bilirubin (100-320 microM) increased [3H]norepinephrine efflux in the absence of Ca2+, suggesting that high bilirubin levels induced leakage of transmitter from vesicles. The nontoxic precursor biliverdin had no effect on Ca2+-dependent exocytosis. Our data indicate that bilirubin directly inhibits both exocytotic release and vesicular storage of brain catecholamines.

• Carvalho, Manoel De; Carvalho, Deborah De; Trzmielina, Sonia; Lopes, Jose M.A. & Hansen, Thor Willy Ruud (1999). Intensified phototherapy using daylight fluorescent lamps. Acta Paediatrica. ISSN 0803-5253. 88, p. 768–771. Full text in Research Archive Show summary

  Jaundice is a common reason for therapeutic intervention in newborn infants. Phototherapy is effective treatment if enough light energy is delivered to a skin surface area of sufficient size. Narrow spectrum blue light is superior to white light, but in developing countries fluorescent blue lamps often have to be imported and are much more expensive than white lamps. We developed a phototherapy unit in which seven daylight fluorescent tubes are placed immediately under the floor of a transparent plexiglass crib. The efficacy of this unit, delivering 19 µW/cm2/nm, was compared to that of two conventional phototherapy units using overhead lamps placed 35 cm above the infants. One unit used daylight fluorescent tubes and delivered 4 µW/cm2/nm, the other unit used special blue fluorescent tubes and delivered 22 µW/cm2/nm. Fifty-one infants were included in the analyses. All of them were breast fed on demand. Serum bilirubin levels were determined spectrophotometrically at 0, 12, and 24 hours. The decrement in serum bilirubin concentrations was significantly greater in infants undergoing phototherapy with the new device or with special blue lamps compared to conventional overhead daylight lamps (p<0.001 both at 12 and at 24 h). We conclude that highly efficient phototherapy may be delivered with daylight fluorescent lamps placed in very close proximity to the patient. Thus, lack of access to expensive imported special blue lamps does not preclude delivery of effective phototherapy in developing countries.

• Hansen, Thor Willy Ruud; Allen, Jeffrey Wray & Tommarello, Steve (1999). Oxidation of bilirubin in the brain - further characterization of a potentially protective mechanism. Molecular Genetics and Metabolism. ISSN 1096-7192. 68, p. 404–409. Full text in Research Archive Show summary

  Bilirubin is a well known neurotoxin and presents a particular problem in newborn infants. This is partly due to the high incidence of unconjugated hyperbilirubinemia in that age group, but may also be due to increased vulnerability to bilirubin toxicity. The brain may be able to protect itself against bilirubin toxicity through a process of oxidation. The responsible enzyme is localized on the inner mitochondrial membrane, appears to be more active in glia than in neurons, and to increase in activity with postnatal maturation. Here we have investigated the possibility that the responsible enzyme might be a cytochrome oxidase, malate dehydrogenase, or monoamine oxidase, all enzymes located on the inner mitochondrial membrane. Mitochondria were obtained from rat brains through homogenization and differential centrifugation in sucrose media. The ability of mitochondrial membranes to oxidize bilirubin was measured by following the change in optical density at 440 nm of a bilirubin solution to which a membrane suspension had been added. The activity was not changed by in vitro inhibitors of malate dehydrogenase or monoamine oxidase, but was moderately inhibited by ketoconazole and clotrimazole, both known inhibitors of hepatic cytochrome P450 oxidases. Activity was inhibited by depletion of cytochrome c in the mitochondria, and reconstituted by reintroducing cytochrome c into the reaction mixture. The reaction was not modified by the addition of a free radical quencher, but was inhibited by removal of oxygen from the reaction mixture. The activity was significantly inhibited by cyanide. Activity was retained in a 100.000 g pellet, and was not influenced by the addition of NAD, NADP, NADH, NADPH, GSH or GSSH to this pellet. We conclude that the bilirubin-oxidizing activity in brain mitochondrial membranes is cytochrome c dependent, but does not appear to be unequivocally identifiable as a cytochrome P450 oxidase.

• Hansen, Thor Willy Ruud (1999). Tidlig utskrivning til hjemmet fra fødeavdeling og neonatalavdeling - begrensninger og muligheter. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 119(13), p. 1893–1896. Full text in Research Archive Show summary

  Tidlig utskrivning av mor og barn fra fødeavdelinger er blitt stadig mer vanlig i det siste tiåret. Drivkreftene har vært dels historiske og ideologiske, men trolig har økonomiske forhold veiet tyngst. Tidlig hjemskrivning har mange steder vært iverksatt uten å forberede oppfølgingsapparatet på forandringen. Dette har ført til hyppigere gjeninnleggelser pga. slike forhold som alvorlig gulsott hos den nyfødte. Et urovekkende stort antall spedbarn møter ikke til metabolsk rescreening etter tidlig utskrivning. Man frykter derfor en økning av tilfeller av mental retardasjon på grunn av dette. Spørsmålet om "riktig" varighet av et barselopphold i sykehus er ikke vitenskapelig analysert på tilfredsstillende måte. Endringer i etablert praksis bør derfor gjennomføres med varsomhet, og det må etableres kontrollmekanismer slik at uforutsette problemer oppdages tidlig. Tidlig utskrivning fra neonatale intensivavdelinger forekommer nå i flere land. I rike land pleies teknologi-avhengige barn i økende grad i hjemmet. Denne praksis har heller ikke vært adekvat studert.

• Hansen, Thor Willy Ruud & Liavaag, Astrid H. (1999). Forsoning, forløsning og vekst - et annet perspektiv på eutanasidebatten. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 119, p. 4359–4362. Full text in Research Archive Show summary

  Spørsmålet om dødshjelp er mye diskutert, og både juridiske, etiske, medisinske og religiøse sider har vært belyst. Etter vårt syn har et viktig aspekt ved veien mot døden vært neglisjert i denne debatten. Døden er mer enn en biologisk prosess og hendelse. Mennesket er mer enn et biologisk vesen. Fordi mennesket også har en sosial og åndelig eksistens, er veien frem mot døden, for den som får anledning til å forberede seg, en sosial, mental og åndelig (eller sjelelig) prosess. Den døende skal gi slipp ikke bare på sin kropp, men også på sin sosiale og åndelige eksistens og sine mellommenneskelige relasjoner. Vi vil hevde at "den gode død" er den som skjer i en tilstand av forsoning med seg selv og sine omgivelser, og i en fullstendig aksept av det uavvendelige. På veien dit vil den døende kunne gi de gjenlevende de siste gaver i form av omsorg og vunnet visdom. Eutanasi kan avskjære den mulighet som måtte finnes til å nå frem til døden i en slik tilstand av aksept og forsoning. En lege som medvirker til eutanasi kan derfor, i sin ytterste konsekvens, frarøve sin pasient den mulighet vedkommende måtte ha til åndelig vekst og modning på det siste stykket av livsveien. Sett i et slikt lys mener vi at eutanasi er det motsatte av helsetjeneste.

• Sigurdsson, Luther; Reyes, Jorge; Kocoshis, Samuel A.; Hansen, Thor Willy Ruud; Rosh, Joel & Knisely, Alex S. (1998). Neonatal hemochromatosis: Outcomes of pharmacological and surgical therapies. Journal of Pediatric Gastroenterology and Nutrition - JPGN. ISSN 0277-2116. 26, p. 85–89. Full text in Research Archive Show summary

  Background: Neonatal hemochromatosis (NN). Also known as perinatal hemochromatosis or neonatal iron storage disease, is a disorder in fetuses and newborn infants. A retrospective study was conducted to report management of patients with NH. Methods: Retrospective analysis was conducted by chart review and by review of histologic material from patients with NH. Results: Neonatal hemochromatosis was diagnosed in 14 patients between 1985 and 1995, All were considered for orthotopic liver transplantation (OLTX). From 1993 onward, all patients were treated with an antioxidant-chelation "cocktail," consisting of deferoxamine, vitamin E. N- acetylcysteine. selenium, and prostaglandin-E1. Of 6 patients with NH diagnosed before 1993, 4 underwent OLTX; only 1 is still alive. Of 8 patients with NH diagnosed after 1993 and treated with the cocktail, 7 expired before OLTX. One stabilized on therapy, but having never recovered full synthetice liver function, underwent OLTX and is now alive and well. Conclusion: Neonatal hemochromatosis carries a grim prognosis, however, successful OLTX is curative. The use of an antioxidant-chelation cocktail did not improve outcomc in the patients studied. Earlier (perinatal) diagnosis may be required for optimal results. Further study of other interventions, including antenatal diagnosis and earlier institution or modification of cocktail therapy appears warranted.

• Allen, Jeffrey Wray; Tommarello, Steve; Carcillo, Joseph & Hansen, Thor Willy Ruud (1998). Effects of endotoxemia and sepsis on bilirubin oxidation by rat brain mitochondrial membranes. Biology of the Neonate. ISSN 0006-3126. 73, p. 340–345. Full text in Research Archive Show summary

  Sepsis is believed to increase the risk of bilirubin brain toxicity, but the mechanism is not known. Adult male Sprague-Dawley rats were injected IP with either 20 mg/kg E.coli lipopolysaccharide, 5x109/kg CFU Listeria monocytogenes or vehicle 48 h prior to sacrifice. Rats were killed with an IP injection of pentobarbital. Mitochondrial membrane fractions were produced by homogenization of the brains and differential centrifugation in 0.32 M sucrose. The mitochondrial pellet was resuspended in distilled water and sonicated to rupture the mitochondria. The protein concentration of the suspension was standardized to 2.5 mg/mL. Bilirubin oxidation was assayed in a pH 8.2, 0.1M barbital buffer containing 10 µmol/L bilirubin, 5 mmol/L EDTA, and 500 U/mL catalase. Optical density was measured at 440 nm before and after a 60 min incubation at 37.5 C. There were no differences between the control, endotoxemic, and septic groups as far as the ability of brain mitochondrial membranes to oxidize bilirubin (bilirubin oxidation rate: 289±11 vs 295±9 vs 296±12 pmol/min/mg protein [mean±SD]). We conclude that endotoxemia or sepsis do not change the ability of brain mitochondrial membranes to oxidize bilirubin. If sepsis truly increases the risk of bilirubin encephalopathy in neonatal jaundice, this is likely to involve other mechanisms.

• Roseth, Svein; Hansen, Thor Willy Ruud; Fonnum, Frode & Walaas, Sven Ivar (1998). Bilirubin inhibits transport of neurotransmitters in synaptic vesicles. Pediatric Research. ISSN 0031-3998. 44(3), p. 312–316. Full text in Research Archive Show summary

  Uptake of neurotransmitters into synaptic vesicles occurs through specific transport proteins which are driven by an ATPase-generated electrochemical force consisting of a proton gradient and a membrane potential. In this study we examined the effects of bilirubin, a well known neurotoxic agent, on the vesicle uptake both of [3H]dopamine (which is driven mostly by the proton gradient) and [3H]glutamate (which is driven mostly by the membrane potential), and compared these to the vesicular proton gradient, which was estimated by analyzing the uptake of [14C]methylamine. Bilirubin inhibited the uptake of both dopamine and glutamate (p < 0.01), with an identical dose-response curve for both transmitters. Inhibition was detected readily at 75 µM. The effects of bilirubin were dependent on the concentration of vesicles in the assay, suggesting that the concentration of bilirubin in the membranes and not the water phase was important. Bilirubin also decreased uptake-dependent efflux of dopamine from the vesicles. In contrast, bilirubin had no effect on the vesicular proton gradient, as measured by methylamine uptake. Our results show that bilirubin has essentially identical inhibitory effects on the uptake of both a monoamine transmitter and an amino acid transmitter into synaptic vesicles, but docs not influence the vesicular 1-1-ATPase or proton translocation. Our data suggest an inhibitory interaction between bilirubin and several transport proteins in synaptic vesicle membranes.

• Sigurdsson, Luther & Hansen, Thor Willy Ruud (1998). Neonatal hemokromatose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 118, p. 882–883. Full text in Research Archive Show summary

  Neonatal hemochromatosis is a disorder which affects fetuses and newborns. It is characterized by hepatocellular insufficiency, often presenting on the first day of life with coagulopathy, hypoalbuminemia, hypoglycemia, and jaundice. While spontaneous recovery has been reported, most of these infants die, and the diagnosis was previously often made at autopsy. With the help of MRI and salivary gland biopsies, in addition to increasing awareness of this disorder, the diagnosis is now often made quite early, and successful liver transplantions have been reported. Recently there have also been encouraging preliminary reports of successful intervention with antioxidant and chelation pharmacotherapy, using a combination of selenium, vitamin E, N-acetylcysteine, deferoxamine, and prostaglandin E. We describe two patients with neonatal hemochromatosis who were both treated with this new "cocktail", one of whom died at 5 days of age, while the other survived but needed a liver transplant at 2½ months of age. The pathology of this condition is characterized by hepatic cirrhosis with giant cell transformation, and by siderosis of extrahepatic tissues. The prognosis is poor, and our experience with antioxidant treatment has been disappointing. Liver transplantation is a therapeutic option, but its use is limited by the scarcity of donor organs and the small size of many of the patients.

• Hansen, Thor Willy Ruud & Tommarello, Steve (1998). Effect of phenobarbital on bilirubin metabolism in rat brain. Biology of the Neonate. ISSN 0006-3126. 73, p. 106–111. Full text in Research Archive Show summary

  Bilirubin is metabolized by brain mitochondrial membranes. This activity increases with postnatal age, is higher in glia than in neurons, and is subject to genetic variability. The rates of oxidation are such that this mechanism probably contributes meaningfully to clearance of bilirubin from brain. Phenobarbital is a well-known inducer of bilirubin-metabolizing enzymes in the liver. Previous incomplete data had suggested that phenobarbital-treatment might also affect bilirubin metabolism in brain. We studied the clearance of bilirubin from brain (branch 1) as well as the oxidation of bilirubin by brain mitochondrial membranes (branch 2) following pretreatment of young adult SPRD rats with phenobarbital 75 mg/kg ip daily for 7 days, controls received solvent only. On day 8 rats in branch 1 (n=8 in both phenobarbital-treated and control groups) were anesthetized and 50 mg/kg bilirubin was infused iv over 5 min. Rats were sacrificed after 60 min and brain bilirubin determined by acid chloroform extraction. In branch 2 (n=7 in both groups) rats were sacrificed with ip pentobarbital, brains were homogenized in 0.32 M sucrose and mitochondria separated out by differential centrifugation. The mitochondrial membrane suspension was added to a 10 µmol/L bilirubin solution, and the rate of bilirubin oxidation was measured at 440 nm. As expected following phenobarbital treatment, serum bilirubin was slightly lower in phenobarbital-treated vs control rats (126±32 vs 140±21 µmol/L, p=0.3 [mean±SD]). Brain bilirubin values were also lower in the phenobarbital-treated rats (0.44±0.06 vs 0.52±0.08 nmol/g, p=0.044). As the lower brain bilirubin values in phenobarbital-treated rats could be due entirely to lower serum bilirubin values, we compared the brain:serum bilirubin ratios in the two groups. These were not different (0.0063±0.0016 vs 0.0064±0011). The rate of bilirubin oxidation was significantly lower in phenobarbital-treated vs control rats (256±10 vs 286±26 pmol/min/ mg protein, p=0.023). We conclude that phenobarbital inhibits bilirubin metabolism in brain. However, albeit statistically significant, the difference is small and may not be biologically meaningful. Thus, pretreatment with phenobarbital had no effect on overall brain bilirubin clearance rate. We speculate that phenobarbital treatment may be neither helpful nor harmful relative to the neurotoxic effects of bilirubin in infants with already established jaundice.

• Watchko, Jon F.; Daood, Monica J. & Hansen, Thor Willy Ruud (1998). Brain bilirubin content is increased in P-glycoprotein-deficient transgenic null mutant mice. Pediatric Research. ISSN 0031-3998. 44(5), p. 763–766. Full text in Research Archive Show summary

  P-glycoprotein (P-gp), encoded by the mdr1a gene, is an ATP-dependent plasma membrane protein that is expressed in abundance on the blood-brain barrier (BBB). P-gp limits the CNS influx and retention of a variety of lipophilic compounds. We hypothesized that brain bilirubin content after an i.v. biliru-bin infusion would be increased in P-gp-deficient mdr1a null mutant transgenic mice (mdr1a(-/-)) compared with controls. Eighteen mdr1a(-/-) null mutant and 18 P-gp-sufficient wild type mice (+/+) were anesthetized and 50 mg/kg bilirubin infused through the tail vein. Brain bilirubin content (mean +/- SEM) 10 min after infusion was significantly higher in mdr1a(-/-) (18.1+/- 2.4 nmol/g) compared with (+/+) (10.4 +/- 1.0 nmol/g). Brain bilirubin content declined 60 min after infusion but remained higher in mdrla(-/-) (10.3 +/- 1.4nmol/g) compared with (+/+) mice (5.3 +/- 0.9 nmol/g). Brain bilirubin clearance did not differ between groups (t1/2. 55 min). We conclude that P-gp-deficient mdr1a(-/-) mice have signif-icantly higher brain bilirubin content compared with controls after an iv bilirubin load. These data suggest that 1) bilirubin is a substrate for P-gp and 2) the increased brain bilirubin content in mdr1a(-/-) mice is due to enhanced brain bilirubin influx. We speculate that BBB P-gp provides a protective effect against bilirubin neurotoxicity by reducing brain bilirubin influx.

• Hansen, Thor Willy Ruud & Allen, Jeffrey Wray (1997). Oxidation of bilirubin by brain mitochondrial membranes - dependence on cell type and postnatal age. Biochemical and Molecular Medicine. ISSN 1077-3150. 60, p. 155–160. Full text in Research Archive Show summary

  Background Bilirubin is oxidized by brain mitochondrial membranes at a rate which may contribute significantly to clearance of bilirubin from brain. Neurons appear to be more sensitive to bilirubin toxicity than glial cells. Clinical experience has suggested that sensitivity to bilirubin neurotoxicity may be greater in the neonate than later in life. We hypothesized that the ability to oxidize bilirubin would be lower in mitochondrial membranes from a pure neuronal compared to a mixed glial/neuronal source, and lower in immature than more mature brains. Methods and results Mitochondria of synaptosomal and non-synaptosomal origin were obtained from young rat brains by differential centrifugation in sucrose gradients. Synaptosomes were lysed by hypoosmotic treatment, and mitochondria were ruptured by sonication. The change in optical density of a bilirubin solution at 440 nm was measured over time following addition of the membrane suspension. The rate of bilirubin oxidation was significantly higher in non-synaptic than in synaptic mitochondrial membranes (99.1 ± 42.3 [mean ± SD] vs 69.9 ± 30.9 pmol/min/mg protein, t = 4.835, p = 0.0003). "Crude" mitochondrial membranes were obtained by differential centrifugation in sucrose from the forebrains of rats of 7, 14, and 21 days postnatal age as well as adults, and from rabbits of 1 and 7 days postnatal age as well as adults. In both species the rates of bilirubin oxidation increased significantly with postnatal age (rats: F = 55.3, p < 0.0001, rabbits: F = 101, p < 0.0001). Conclusion Mitochondrial membranes form a pure neuronal source oxidize bilirubin at a significantly lower rate than membranes from a mixed glial/neuronal source. This suggests that neurons may be less able to detoxify bilirubin locally, and thus might contribute to the apparent higher sensitivity to bilirubin toxicity in these cells vs glia. Similarly, the lower bilirubin-oxidizing ability of mitochondrial membranes from immature brains seems compatible with the clinical impression of increased vulnerability to bilirubin neurotoxicity in the newborn.

• Fjær, Rannveig Bremer; Abrahamsen, Tore G; Bruu, Anne-Lise & Hansen, Thor Willy Ruud (1997). Cytomegalovirusinfeksjon hos nyfødte. Erfaringer med diagnostikk og behandling. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 117, p. 1460–1464. Full text in Research Archive Show summary

  Approximately 0.5-1% of all newborns are born infected with cytomegalovirus (CMV), but of these only one out of ten show symptoms at birth, most often with hepatosplenomegaly, thrombocytopenia, and/or brain affection. Of the remaining nine, one may later develop sequelae with hearing loss and/or mental retardation. CMV infection may also be acquired perinatally or in the newborn period, and may cause pneumonia and/or sepsis, possibly also gastrointestinal symptoms like blood in the stool, and poor weight-gain. We have diagnosed CMV infection in ten neonates and infants, and describe these patients in terms of symptoms, diagnosis and treatment. Ganciclovir is being tested in clinical trials as a treatment for congenital CMV infection, and was given to two of our patients with apparently good results.

• Hansen, Thor Willy Ruud; Mathiesen, Siri B. W. & Walaas, Sven Ivar (1997). Modulation of the effect of bilirubin on protein phosphorylation by lysine-containing peptides. Pediatric Research. ISSN 0031-3998. 42, p. 615–617. Full text in Research Archive Show summary

  Protein phosphorylation is an important mechanism for regulation of cell processes. Bilirubin inhibits phosphorylation of several peptides/proteins by a number of different kinases, and this may contribute to the toxic effects of bilirubin on cells, particularly neurons. Bilirubin binds to lysine residues on both albumin and ligandin. The ATP-binding subdomain II on protein kinases contains an invariant lysine, which might hypothetically be involved in mediation or modulation of bilirubin-inhibition of protein phosphorylation. We have studied the ability of lysine-containing peptides to modulate the effects of bilirubin, using phosphorylation of a phospholemman peptide catalyzed by protein kinase A as a model system. Addition of bilirubin (50µM) decreased the activity of the catalytic subunit of PKA by 75%. A synthetic lysine- containing decapeptide which mimicked part of subdomain II on the protein kinase family was partially able to prevent the bilirubin effects. Similar effects were not observed with two other decapeptides in which lysine had been replaced by arginine or alanine. Polylysine 100 µM completely prevented the inhibitory effect of 50 µM bilirubin, while polyglutamate and polyarginine did not have this effect. Poly-D-lysine and poly-L-lysine appeared to be equivalent in their ability to prevent the bilirubin effect. These data support the notion that binding of bilirubin to lysine may play a role in the mediation and/or modulation of bilirubin neurotoxicity.

• Hansen, Thor Willy Ruud (1997). Acute management of extreme neonatal jaundice - the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation. Acta Paediatrica. ISSN 0803-5253. 86, p. 843–846. Full text in Research Archive Show summary

  Increasing numbers of neonates are being admitted to hospitals because of extreme jaundice. Phototherapy should be very effective in such infants, because the efficacy of phototherapy is proportional to the concentration of bilirubin in the skin. I report on four infants who were admitted for indirect serum bilirubin levels of >500 µmol/L ( 30 mg/dL). In one of them unrecognized Rhesus immunization was the main cause of hyperbilirubinemia, while in the three others increased enterohepatic circulation of bilirubin was thought to be an important contributory factor. In all four infants phototherapy (11-14 µW/cm2/nm) with whole body exposure plus ad lib feeding with milk were initiated immediately upon admission to the nursery. After two hours serum bilirubin values were reduced by 170-185 µmol/L (10-11 mg/dL) in the first three infants, while in the fourth infant a reduction of 195 µmol/L (11.3 mg/dL) was seen in the 5 h interval between the first and second bilirubin measurement. This experience suggests that in some infants with extreme jaundice, intensified phototherapy plus feeding with milk may be very effective in reducing serum bilirubin levels. Even if an exchange transfusion is performed, using this strategy in the waiting period may be beneficial, as both the rapid reduction in serum bilirubin levels as well as the conversion of significant amounts of bilirubin into water soluble isomers may reduce the risk of neurotoxicity.

• Medbø, Sverre; Finne, Per Haavardsholm & Hansen, Thor Willy Ruud (1997). Respiratory syncytial virus pneumonia ventilated with high frequency oscillatory ventilation. Acta Paediatrica. ISSN 0803-5253. 86, p. 766–768. Full text in Research Archive Show summary

  Four infants below 6 months of age with proven respiratory syncytial virus infection in need of assisted mechanical ventilation were successfully treated by high-frequency oscillatory ventilation. One of the four infants fulfilled the criteria for extracorporeal membrane oxygenation before the start of oscillation, and one on the second day of high-frequency oscillatory ventilation. However, extracorporeal membrane oxygenation was not needed in any of the infants. All survived, and three appear to be without any pulmonary sequelae.

• Hansen, Thor Willy Ruud; Tommarello, Steve & Allen, Jeffrey Wray (1997). Oxidation of bilirubin by rat brain mitochondrial membranes - genetic variability. Biochemical and Molecular Medicine. ISSN 1077-3150. 62, p. 128–131. Full text in Research Archive Show summary

  Background Bilirubin is oxidized by brain mitochondrial membranes at a rate which may contribute significantly to clearance of bilirubin from brain. Different strains of congenitally jaundiced rats (Gunn rats) vary widely as far as the mortality rate of the homozygous (jaundiced) pups. Because the ability to oxidize bilirubin in brain may protect against toxicity, we hypothesized that the ability to oxidize bilirubin would be lower in Gunn rat strains with a high mortality rate in the homozygous pups. Methods and results Mitochondria were obtained from young rat brains by differential centrifugation in sucrose gradients. Synaptosomes were lysed by hypoosmotic treatment, and mitochondria were ruptured by sonication. The change in optical density of a bilirubin solution at 440 nm was measured over time following addition of the membrane suspension. The rate of bilirubin oxidation was significantly lower in rats of the RHA/N-j strain both at 7-8 days of age and in adults, compared to rats of the ACI/N-j as well as the Sprague-Dawley strains at the same age points. Conclusion Differences in mortality rates between the RHA/N-j and the ACI/N-j strains of Gunn rats could not be explained on the basis of differences in the ability of brain mitochondrial membranes to oxidize bilirubin, as these activities were lower in the RHA/N-j rats who also have lower mortality rates, but higher in the ACI/N-j rats who have remarkably high mortality rates. This study also confirmed previous findings relative to age maturation of the enzyme activity. Key words: Kernicterus; Bilirubin encephalopathy; Bilirubin oxidation; Mitochondrial membranes; Genetics

• Hansen, Thor Willy Ruud; Henrichsen, B.; Rasmussen, Randi Korsvig; Carling, A.; Andreassen, Anne B. & Skjeldal, Ola (1996). Neuropsychological and linguistic follow-up studies of children with galactosemia from an unscreened population. Pediatric Research. ISSN 0031-3998. 39, p. 858–858. Full text in Research Archive
• Rasmussen, Randi Korsvig; Andreassen, Anne B.; Strømholm, Per & Hansen, Thor Willy Ruud (1996). Learning disabilities and language pathology in patients with galactosemia. Logopedics, Phoniatrics, Vocology. ISSN 1401-5439. 21, p. 157–162. Full text in Research Archive
• Hansen, Thor Willy Ruud (1996). Therapeutic practices in neonatal jaundice: An international survey. Clinical Pediatrics. ISSN 0009-9228. 35, p. 309–316. Full text in Research Archive
• Hansen, Thor Willy Ruud (1996). Bilirubin entry into and clearance from rat brain during hypercarbia and hyperosmolality. Pediatric Research. ISSN 0031-3998. 39, p. 72–76. Full text in Research Archive
• Hansen, Thor Willy Ruud; Mathiesen, Siri B. W. & Walaas, Sven Ivar (1996). Bilirubin Has Widespread Inhibitory Effects on Protein Phosphorylation. Pediatric Research. ISSN 0031-3998. 39(6), p. 1072–1077. Full text in Research Archive
• Hansen, Thor Willy Ruud; Henrichsen, B.; Rasmussen, Randi Korsvig; Carling, A.; Andreassen, Anne B. & Skjeldal, Ola (1996). Neuropsychological and linguistic follow-up studies of children with galactosemia from an unscreened population. Acta Paediatrica. ISSN 0803-5253. 85, p. 1197–1201. Full text in Research Archive

View all works in NVA

• Hansen, Thor Willy Ruud (2024). Neonatal Jaundice. Medscape.com. Full text in Research Archive Show summary

  Jaundice is the most common condition that requires medical attention and hospital readmission in newborns. The yellow coloration of the skin and sclera in newborns with jaundice is the result of accumulation of unconjugated bilirubin. In most infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin IXα (Z,Z) is neurotoxic and can cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus). [1] For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation. Neonatal jaundice may have first been described in a Chinese textbook 1000 years ago. Medical theses, essays, and textbooks from the 18th and 19th centuries contain discussions about the causes and treatment of neonatal jaundice. Several of these texts also describe a lethal course in infants who probably had Rh isoimmunization. In 1875, Orth first described yellow staining of the brain, in a pattern later referred to by Schmorl as kernicterus.

• Hansen, Thor Willy Ruud; Akkøk, Cigdem Ahaein & Watchko, Jon F. (2022). International guidelines regarding the role of intravenous immunoglobulin in the management of RhD- and ABO-mediated haemolytic disease of the newborn—reconsidering the recommendations. British Journal of Haematology. ISSN 0007-1048. 199(3), p. 452–453. doi: 10.1111/bjh.18421. Full text in Research Archive
• Paris, John J. & Hansen, Thor Willy Ruud (2022). Illegitimacy Before and Now: The Times They Are A'Changin'. Neonatology. ISSN 1661-7800. doi: 10.1159/000525307. Full text in Research Archive
• Hansen, Thor Willy Ruud & Førde, Reidun (2021). First judgement on clinical ethics committees? Archives of Disease in Childhood. ISSN 0003-9888. 106(9), p. 929–931. doi: 10.1136/archdischild-2021-321735. Full text in Research Archive
• Hansen, Thor Willy Ruud & Wilson, Dominic JC (2021). Continuous deep sedation in the newborn – knowledge and need. Neonatology. ISSN 1661-7800. doi: 10.1159/000518659. Full text in Research Archive
• Hansen, Thor Willy Ruud; Maisels, Maisels Jeffrey; Ebbesen, Finn; Vreman, Hendrik J.; Stevenson, David K. & Wong, Ronald J. [Show all 7 contributors for this article] (2020). Sixty years of phototherapy for neonatal jaundice: from serendipitous observation to standardized treatment and rescue for millions. Journal of Perinatology. ISSN 0743-8346. 40(10), p. 1582–1583. doi: 10.1038/s41372-020-0712-3. Full text in Research Archive
• Hansen, Thor Willy Ruud (2016). Re: På tide å innføre spesialisteksamen. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(16), p. 1328–1328. doi: 10.4045/tidsskr.16.0694. Full text in Research Archive
• Hansen, Thor Willy Ruud (2016). Pathophysiology of kernicterus. Fetal and neonatal physiology, 5th ed. Elsevier. ISSN 9780323352147. p. 1657–1667. Full text in Research Archive
• Solheim, Bjarte G.B.; Grønn, Morten & Hansen, Thor Willy Ruud (2016). Hemolytic disease of the fetus and newborn, Rossi’s Principles of Transfusion Medicine, 5th ed. John Wiley & Sons. ISSN 9781119012993. p. 528–534. Full text in Research Archive
• Glosli, Heidi & Hansen, Thor Willy Ruud (2016). Palliasjon av barn – hva er spesielt? In Kaasa, Stein & Loge, Jon Håvard (Ed.), Palliasjon. Nordisk lærebok. 3. utgave. Gyldendal Akademisk. ISSN 9788205488403. p. 748–761. Full text in Research Archive
• Glosli, Heidi & Hansen, Thor Willy Ruud (2016). Når og hvordan avslutte livsforlengende behandling av barn. In Kaasa, Stein & Loge, Jon Håvard (Ed.), Palliasjon. Nordisk lærebok. 3. utgave. Gyldendal Akademisk. ISSN 9788205488403. p. 784–794. Full text in Research Archive
• Glosli, Heidi; Hansen, Thor Willy Ruud & Einen, Margrete (2016). Smerte og symptomlindring hos barn. In Kaasa, Stein & Loge, Jon Håvard (Ed.), Palliasjon. Nordisk lærebok. 3. utgave. Gyldendal Akademisk. ISSN 9788205488403. p. 772–783. Full text in Research Archive
• Hansen, Thor Willy Ruud & Glosli, Heidi (2016). Palliativ behandling av barn på intensivavdeling. In Kaasa, Stein & Loge, Jon Håvard (Ed.), Palliasjon. Nordisk lærebok. 3. utgave. Gyldendal Akademisk. ISSN 9788205488403. p. 762–771. Full text in Research Archive
• Fredheim, Olav Magnus; Hansen, Thor Willy Ruud; Haugen, Guttorm & Magelssen, Morten (2016). O. Fredheim og medarbeidere svarer :. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(11), p. 980–981. doi: 10.4045/tidsskr.16.0488. Full text in Research Archive
• Hansen, Thor Willy Ruud & Førde, Reidun (2016). Premature og behandlingsgrenser. 136, p. 45–47. Full text in Research Archive
• Fredheim, Olav Magnus; Hansen, Thor Willy Ruud; Haugen, Guttorm & Magelssen, Morten (2016). Re: Keisersnitt ved trisomi 13 og 18 - en verdibasert vurdering :. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(14/15), p. 1187–1187. doi: 10.4045/tidsskr.16.0660. Full text in Research Archive
• Hansen, Thor Willy Ruud (2016). Kernicterus in neonatal jaundice-finding the needle in the haystack. Pediatric Critical Care Medicine. ISSN 1529-7535. 17(3), p. 266–267. doi: 10.1097/PCC.0000000000000652. Full text in Research Archive
• Fredheim, Olav Magnus; Hansen, Thor Willy Ruud; Haugen, Guttorm & Magelssen, Morten (2016). O. Fredheim og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(10), p. 893–893. doi: 10.4045/tidsskr.16.0440. Full text in Research Archive
• Hansen, Thor Willy Ruud (2015). Kliniske etikk-komitéer og behandling av barn. Nordisk tidsskrift i barnepalliasjon. 2, p. 13–17. Full text in Research Archive
• Solberg, Marianne Trygg; Hansen, Thor Willy Ruud & Bjørk, Ida Torunn (2014). Challenges in coordination of ventilator treatment in premature and sick newborns in a Norwegian Neonatal Intensive Care Unit (NICU). Full text in Research Archive
• Rønnestad, Arild Erlend & Hansen, Thor Willy Ruud (2014). Nevrologiske tilstander hos nyfødte, Nevrologi og nevrokirurgi fra barn til voksen, 6.utgave. Forlaget Vett & Viten AS. ISSN 9788241207099. p. 155–172. Full text in Research Archive
• Hansen, Thor Willy Ruud & Haaland, Kirsti (2014). Nevrologisk undersøkelse av nyfødte, Nevrologi og nevrokirurgi fra barn til voksen, 6.utgave. Forlaget Vett & Viten AS. ISSN 9788241207099. p. 31–41. Full text in Research Archive
• Hansen, Thor Willy Ruud (2013). Reflections from across the Atlantic on SUPPORT, disclosure, consent, and the need for neonatal research. American Journal of Bioethics. ISSN 1526-5161. 13(12), p. 39–41. doi: 10.1080/15265161.2013.849306. Full text in Research Archive
• Hansen, Thor Willy Ruud (2013). Forstår de hva de gjør? 3, p. 4–7. Full text in Research Archive
• Mreihil, Khalaf; Madsen, Poul; Saltythe-Bent, Jurate; Nakstad, Britt; Ebbesen, Finn & Hansen, Thor Willy Ruud (2013). Formation of bilirubin photoisomers during intensive phototherapy is not influenced by light source or irradiance. Full text in Research Archive
• Hansen, Thor Willy Ruud (2013). An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation, Year Book of Neonatal and Perinatal Medicine. Elsevier Mosby. ISSN 9781455772780. p. 222–224. Full text in Research Archive
• Hansen, Thor Willy Ruud (2012). Let there be light - but should there be less? Journal of Perinatology. ISSN 0743-8346. 32(9), p. 649–651. doi: 10.1038/jp.2012.80. Full text in Research Archive
• Solberg, Marianne Trygg; Bjørk, Ida Torunn & Hansen, Thor Willy Ruud (2012). Adherence to ventilation and oxygenation targets in mechanically ventilated premature and sick newborns – a retrospective study. Full text in Research Archive
• Hansen, Thor Willy (2010). Nevrologisk undersøkelse av nyfødte. In Gjerstad, Leif; Helseth, Eirik & Rootwelt, Terje (Ed.), Nevrologi og nevrokirurgi. Fra barn til voksen. 5.utgave. Forlaget Vett & Viten AS. ISSN 9788241206863. p. 31–42. Full text in Research Archive
• Rønnestad, Arild Erlend; Rootwelt, Terje & Hansen, Thor Willy (2010). Nevrologiske tilstander hos nyfødte. In Gjerstad, Leif; Helseth, Eirik & Rootwelt, Terje (Ed.), Nevrologi og nevrokirurgi. Fra barn til voksen. 5.utgave. Forlaget Vett & Viten AS. ISSN 9788241206863. p. 159–176. Full text in Research Archive
• Hansen, Thor Willy (2010). Treatment of Jaundice in the Newborn Infant - "Many Roads to Rome". Indian Pediatrics. ISSN 0019-6061. 47(5), p. 396–397. Full text in Research Archive
• Hansen, Thor Willy (2010). Twists and turns in phototherapy for neonatal jaundice. Acta Paediatrica. ISSN 0803-5253. 99(8), p. 1117–1118. doi: 10.1111/j.1651-2227.2010.01898.x. Full text in Research Archive
• Hansen, Thor Willy (2009). Management of jaundice in newborn nurseries - measuring, predicting, and avoiding the sequelae. Acta Paediatrica. ISSN 0803-5253. 98, p. 1866–1868. Full text in Research Archive
• Hansen, Thor Willy (2008). Extreme neonatal jaundice: How frequent is it ? Acta Paediatrica. ISSN 0803-5253. 97, p. 1002–1003. doi: 10.1111/j.1651-2227.2008.00897.x. Full text in Research Archive
• Hansen, Thor Willy (2008). Fucidic acid and heparin lock solution for the prevention of catheter-related bloodstream infections in neonates cannot be recommended as a routine yet reply. Pediatric Critical Care Medicine. ISSN 1529-7535. 9(6), p. 668–669. doi: 10.1097/PCC.0b013e31818c8765. Full text in Research Archive
• Hansen, Thor Willy (2007). Avoiding catheter-related bloodstream infections-Killing the bugs or improving the procedures? Pediatric Critical Care Medicine. ISSN 1529-7535. 8(6), p. 589–591. doi: 10.1097/01.PCC.0000288675.22917.9A. Full text in Research Archive
• Kalikstad, Betty; Wesenberg, Finn; Brunvand, Leif; Stiris, Tom & Hansen, Thor Willy (2007). Sikrere medisiner for barn. Aftenposten (morgenutg. : trykt utg.). ISSN 0804-3116. Full text in Research Archive Show summary

  Det er på høy tid at Norge er med på å ta et ansvar for å utvikle sikrere og bedre legemiddelbehandling av barn. A-Magasinet 23. mars gir informasjon om åpningen av Nordens første forskningspost for medikamentell behandling av barn ved Haukeland Universitetssykehus.

• Hansen, Thor Willy (2007). Patency of the ductus arteriosus in the newborn - Now you want it, now you don't. Pediatric Critical Care Medicine. ISSN 1529-7535. 8(3), p. 302–303. doi: 10.1097/01.PCC.0000262886.67502.2B. Full text in Research Archive
• Hansen, Thor Willy (2006). Prophylaxis of intraventricular hemorrhage in premature infants: New potential tools, new potential challenges. Pediatric Critical Care Medicine. ISSN 1529-7535. 7(1), p. 90–92. Full text in Research Archive Show summary

  In recent decades neonatology has made tremendous strides forward, resulting in increased survival for many groups of sick neonates. Infants born prematurely benefited perhaps more than other groups, resulting in very significant increases in survival of the smallest and most vulnerable. Thus, in a 2-yr (1999–2000) national Norwegian cohort of extremely low-birth-weight infants (birth weight of 500–999 g or gestational age of 22–27 completed wks) the overall survival rate was 59%, and among those admitted to a neonatal intensive care unit and treated, the rate was 81% (1). However, although good treatment can now be offered for the majority of problems afflicting extremely premature infants, effective therapy for intraventricular hemorrhage (IVH) is still needed

• Bratlid, Dag & Hansen, Thor Willy Ruud (2006). Nasjonale retningslinjer for behandling av hyperbilirubinemi? Full text in Research Archive
• Kalikstad, Betty & Hansen, Thor Willy (2006). Medisin til barn en utfordring. Full text in Research Archive Show summary

  Før og nå. Medikamentell behandling av barn er en utfordring. Stortingsmelding nr. 18 "Rett kurs mot riktigere legemiddelbruk" kom våren 2005. I meldingen ble Helse- og omsorgsdepartementet bedt om å ta et initiativ til dannelse av et kompetansenettverk for medikamentell behandling av barn.

• Saugstad, Ola Didrik; Hansen, Thor Willy; Nakstad, Britt; Tølløfsrud, Per Arne; Reinholt, F & Hamvas, A [Show all 12 contributors for this article] (2006). Novel mutations in the gene encoding ABCA3 resulting in fatal neonatal lung disease. Biology of the Neonate. ISSN 0006-3126. 89, p. 349–349. Full text in Research Archive
• Hansen, Thor Willy (2006). Procedural skills in neonatology - a lab-based approach to learning. Full text in Research Archive
• Hansen, Thor Willy (2005). Teaching and maintaining procedural skills in neonatology through a lab-based course. Full text in Research Archive
• Hankø, Erik; Hansen, Thor Willy; Almaas, R.; Lindstad, Julie K. & Rootwelt, Terje (2005). Bilirubin induces apoptosis and necrosis in human NT2-N neurons. Pediatric Research. ISSN 0031-3998. 57, p. 179–184. Full text in Research Archive Show summary

  Studies on primary cultures of newborn rodent neurons have suggested that neuronal death induced by unconjugated bilirubin (UCB) is mainly apoptotic in nature. We exposed a human teratocarcinoma-derived cell line, NT2-N neurons, to different concentrations of UCB and albumin at a 1.5 molar ratio and used multiple, independent measures of cell damage to evaluate neuronal injury after 6, 24, and 48 h. Low doses of UCB (0.66, 2, and 5 µM) induced a moderate loss of 3�4[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide (MTT) cleavage accompanied by delayed morphologic changes consistent with apoptosis (2 and 5 µM). Moderate concentrations of UCB (10 and 25 µM) resulted in early (6 h) necrosis in a subset of neurons, while remaining neurons underwent progressive impairment of MTT cleavage and increasing lactate dehydrogenase (LDH) release accompanied by predominantly delayed apoptosis. High concentrations of UCB (100 µM) induced severe impairment of MTT cleavage, extensive LDH release, and morphologic changes consistent with necrosis within 6 h. Used as a positive control for apoptosis, 2 µM STS induced progressive impairment of MTT cleavage and morphologic changes consistent with apoptosis over the entire observation period. DNA electrophoresis at 48 h was compatible with apoptosis both after treatment with STS and UCB concentrations 25, but not at 100 µM. Cleavage of poly (ADP-ribose) polymerase (PARP) was only seen in neurons treated with low UCB concentrations and STS. We conclude that UCB induces early necrosis at high and moderate concentrations and predominantly delayed apoptosis at low and moderate concentrations in cultured human NT2-N neurons

• Hansen, Thor Willy (2005). The jaundiced infant - perspectives on drug treatment. Full text in Research Archive
• Hansen, Thor Willy (2005). Underkoding er vanligere enn overkoding. 125(16), p. 2244–2244. Full text in Research Archive Show summary

  DRG-systemet kan og bør forbedres ved at alle sykehusopphold kodes for diagnoser og prosedyrer mest mulig fullstendig. Dette vil gi et mer korrekt grunnlag for beregning av kostnadsvekter, forutsatt at taket på rapportering av diagnoser og prosedyrer fjernes.

• Hansen, Thor Willy (2004). Kronisk lungesykdom. Full text in Research Archive
• Hansen, Thor Willy (2004). Pasientklassifikasjon. Full text in Research Archive
• Hansen, Thor Willy (2004). Resuscitation of newborns. Full text in Research Archive
• Hansen, Thor Willy (2004). Forbedring av medisinsk koding. Full text in Research Archive
• Hansen, Thor Willy (2004). Pharmacotherapy in the jaundiced neonate. Full text in Research Archive
• Hansen, Thor Willy (2004). High frequency ventilation. Full text in Research Archive
• Hansen, Thor Willy (2004). Management of persistent pulmonary hypertension of the newborn: Nitric oxide and other fun tools in the NICU. Full text in Research Archive
• Hansen, Thor Willy (2004). Inhaled nitric oxide. Full text in Research Archive
• Finne, Per Haavardsholm; Dalen, Ingvild; Ikonomou, N; Ulimoen, G & Hansen, Thor Willy (2004). Undersøkelse av hofteledd hos nyfødte ved Bærum Sykehus og Martina Hansens Hospital 1992-2001. Full text in Research Archive Show summary

  Abstract nr. 283

• Hansen, Thor Willy (2004). Resuscitering av nyfødte. Full text in Research Archive
• Hansen, Thor Willy (2004). American Academy of Pediatrics: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Bør vi ha disse retningslinjene i Norge? Full text in Research Archive
• Hansen, Thor Willy (2004). Management of extremely low birthweight infants in Norway � Organization, practices, results, and challenges. Full text in Research Archive
• Hansen, Thor Willy (2004). Management of neonatal jaundice - practices and guidelines. Full text in Research Archive
• Hansen, Thor Willy (2004). Kernicterus and bilirubin toxicity. - The basic science story. Full text in Research Archive
• Hansen, Thor Willy (2004). Update on neonatal hyperbilirubinemia. Full text in Research Archive
• Hansen, Thor Willy (2004). Inhaled Nitric Oxide and the Societal Perspective. Pediatrics. ISSN 0031-4005. 113(6), p. 1849–1851. Full text in Research Archive Show summary

  Three articles in the December issue of Pediatrics provide fascinating and at the same time disturbing reading. Angus et al,1 from Pittsburgh, Pennsylvania, studied the cost-effectiveness of inhaled nitric oxide (iNO) in the treatment of neonatal respiratory failure, and Field et al2 provide a commentary on their article. The third article that caught my attention was "Annual Summary of Vital Statistics�2002,"3 which shows that, in spite of its huge investment in health care, the United States continues to lag behind most of the industrialized world and even some developing countries as far as infant mortality rates. The study by the Pittsburgh group1 and the Field et al commentary2 are fascinating, because they show that, even in science, it is possible to look at facts from such different vantage points that the realities one perceives are literally "worlds apart." These 2 articles are deeply disturbing also because they document that accepting support from industry sources, as appropriately acknowledged both by Field et al and Angus et al, can so narrow your field of vision that the forest disappears and all you see is a lone tree. The Pittsburgh group concludes that "from a US societal perspective, iNO has a favorable cost-effectiveness profile...,"1 whereas Field et al conclude that the Pittsburgh study "goes some way to justifying the use of NO at the present price."2 To wit, the cost of the iNO they are talking about is INOmax from INO Therapeutics. I suspect champagne corks were flying at INO Therapeutics' headquarters when these 2 articles appeared. The rest of us, as I shall discuss, may have less reason to be pleased.

• Hansen, Thor Willy (2004). Tiltredelsesforelesning ved Barneklinikken og Pediatrisk Forsknings-institutt, Neonatal jaundice and bilirubin toxicity � A clinician�s quest for understanding of basic science mechanisms. Full text in Research Archive
• Hansen, Thor Willy Ruud (2003). Rhubarb - an old treatment for neonatal jaundice seen through modern eyes. Full text in Research Archive
• Hansen, Thor Willy Ruud (2003). The jaundiced infant - perspectives on drug treatment. Full text in Research Archive
• Hansen, Thor Willy Ruud (2003). Ibuprofen vs indomethacin for luking av PDA. Heite Emner i Nyfødtmedisin. Full text in Research Archive
• Hansen, Thor Willy Ruud (2003). NO - Thank You. Full text in Research Archive
• Hansen, Thor Willy Ruud (2003). Innlegg Stabsmøtet, RH. Full text in Research Archive
• Kalikstad, Betty; Skjerdal, Åse S. & Hansen, Thor Willy Ruud (2003). Drug compatibility in the NICU. Full text in Research Archive
• Hansen, Thor Willy Ruud (2003). Neonatal jaundice � Anno Domini 2003. Full text in Research Archive
• Kalikstad, Betty; Skjerdal, Åse S. & Hansen, Thor Willy Ruud (2003). Drug compatibility in the NICU. Full text in Research Archive
• Hansen, Thor Willy Ruud (2003). Do diagnoses and procedure codes on discharge summaries adequately reflect patient coplexity in neonatal medicine? [Abstract]. Pediatric Research. ISSN 0031-3998. 53, p. 228–228. Full text in Research Archive Show summary

  [Abstract]

• Hansen, Thor Willy Ruud (2003). Changes in the utilization of diagnostic categories in neonatology following introduction of national activity-based financing. Pediatric Research. ISSN 0031-3998. 53, p. 162–162. Full text in Research Archive Show summary

  [Abstract]

• Hansen, Thor Willy Ruud (2003). Curing familial, lethal neonatal with �the language of friendship an rays of hope� at the turn of the 18th century. [Abstract]. Pediatric Research. ISSN 0031-3998. 53, p. 305–305. Full text in Research Archive Show summary

  [Abstract]

• Hankø, Erik; Hansen, Thor Willy Ruud; Lindstad, Julie K.; Almaas, Runar & Rootwelt, Terje (2003). Bilirubin induserer apoptose og nekrose i humane NT2-N nevroner. Full text in Research Archive
• Hansen, Thor Willy Ruud & Paulsen, Berit Smestad (2003). Treatment of neonatal jaundice in 18th and 19th century Europe [Abstract]. Pediatric Research. ISSN 0031-3998. 53, p. 162a–162a. Full text in Research Archive Show summary

  [Abstract]

• Hankø, Erik; Hansen, Thor Willy Ruud; Lindstad, Julie K.; Holt, Anne & Rootwelt, Terje (2003). Unconjugated bilirubin induces rapid onset necrosis at high consentrations and slow onset apoptosis av low concentrations in cultured human NT2-N neurons. Full text in Research Archive Show summary

  From signalling pathways to therapeutic tools

• Hansen, Thor Willy Ruud (2003). Bruk av diagnose- og prosedyrekoder i nyfødtmedisinen - effekter av innsatsstyrt finansiering (ISF). Master of Health Administration degree. Full text in Research Archive Show summary

  Studien er utført på et pasient- og datamateriale hentet fra Nyfødtseksjonen, Barneklinikken, Rikshospitalet, og omfatter årsklassene 1994, 1996, 1998 og 2000. Data har vært hentet fra flere kilder: Neonatalprogrammet er et internt registrerings-program som har vært brukt ved Nyfødtseksjonen i hele den aktuelle perioden. Data er også hentet fra PIMS, Rikshospitalets pasientadministrative system. Endelig ble det gjort et randomisert utvalg på 10% av alle opphold, i alt 296. Etter at forfatteren hadde satt sine diagnoser og prosedyrekoder, ble blindingen fjernet og de opprinnelig satte diagnoser og prosedyrekoder ble registrert. Det gjennomsnittlige antall registrerte diagnoser og prosedyrekoder per pasient i Neonatalprogrammet økte signifikant i perioden 1994-2000. En tilsvarende endring kunne ikke observeres i de utvalgte 10% av journalene fra hver årsklasse, hverken etter de diagnoser og prosedyrekoder som opprinnelig ble satt, eller de som ble satt av forfatteren. Data både fra Neonatalprogrammet og fra epikrisene viste imidlertid en signifikant underrapportering både av diagnoser og prosedyrer i forhold til de registreringer som ble gjort av forfatteren, selv om registreringene i Neonatalprogrammet nærmet seg “virkeligheten” mot slutten av perioden. Disse funnene viser altså at både data fra epikrisene og fra Neonatalprogrammet er ufullstendige og gir et underdimensjonert bilde av kompleksiteten hos den gjennomsnittlige nyfødtmedisinske pasienten. I perioden 1994-2000 skjedde det en dreining i bruken av visse diagnose-kategorier i Neonatalprogrammet. Denne dreiningen reflekterer sannsynligvis, i hvert fall i noen grad, tilpasning til de refusjonsordningene som er knyttet til DRG. Data fra PIMS pekte i samme retning, idet bruken av visse diagnoser som hoveddiagnose varierte på en måte som ikke stod i samsvar med det totale antall pasienter som fikk slike diagnoser. Registreringene i PIMS som er de som knyttes til DRG-vekting og derfor DRG-refusjon, medfører i mange tilfeller en betydelig underestimering av komplekse sykehusopphold. Revisjonen av DRG-vektene for HDG15 i 1999 var særlig uheldig fordi denne for viktige pasientgruppers del gjorde økt dybde-kompleksitet “straffbart”. Det er grunn til å tro at særlig universitetsklinikkene med et større innslag av normalstore nyfødte blandt sine intensivpasienter kom særlig dårlig ut av 1999-revisjonen. Denne studien har vist at det er betydelige problemer knyttet til innføringen og bruken av DRG/ISF i nyfødtmedisinen. Noen utilsiktede bivirkninger, slik som dreining i bruk av diagnosekategorier, kan ha uheldige konsekvenser for den epidemiologiske oversikten i fagfeltet. Det er behov for et stort arbeid for å bedre tilpasningen av HDG15 til den kliniske virkeligheten.

• Hansen, Thor Willy Ruud (2002). Epidemiology of neonatal jaundice in Norway - A project proposal. Full text in Research Archive
• Hansen, Thor Willy Ruud (2002). Bronchopulmonal dysplasi - synspunkter på væske og ernæring. Full text in Research Archive
• Aagenæs, Ingegerd; Brun, Henrik; Husby, Henrik; Smevik, Bjarne; Rootwelt, Terje & Hansen, Thor Willy Ruud (2002). Neonatal cranial ultrasonography in twins with significant birth weight difference. Full text in Research Archive
• Kalikstad, Betty; Hansen, Thor Willy Ruud & Skjerdal, Åse S. (2002). Drug compatibility in the NICU. Full text in Research Archive
• Biniwale, Manoj; Daood, Monica J.; Hansen, Thor Willy Ruud & Watchko, Jon F. (2002). Microarray analysis of the differential gene expression in cerebellar tissue of the hyperbilirubinemic Gunn rat. Full text in Research Archive
• Hansen, Thor Willy Ruud (2002). Nils Rosén von Rosenstein and neonatal jaundice in 1764. Full text in Research Archive
• Hansen, Thor Willy Ruud (2002). A Quisling on neonatal jaundice. Full text in Research Archive
• Wingaard, Lisbeth; Kaldestad, Runa Helen & Hansen, Thor Willy Ruud (2002). Low rate of referral using a two-stage screening protocol for congenital hearing loss in healthy term and near-term infants. Full text in Research Archive
• Brun, Henrik; Aagenæs, Ingegerd; Husby, Henrik; Rootwelt, Terje & Hansen, Thor Willy Ruud (2002). Discordant twins - cerebral ultrasound findings in the neonatal period. Full text in Research Archive
• Hansen, Thor Willy Ruud (2002). Basofil punktering av erytrocytter og blyforgiftning. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 122(18), p. 1817–1818. Full text in Research Archive
• Hankø, Erik; Hansen, Thor Willy Ruud; Lindstad, Julie K. & Rootwelt, Terje (2002). MK-801, but not caspase inhibitors, protects against bilirubin induced cell death in cultured NT2-N neurons. Full text in Research Archive
• Kalikstad, Betty; Skjerdal, Åse S. & Hansen, Thor Willy (2001). Drug Compatibility in the NICU. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Phototherapy and mesenteric blood flow -- too much, not enough, or the wrong kind? Pediatrics. ISSN 0031-4005. 107, p. 610–611. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Neonatal jaundice in 19th century German pediatric textbooks. Full text in Research Archive
• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (2001). Deaths in a NICU - A 10 year perspective. II. End-of-life decisions and the involvement of parents. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Bilirubin brain toxicity. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Tidlig hjemreise - utfordringer og muligheter. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Hyperbilirubinemi. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Behandling og oppfølgning av nyfødte med gulsott. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Neonatal jaundice in 1753. Full text in Research Archive
• Hankø, Erik; Hansen, Thor Willy Ruud; Østvold, Anne Carine & Walaas, Sven Ivar (2001). Magnitude of bilirubin-mediated inhibition of protein phosphorylation is dependent on substrate characteristics. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Hørsels-screening av nyfødte. Hva skjer ellers i verden? Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Nyfødtmedisin - arbeid i livets grenseland. Full text in Research Archive
• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (2001). Deaths in a NICU - A 10-year perspective. I. Population characteristics. Full text in Research Archive
• Dukovic, Betty; Skjerdal, Åse S. & Hansen, Thor Willy Ruud (2001). Drug compatibility in the NICU. Full text in Research Archive
• Hansen, Thor Willy Ruud (2001). Caesarean section in preterm deliveries. Full text in Research Archive
• Dukovic, Betty; Skjerdal, Åse S. & Hansen, Thor Willy Ruud (2000). Forlikelighet/blandbarhet av medikamenter i nyfødtintensivavdeling. Full text in Research Archive
• Hankø, Erik; Tommarello, Steve; Hansen, Thor Willy Ruud & Watchko, Jon F. (2000). Pharmacological inhibition of blood-brain barrier P-glycoprotein increases brain bilirubin and alters regional distribution of bilirubin in rat brain. Full text in Research Archive
• Daood, Monica J.; Tsai, Cathy; Hansen, Thor Willy Ruud & Watchko, Jon F. (2000). Regional Expression of P-Glycoprotein in Adult Mouse Brain. Full text in Research Archive Show summary

  OBJECTIVE: To test the hypothesis that P-glycoprotein (P,gp), an ATP-dependent efflux pump, is expressed in a regionally specific fashion within the central nervous system (CNS) of adult mice. BACKGROUND: P-glycoprotein, an ATP-dependent integral plasma membrane efflux pump is expressed in brain capillary endothelial cells and astrocytes of the blood-brain barrier (BBB) where it limits the CNS uptake of various lipophilic compounds including numerous xenobiotics and bilirubin. The strategic localization of Pgp in the BBB points to a protective role for Pgp against the CNS uptake of potentially neurotoxic agents. The regional expression of Pgp within the CNS, however, is largely unknown. In the current study we tested the hypothesis that Pgp is expressed in a regionally specific fashion within the CNS of adult mice. DESIGN/METHODS: Western immunoblots of twelve anatomically distinct areas (100 ug protein per region) of Balb/c adult male mouse brain [n=3]( Brain Blot, Chemicon) were performed using a monoclonal Pgp specific antibody (C219). Brain regions studied included: frontal cortex, posterior cortex, cerebellum, hippocampus, olfactory bulb, striatum, thalamus (including subthalamic nuclei and globus pallidus), midbrain, entorhinal cortex, pons, medulla. and spinal cord. Pgp expression by region is reported as a percent of that expressed in the frontal cortex (mean +/- SEM). RESULTS: Abundant Pgp expression C219 was observed in tie frontal cortex (100%). Comparable levels of Pgp were seen in the cerebellum (96±5% ) and posterior cortex (85±6% ). Significantly lower Pgp levels were observed in the striatum (53±7%), olfactory bulb (64±16%), midbrain (62±12%), pons (54±6%), medulla (62±23%), and hippocampus (53±24%)[P<0.05]. The lowest levels of Pgp expression were noted in the thalamus (38±17%) and spinal cord (15±8%.)[P<0.01]. CONCLUSIONS: We conclude that P;vp is expressed in a regionally specific pattern within the CNS. The cortex and cerebellum evince more abundant Pgp expression than other brain regions with only limited Pgp expression noted in the thalamus (including subthalamic nucleus and globus pallidus) and spinal cord. We speculate that differences in regional Pgp CNS expression may impact the uptake and distribution of Pgp substrates within the brain. Limited Pop expression in the thalamus and spinal cord may predispose these regions to injury by neurotoxins including bilirubin. Supported by NIH NS38993 (JFW) and HD358-17 (JFW).

• Hansen, Thor Willy Ruud (2000). Neonatal jaundice and scientific fraud in the early 19th century. Full text in Research Archive Show summary

  BACKGROUND: In 1785 Jean Baptiste Timothee Baumes was awarded a prize by the University of Paris for an essay on neonatal jaundice, in which he presented 10 case reports and discussed the causes and treatment of that condition. A second, revised edition was published in 1806. In the preface Baumea accused dr.Francois Bidault of outright plagiarism of his work. Bidault defended his doctoral thesis in 1804 on the topic of neonatal jaundice. DESIGN/METHODS: The two publications were: compared case by case. RESULTS: A comparison of Baumes' essay and Bidault's thesis supports Baumes' claim of plagiarism. The first four case presentations were clearly of the same patients in both publications. The first case. Baumes own daughter Justine, was renamed Caroline in Bidault's essay, but otherwise the latter is an almost verbatim copy of the former. In the following three cases, Bidault had abbreviated the names of the patients and saved himself further effort by skipping parts of Baumes' speculations. Cases 5 and 6 are missing in the 2nd edition of Bauntes' essay. Case 7 is undoubtedly the same patient in both works, though Bidault had omitted Baunies' angry rantings at the grandmother who fed the baby sweet almond oil. In case 8 the poor baby was fed hot wine with sugar. He died after three weeks in Baumes' version, while Bidault felt that two weeks was enough. Case 9 is missing from Baumes' 2nd edition. Case 10 concerns an infant who died at four weeks of age, and in Baumes' version was autopsied by dr.M, while Bidault let "two surgeons" do it. Their findings were identical, though Bidault again skipped many of the details. After this, one is not surprised to find the authors agreeing that meconium retention is the most important cause of neonatal jaundice. The authors, however, admitted that there may be other causes of neonatal jaundice which had escaped their attention, because, as both claim: "I have limited myself to the examples that have passed beneath my eyes". The veracity of this claim, as far as it pertains to Bidault, would appear to be very much in doubt. CONCLUSIONS: Francois Bidault's 1804 thesis was undoubtedly copied, in part verbatim, from Jean Baptiste Timothee Baumes' 1785 essay. Baumes' work was not quoted or referenced anywhere in Bidault's work. Scientific fraud is not new!

• Hankø, Erik; Tommarello, Steve; Watchko, Jon F. & Hansen, Thor Willy Ruud (2000). Inhibition of Blood-Brain Barrier (BBB) P-glycoprotein (PGP) by Rifampin Increases Brain Biliruhin and Alters the Regional Distribution of Biliruhin (B) in Brain. Full text in Research Archive Show summary

  OBJECTIVE: To study the effect of inhibition of PGP on the regional distribution of B in brain. BACKGROUND: B is a substrate for PGP at the BBB (Watchko, JF et al. Pediatr Res 4-1:763-6,1990). PGP function can be inhibited by several different drugs. Drug-mediated inhibition of PGP at the BBB increases the accumulation of B in brain. We hypothesized that inhibition of BBB PGP by rifampin would alter the distribution of B in brain. DESIGN/METHODS: Young adult rats were anesthetized and given either saline (C) or rifampin (R) 10 mg/kg iv (n=10 in both groups). R has been shown to inhibit PGP and to increase B accumulation in rat brain 10 min after the drug bolus the rats were given 50 mg/kg H3-B (appr. 20 ìCi) iv over 5 min. Rats were sacrificed 10 min after the start of the B infusion. The brain vasculature was flushed in situ to remove blood. The brain was dissected into 7 regions. Serum B was analyzed by diazo method and brain B by scintillation counting. RESULTS: There were significant differences both between the groups (p=0.007) and between regions (p<0.0001). Brain B was higher in the R-treated rats, in accordance with previous findings (Hansen, TWR et al. Pediatr Res -f3:176A, 1995). The regional distribution of B in brain was also different. Thus, in the R-treated rats the cerebral cortex B concentration was significantly lower than in the other brain regions, while in controls the concentration of B in the cerebellum was higher than in the other regions. CONCLUSIONS: While not fully compatible with a kernicteric staining pattern, the change in brain regional B distribution seen after PGP inhibition by R suggests the possibility that altered function of BBB PGP may play a role in the distribution pattern of B in brain. The extent to which regional BBB PGP function or expression may be modulated by maturation or by other factors known to increase B entry into brain, will need to be studied further. We speculate that drugs known to inhibit PGP should probably be avoided in infants with significant neonatal hyperbilirubinemia.

• Kalikstad, Betty; Skjerdal, Åse S. & Hansen, Thor Willy (2000). Medikamentkompatibilitet i Nyfødt Intensiv Avdeling � en oversikt over Cytokrom Oxidase-systemet og legemiddel interaksjoner som forårsaker arrytmi hos barn. Full text in Research Archive
• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (2000). Hvorfor er behandlingsunnlatelse så vanskelig? Endring i behandlingsavslutninger siste 10 år i pediatrien. Full text in Research Archive
• Meslo, Marit; Tveiten, Laila & Hansen, Thor Willy Ruud (2000). Effektivisering av lysbehandling med enkle midler. Jordmorbladet. ISSN 0805-0562. 7(4), p. 18–21. Full text in Research Archive Show summary

  Gulsott er en av de vanligste tilstander hos nyfødte som krever utredning og behandling. Bortimot 10% av norske nyfødte behandles for gulsott med fototerapi. Bakgrunnen for behandlingen er at sterk gulsott i sjeldne tilfelle kan føre til varig hjerneskade. Lysbehandling omdanner gallefargestoffet bilirubin til vannløselig form slik at det kan skilles ut selv om leverfunksjonen fortsatt er umoden. Undersøkelser har vist at lysbehandling ved norske sykehus ofte foregår med dårlig utstyr og under betingelser som er langt fra optimale. Dette fører til at barna blir liggende i lys lenger enn det som hadde vært nødvendig med effektiv fototerapi. Ved Barselavdelingen, Rikshospitalet så vi over vårt lysbehandlingsutstyr og målte lysenergien som dette utstyret leverte. Deretter skiftet vi til mer effektive lysstoffrør, innskjerpet at barnet skulle ligge i riktig avstand fra lyskilden, og kledde sengen og apparatet med hvitt, lysreflekterende tøy. Dette medførte en betydelig økning i den lysenergien som ble levert til barnets hudoverflate. Vi sammenlignet effekten av lysbehandling hos 20 barn før og 20 barn etter endringen av utstyret. Endringen førte til fem timer mindre tid i lyskasse, fra 21.8±9.8 timer til 16.8±6.1 timer (p=0.03). I denne artikkelen beskriver vi de endringene som ble gjennomført, og diskuterer hva som skal til for at lysbehandling skal bli mest mulig effektiv, og derfor av kortest mulig varighet.

• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (2000). Dødsfall på en nyfødtavdeling - aspekter av et fag i endring. Full text in Research Archive Show summary

  Bakgrunn: Hverdagen i nyfødt intensivmedisin endrer seg stadig. For å beskrive noen aspekter ved disse endringene har vi studert barn som døde i en neonatalavdeling på et regionsykehus. Spesifikt postulerte vi at de barna som døde på slutten av 1990-tallet representerte andre diagnoser og problemstillinger enn de som døde ti år tidligere. Samtidig postulerte vi at vår medisinske, etiske og medmenneskelige tilnærming til disse barna har endret seg betydelig i samme tidsrom. Materiale og metode: Barn som døde ved Nyfødtseksjonen, Barneklinikken, Rikshospitalet i 1987 og 1988 ble sammenlignet med barn som døde i 1997 og 1998. I den første toårs perioden døde 101 barn (mortalitet 6,9%), i den siste toårs perioden døde 58 barn (mortalitet 3,4%). Journalene til 92 barn i den første gruppen (91%) og 52 barn i den siste gruppen (90%) lot seg lokalisere og ble gjennomgått retrospektivt. Vi registrerte fødselsvekt og gestasjonsalder, samt diagnoser som bidro til dødsfallet. Videre registerte vi bl.a. hvorvidt barnet døde under pågående behandling, eller etter avslutning av livsunderstøttende behandling. Andre parametre som liggetid, tilstedeværelse av foreldre og ytterligere familie ved dødstidspunktet, hvor barnet døde, og oppfølging av foreldrene under og etter dødsfallet er undersøkt. Endelig ble journalnotater fra leger og sykepleiere vurdert i forhold til det som sies om kommunikasjon med foreldrene med tanke på barnets tilstand, prognose og berettigelsen av fortsatt behandling. Materialet ble analysert med vanlige deskriptive statistiske metoder. Resultater: Reduksjonen i mortalitet var signifikant mellom de to periodene. Signifikant flere barn døde i 1997/98 som følge av elektiv tilbaketrekning av livsunderstøttende behandling (64,5 vs 22,8%, p<0.0001). Tiden fra innleggelsen til barnet døde gikk noe ned (fra 11,3 til 7,4 døgn), men denne endringen var ikke signifikant (p=0,075). Barna i 97/98 populasjonen var signifikant større (2186 vs 1699 g, p<0.05) og hadde høyere gestasjonsalder (34.0 vs 32.0 uker, p<0.05 ) enn barna som døde i 87/88. Det var en klar økning i andelen av barn som døde med komplekse misdannelser i 97/98-gruppen (28/52 vs 26/92, p<0,005). De premature barns andel av dødsfallene har gått noe ned, men endringen er ikke helt signifikant (46,2 vs 64,1 %, p=0,053). I perioden 97/98 var foreldrene mye oftere til stede når døden inntraff, likeledes var andre familiemedlemmer oftere med, og barnet var oftere på fanget til en av foreldrene eller på uterom med foreldrene ved dødstidspunktet, sammenlignet med 10 år tidligere. Det var klare endringer i journalføring i denne tiårsperioden. Oppfølgingen av og kommunika-sjonen med foreldrene, slik den ble reflektert i legers og sykepleieres notater, ble gradert på en skala fra 1 til 8. Det var en meget signifikant økning i skåre fra 87/88 til 97/98 (p<0.0001). Foreldrene fikk i 97/98 signifikant oftere muligheten til å legge fram sitt syn på legenes avgjørelse om avslutning av behandlingen. I journalene fra 87/88 fant vi ikke et eneste referat fra samtaler mellom foreldre og lege, i motsetning til den siste gruppen der 20/52 hadde ett eller flere slike referater. Diskusjon: Det har skjedd store endringer i den aktuelle tiårsperioden når det gjelder barn som dør i en regional nyfødtavdeling. Tyngden har dreid fra prematuritet i retning av større barn med komplekse misdannelser. I den grad journalene reflekterer den kliniske virkelighet, legges det i dag et betydelig større arbeid i kommunikasjonen med foreldrene under oppholdet og etter dødsfallet. Man har i økende grad stilt spørsmål ved berettigelsen av fortsatt intensivbehandling av barn med svært dårlige overlevelsesutsikter og/eller prognose. Denne problematiseringen har medført en økende grad av aktiv holdning i forhold til avslutning av livsunderstøttende behandling. Helsevesenet kritiseres av og til for behandling in absurdum.

• Hankø, Erik; Tommarello, Steve; Watchko, Jon F. & Hansen, Thor Willy Ruud (2000). Pharmacological inhibition of blood-brain barrier P-glycoprotein ingreases brain bilirubin and alters regional distribution of bilirubin in rat brain. Full text in Research Archive
• Hankø, Erik; Lindeman, Rolf & Hansen, Thor Willy Ruud (2000). Spectrum of Outcome in Infants with Extreme Neonatal Jaundice. [Radio]. Boston, MA, USA : Pediatric Academic Societies. Full text in Research Archive Show summary

  OBJECTIVE: To describe patients with extreme neonatal jaundice in whom the Outcome ranged from overt kernicterus to apparent lack of sequelae. BACKGROUND: Kernicterus has recently reemerged in the industrialized world. Earlier postnatal discharge combined with less concern over jaundice in term infants may be involved in this new "epidemic". Many case reports of kernicterus have been published, but little has been written about infants who survived comparable levels of serum bilirubin without harm. DESIGN/METHODS: Case reports. RESULTS: Case 1 was a 37 W GA, 2930 g BW male African infant who presented on day 2 of life with jaundice (650 ìmol/L at 40 h). Blood ;coups were 0 (M), A (I ). Coombs neg. After 2 exchange transfusions serum bilirubin (SB) stabilized at <400 ìmol/L by 48 h. A blood culture grew Staph. aureus and enterococci, but CRP remained normal. He had repeated convulsions during the first days. At 4 months he had severe CP, generalized developmental delay, and deafness confirmed by ABRs. Case 2 was a 42 W GA. 3680 g BW male African infant. SB was 683 ìmol/L at 54 h, and 717 ìmol/L at 59 h when an exchange transfusion was initiated. Blood groups were 0 (M). B (I). Coombs neg. After 3 exchange transfusions the SB stabilized at <400 ìmol/L by 69 h. His neurological development has been normal except for moderate/severe hearing loss confirmed by ABRs. Case i was a 37 W GA, 2900 G BW female infant of an African-American father and a Norwegian mother. Blood groups were 0 (M). B (I), Coombs pos. SB at I5 h of life was 598 ìmol/L, and 636 ìmol/L at 17 h when an exchange transfusion was initiated. After 3 exchange transfusions SB stabilized below exchange levels by 35 h of age. Her follow-up neurological exams have been normal. CONCLUSIONS: All infants were judged to have ABO incompatibility based on blood films, though Coombs' test was positive only in one. G6PD activity was normal in cases 2 and 3, but not done in case I . The patient who escaped damage differed from the other two in being female, earlier detection, and a shorter duration of exposure to high SB values. The more severely damaged patient had seizures and a positive blood culture for which he was treated with antibiotics, though clinically the diagnosis of sepsis was thought to be in doubt. We speculate that important information may be found by contrasting patients with sequelae with those who escaped, and invite colleagues who have seen other patients with extreme jaundice escape unharmed to either publish these cases or communicate them to us (TWRH).

• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (2000). Hvordan helsepersonell forholder seg til familie og barn når et barn holder på å dø. Full text in Research Archive
• Hansen, Thor Willy Ruud (2000). Gulsott og hjerneskade hos nyfødte - klinikeren som nevrobiologisk amatørdektektiv. Full text in Research Archive
• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (2000). Dødsfall på Nyfødtseksjonen, Barneklinikken - mye har endret seg på ti år. Full text in Research Archive
• Tsai, Cathy; Lane, R.H.; Daood, Monica J.; Hansen, Thor Willy Ruud & Watchko, Jon F. (1999). The ontogeny of P-glycoprotein expression in mouse brain microvessels. Full text in Research Archive
• Hansen, Thor Willy Ruud (1999). The first neuropathological descriptions of kernicterus: Johannes Orth and Christian Schmorl. Full text in Research Archive
• Hansen, Thor Willy Ruud (1999). Hervieux and his 1847 study of neonatal jaundice. Full text in Research Archive
• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (1999). Dødsfall på en nyfødtavdeling: Omsorg og rutiner - hva ble gjort og hva ble skrevet? Full text in Research Archive Show summary

  Bakgrunn: Hverdagen i nyfødt intensivmedisin og -sykepleie endrer seg stadig. For å beskrive noen aspekter ved disse endringene har vi tatt for oss barn som døde i en neonatalavdeling på et regionssykehus. Spesifikt postulerte vi at de barna som døde på slutten av 1990-tallet representerte andre diagnoser og problemstillinger enn de som døde ti år tidligere. Samtidig postulerte vi at vår medisinske og etiske tilnærming til disse barna, samt rutinene rundt kommunikasjon med foreldrene og tilrettelegging av forholdene under- og etter dødsfallet har endret seg betydelig i samme tidsrom. Materiale og metode: Barn som døde ved Nyfødtseksjonen, Barneklinikken, Rikshospitalet i 1987 og 1988 ble sammenlignet med barn som døde i 1997 og 1998. I den første toårs perioden døde 101 barn (mortalitet 6,9%), i den siste toårs perioden døde 58 barn (mortalitet 3,4%). Journalene til 92 barn i den første gruppen (91%) og 52 barn i den siste gruppen (90%) lot seg lokalisere og ble gjennomgått retrospektivt. Vi registrerte fødselsvekt og gestasjonsalder, samt diagnoser som bidro til dødsfallet. Videre registerte vi bl.a. hvorvidt barnet døde under pågående behandling, eller etter avslutning av livsunderstøttende behandling. Andre parametre som liggetid, tilstedeværelse av foreldre ved dødstidspunktet, øvrig familie som deltok i prosessen, hvor barnet døde, og oppfølging av foreldrene under og etter dødsfallet er undersøkt. Endelig ble journalnotater fra leger og sykepleiere vurdert i forhold til det som sies om kommunikasjon med foreldrene med tanke på barnets tilstand, prognose og berettigelsen av fortsatt behandling. Materialet ble analysert med vanlige deskriptive statistiske metoder. Resultater: Reduksjonen i mortalitet mellom de to periodene var signifikant (p<0.0001). Sammenlignet med 87/88 døde signifikant flere barn i 97/98 som følge av elektiv tilbaketrekning av livsunderstøttende behandling (64,5 vs 22,8%, p<0.0001). Tiden fra innleggelsen til barnet døde gikk noe ned (fra 11,3 til 7,4 døgn), men denne endringen var ikke signifikant (p=0,075). Barna i 97/98 populasjonen var signifikant større og hadde høyere gestasjonsalder enn barna som døde i 87/88. Det har skjedd en meget signifikant endring i følgende parametre: I gruppen fra 97/98 ser vi at foreldrene i betydelig større grad enn tidligere er tilstede når døden inntreffer, andre familiemedlemmer er også oftere til stede i forbindelse med dødsfallet, og barnet er oftere på fanget til en av foreldrene eller på uterom med foreldrene ved dødstidspunktet, sammenlignet med 10 år tidligere. Det er meget interessant å se endringene i journalføring i denne tiårsperioden. Oppfølgingen av og kommunikasjonen med foreldrene, slik den ble reflektert i legers og sykepleieres notater, ble gradert på en skala fra 1 til 8. Det var en meget signifikant økning i skåre fra 87/88 til 97/98 (p<0.0001). Hvis journalene reflekterer det som virkelig skjedde, får foreldrene i 97/98 signifikant oftere muligheten til å legge fram sitt syn på legenes avgjørelse om avslutning av behandlingen. I journalene fra 87/88 fant vi ikke et eneste referat fra samtaler mellom foreldre og lege, i motsetning til gruppen fra 97/98 der vi i 20/52 journaler fant ett eller flere slike referater. Dette kan enten skyldes at vi faktisk snakker mer med foreldrene nå, eller at vi er blitt flinkere til å dokumentere det som skjer. Diskusjon: Det har skjedd store endringer i den aktuelle tiårsperioden når det gjelder barn som dør i en regional nyfødtavdeling. I den grad journalene reflekterer den kliniske virkelighet, legges det i dag et betydelig større arbeid i kommunikasjon med foreldrene under oppholdet og etter dødsfallet. I tillegg er det tydelig at sykepleien rundt barnets familie er mer omfattende i 97/98 sammenlignet med 87/88.

• Mahmood, Burhan; Lane, R.H.; Daood, Monica J.; Hansen, Thor Willy Ruud & Watchko, Jon F. (1999). Small intestinal P-glycoprotein mRNA levels and protein expression increase with postnatal maturation in mice. Full text in Research Archive
• Hansen, Thor Willy Ruud; Allen, Jeffrey Wray & Tommarello, Steve (1999). Bilirubin oxidation in brain. Full text in Research Archive Show summary

  Background B is cleared from brain by various mechanisms. A study by Brodersen and Bartels (Eur J Biochem 1969) suggested that B may be oxidized by brain tissue. We aimed to investigate this process in more detail. Materials/Methods Brains from rats and rabbits of various postnatal ages were used to produce mitochondria by differential centrifugation in sucrose media. Mitochondria were lysed by sonication to produce mitochondrial membranes (MM). B oxidation was studied by measuring the decay of optical density at 440 nm in a 10 µM B solution following the addition of 0.5 mg of MM protein. We studied this activity as a function of postnatal age, and compared the activity in MM from a pure neuronal vs a mixed glial/neuronal source as well as in MM from different brain regions. Genetic variability was studied by comparing the activity in MM from three different rat strains. We further studied the effects of sepsis, endotoxemia, and pretreatment with phenobarbital. Finally we attempted to identify the responsible enzyme by using various inhibitors and stimulators of known mitochondrial enzymes. Results We have verified the existence of a brain mitochondrial enzyme which oxidizes B at a rate (100-300 pM B/min/mg protein) which may contribute significantly to the clearance of B from brain. The activity increased with postnatal age, was lower in MM from a pure neuronal than a mixed neuronal/glial source, and appeared to be subject to genetic variability. Activities differed between brain regions, but not in a pattern corresponding to kernicterus. Pretreatment with phenobarbital inhibited B oxidation by brain MM, but the difference was small and probably not biologically important. Endotoxemia and sepsis had no effect on B oxidation by brain MM. The activity was inhibited by ketoconazole and clotrimazole, both of which inhibit cytochrome P450 oxidases, but not by inhibitors of monoamine oxidase or malate dehydrogenase. The activity was also inhibited by cyanide, and by partial removal of cytochrome c from the MM. In the latter experiments activity was restored by adding fresh cytochrome c to the incubate. However, no activity was found using cytochrome c alone without the presence of MM. Discussion B is oxidized by brain MM. Our data suggest that the responsible enzyme may be a cytochrome oxidase. The immature brain is believed to be more vulnerable to B toxicity than the mature brain, and the same is thought to be the case for neurons vs glia. The lower activity of the B-oxidizing enzyme in immature brains, and in neurons vs glia appears to be compatible with a speculation that B oxidation may serve to protect the brain against B toxicity. However, the data on B oxidation from Gunn rat strains with widely different mortality rates in the homozygous offspring are more difficult to reconcile with this hypothesis. Further studies are needed to identify the specific enzyme and to elucidate its role in the mechanisms underlying B brain toxicity.

• Hansen, Thor Willy Ruud (1999). Lever og galleveissykdommer hos barn. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 119(25), p. 3788–3788. Full text in Research Archive
• Hansen, Thor Willy Ruud (1999). Gulsott og hjerneskade hos nyfødte - en kliniker forsøker seg som nevrobiolog. Full text in Research Archive
• Wilhelmsen, Cathrine Monrad & Hansen, Thor Willy Ruud (1999). Dødsfall i en neonatal intensiv enhet - et tiårs perspektiv. Full text in Research Archive Show summary

  Bakgrunn: Hverdagen i neonatal intensivmedisin endrer seg stadig. For å beskrive noen aspekter av disse endringene, har vi tatt for oss barn som dør i en neonatalavdeling på et regionssykehus. Spesifikt postulerte vi at de barna som døde på slutten av 1990-tallet representerte andre diagnoser og problemstillinger enn de som døde ti år tidligere. Samtidig postulerte vi at vår medisinske og etiske tilnærming til disse barna har endret seg betydelig i samme tidsrom. Materiale og metode: Barn som døde ved Nyfødtseksjonen, Barneklinikken, Rikshospitalet i 1987 og 1988 ble sammenlignet med barn som døde i 1997 og 1998. I den første toårs perioden døde 101 barn (mortalitet 6,9%), i den siste toårs perioden døde 58 barn (mortalitet 3,4%). Journalene til 92 barn i den første gruppen (91%) og 52 barn i den siste gruppen (90%) lot seg lokalisere og ble gjennomgått retrospektivt. Vi registrerte fødselsvekt og gestasjonsalder, samt hoved- og bidiagnoser som bidro til dødsfallet. Videre registerte vi bl.a. hvorvidt barnet døde under pågående behandling, eller etter avslutning av livsunderstøttende behandling. Endelig ble journalnotater fra leger og sykepleiere vurdert i forhold til det som sies om kommunikasjon med foreldrene med tanke på barnets tilstand, prognose og berettigelsen av fortsatt behandling. Materialet ble analysert med vanlige deskriptive statistiske metoder. Resultater: Reduksjonen i mortalitet var signifikant mellom de to periodene (p<0.0001). Signifikant flere barn døde i 1997/98 som følge av elektiv tilbaketrekning av livsunderstøttende behandling (64,5 vs 22,8%, p<0.0001). Tiden fra innleggelsen til barnet døde gikk noe ned (fra 11,3 til 7,4 døgn), men denne endringen var ikke signifikant (p=0,075). Barna i 97/98 populasjonen var signifikant større (fødselsvekt 2186 g vs 1699 g, p=0.012) og hadde høyere gestasjonsalder (34,0 vs 32,0 uker, p<0.05) enn barna som døde i 87/88. Det var en klar økning i andelen av barn som døde med komplekse misdannelser i 97/98-gruppen (28/52 vs 26/92, p<0,005). De premature barnas andel av dødsfallene har gått noe ned, uten at denne endringen helt tilfredsstiller signifikanskravet (46,2 vs 64,1 %, p=0,053). Det er meget interessant å se endringene i journalføring i denne tiårsperioden. Oppfølgingen av og kommunikasjonen med foreldrene, slik den ble reflektert i legers og sykepleieres notater, ble gradert på en skala fra 1 til 8. Det var en meget signifikant økning i skåre fra 87/88 til 97/98 (p<0.0001). Diskusjon: Det har skjedd store endringer i den aktuelle tiårsperioden når det gjelder barn som dør i en regional neonatalavdeling. Tyngden har dreid fra prematuritet i retning større barn med komplekse misdannelser. I den grad journalene reflekterer den kliniske virkelighet, legges det i dag et betydelig større arbeid i kommunikasjon med foreldrene under oppholdet og etter dødsfallet. Man har i økende grad stilt spørsmål ved berettigelsen av fortsatt intensivbehandling av barn med svært dårlige overlevelsesutsikter og/eller prognose. Denne problematiseringen har medført en økende grad av aktiv holdning i forhold til avslutning av livsunderstøttende behandling. Refleksjonsnivået, i hvert fall slik det fremgår av journalnotatene, er blitt betydelig mer sofistikert. Helsevesenet kritiseres av og til for behandling in absurdum. Dette stemmer dårlig med den virkelighet som journalene fra 1997/98 beskriver fra nyfødtmedisinen.

• Mahmood, Burhan; Daood, Monica J.; Hansen, Thor Willy Ruud & Watchko, Jon F. (1998). Expression of P-glycoprotein in brush border membranes of mouse small intestine increases with postnatal maturation. Full text in Research Archive
• Hansen, Thor Willy Ruud (1998). The mechanisms of bilirubin brain toxicity. Full text in Research Archive
• Hansen, Thor Willy Ruud; Tommarello, Steve; Daood, Monica J. & Watchko, Jon F. (1998). P-glycoprotein in the blood-brain barrier - another unknown in the bilirubin encephalopathy puzzle. Full text in Research Archive Show summary

  PGP er et ATP-avhengig membranprotein som kodes for av genet mdr1a (mdr= multidrug resistance). Når PGP uttrykkes i cancer-celler i høy grad, er det forbundet med resistens mot cytostatika. PGP uttrykkes imidlertid også i normale vev, deriblant i blod-hjerne-barrieren. I denne lokalisasjonen ser PGP ut til å være assosiert med hemmet inntrengen av og/eller redusert retensjon av en rekke amfipatiske stoffer i hjernen. Vår hypotese var at bilirubin (B) ville vise seg å være et substrat for PGP, og at hemning eller manglende ekspresjon av PGP ville ledsages av økt B-konsentrasjon i hjerne ved hyperbilirubinemi. Materiale og metoder I første forsøksserie ble B innfundert iv i en bolusdose på 50 mg/kg over 5 min hos genetiske mutante mus som ikke uttrykker PGP (mdr1a[-/-] null mutant), og hos PGP-suffisiente kontrollmus. Musene ble drept etter enten 10 eller 60 min, og B i hjernen ble analysert med kloroformekstraksjon til surt medium. Halveringstiden av B i hjerne ble kalkulert ved eksponentiell tilpasning. Statistiske sammenligninger ble foretatt med uparret t-test. I andre del av forsøksserien ble en tilsvarende bolus-dose B gitt til Sprague-Dawley rotter etter at de var blitt forbehandlet med medikamenter som er vist å hemme PGP-ekspresjon eller funksjon (verapamil, propanolol, ceftriaxon, erytromycin eller rifampin). Kontrolldyrene fikk en tilsvarende mengde saltvann. Alle dyrene ble drept 10 min etter starten av B-infusjonen, og hjerne-B ble bestemt som beskrevet ovenfor. I tredje del av forsøksserien ble Sprague-Dawley rotter forbehandlet med ceftriaxon og fikk deretter 50 mg B iv, men med tilsats av 20 µCi tritium-merket B. Hjernen ble dissekert i syv regioner, og konsentrasjonen av B i hjerne ble bestemt ved scintillasjonstelling. Statistisk sammenligning ble i denne serien foretatt med enveis Anova. Resultater Konsentrasjonen av B i hjerne var signifikant høyere både ved 10 og 60 min hos PGP "knock-out" mus sammenlignet med kontrollene (hhv. 10.6±1.4 vs 6.1±0.7 og 6.0±0.8 vs 3.1±0.5 µg B/g hjerne, p<0.05 ved begge tidspunkter). Halveringstiden var ikke forskjellig i de to gruppene. Med unntak av erytromycin førte alle de andre PGP-hemmende medikamentene til signifikant (p<0.05) øket akutt inntreden av B i hjerne. Forbehandling med ceftriaxon økte hjerne-konsentrasjonen av B, men endret derimot ikke den regionale fordelingen av B i rottehjerne sammenlignet med kontrolldyrene. Diskusjon Våre funn viser at B er et substrat for PGP i blod-hjerne-barrieren. Når PGP hemmes eller ikke uttrykkes, øker den akutte inntreden av B i hjernen, mens halveringstiden derimot ikke påvirkes. En rekke vanlige farmaka vil gjennom hemning av PGP medføre økt akutt inntreden av B i hjernen og således potensielt være forbundet med økt risiko for B-påvirkning av hjernen. Vi har også holdepunkter for at ekspresjonen av PGP i blod-hjerne-barrieren øker betydelig med postnatal alder. Disse funn belyser en hittil ukjent mekanisme for modulering av interaksjonen mellom B og hjerne. Videre studier vil være nødvendige for å ytterligere avklare betydningen av PGP ved B encefalopati og kjerneikterus.

• Hansen, Thor Willy Ruud & Tommarello, Steve (1998). In vivo subcellular distribution of bilirubin in rat brain during hypercarbia and hyperosmolality. Full text in Research Archive Show summary

  Background There is as yet no agreement on what the basic mechanism(s) for B toxicity is/are. In designing and evaluating in vitro studies of B toxicity on cell organelles, it would be helpful to know what concentrations of B might be found in cell organelles in vivo. Materials and methods Young adult Sprague-Dawley rats were allocated to one of three groups: control, HC (inhalation of 15% CO2 in air [pH 6.89±0.07, PCO2 14.49±5.83 kPa]), and HO (infusion of carbamide IV [serum osmolality 408±31 mosm/L]). Each was then given a 5-min bolus dose of B 50 mg/kg IV (with 200 µCi 3H-B). Rats were killed 10 or 30 min after the start of the B infusion (n=8 in the control group at 30 min, n=7 in all other groups and time points), and the brain vessels were flushed in situ with ice cold saline. Each brain was then homogenized in 0.32 M sucrose in a glass-Teflon homogenizer and subcellular fractions were isolated by high-speed gradient centrifugation in sucrose media. Protein content was determined in all fractions/aliquots. The content of B per mg of protein was determined by scintillation counting. Statistical comparisons were performed with Kruskal-Wallis non-parametric Anova and Dunn's multiple comparisons test. Results There were highly significant differences between the B content of subcellular compartments (p<0.0001 for all groups at both time points). Mean values ranged from 10-813 pmol B per mg protein. In all groups there were relatively high concentrations of B in the myelin fraction. Concentrations were higher overall in the HO than in the two other groups, and particularly high in the HO cytoplasm fraction. Discussion The finding of high B concentrations in the myelin fractions is interesting in light of theories and data suggesting that membranes are an important target for B toxicity. The generally very high concentration of B relative to protein in the HO group is also notable in light of data from some studies of hyperbilirubinemic animals where changes in electrophysiology or energy metabolism only appeared after HO opening of the blood-brain barrier. Finally, data from whole brain have shown that HC is associated with rapid entry of B into brain in high concentrations, whereas the present data suggest that HO causes the highest concentrations of B in the subcellular compartments of brain cells.

• Carvalho, Manoel De; Carvalho, Deborah De; Trzmielina, Sonia; Lopes, Jose M.A. & Hansen, Thor Willy Ruud (1998). Intensified phototherapy using daylight fluorescent lamps. Full text in Research Archive Show summary

  Phototherapy (PT) reduces serum bilirubin concentration (SBC) with efficacy that depends on the intensity of irradiation, spectral emission curve, and exposed surface area. Special blue fluorescent tubes (SB) close to the patient give best results. However, SB are not manufactured in most developing countries and are often unaffordable. We developed a system that provides IPT using 7 DFL placed 1cm under the floor of a Plexiglas crib. The sides and top of the crib are covered with a reflecting film, giving the baby direct light from below and reflected light from above and sides. The purpose of this study was to compare the clinical efficacy of this device with overhead PT units using DFL or SB(Philips TL 20W/52) (each with 7 tubes 35 cm above the infant). The subjects were 22 full-term healthy newborn infants who developed non-hemolytic jaundice between 24-72 h of life. Mean birth weight was 3355 + 86g and gestational age 39.4 + 0.3 weeks. PT was started at SBC >12mg%. A capillary blood sample was obtained in all infants at the start of the treatment and every 12h thereafter. All infants were unclothed except for disposable diapers and eye covers. PT was interrupted only for feeding, cleaning and blood sampling. Allocation to the PT devices was random. Outcome variable was the percent fall in SBC after 12 and 24h of treatment. Results are shown in the table (mean+/-SEM, *p<0.05 **p<0.001 compared ty IPT). The mean temperature at the bottom of the cradle was 33 + 1.5ºC. The irradiances delivered by IPT and SB were similar, but the rate of SBC decrease was significantly greater in infants treated with IPT. This can be explained by the greater skin surface area exposed to light in babies receiving IPT. The device we have described provides IPT using DFL. Its simplicity and low cost makes it accessible to nurseries of developing countries where acquisition of imported technology is difficult.

• Tsai, Cathy; Daood, Monica J.; Hansen, Thor Willy Ruud & Watchko, Jon F. (1998). Expression of P-glycoprotein is lower in brain microvessels of immature as compared with adult mice. Full text in Research Archive
• Hansen, Thor Willy Ruud; Tommarello, Steve & Watchko, Jon F. (1998). Inhibition of blood-brain barrier P-glycoprotein function by ceftriaxone does not alter the regional distribution of bilirubin entry into rat brain. Full text in Research Archive Show summary

  Background Entry of B into brain is enhanced by inhibition of PGP in the BBB. The mechanism for distribution of B to the basal ganglia (kernicterus) is not known. We postulated that pretreatment with ceftriaxone, a drug known to inhibit PGP, would alter the regional distribution of B in brain in a pattern corresponding to kernicterus. Materials and methods Young adult Sprague-Dawley rats (n=10 in both groups) were anesthetized and pretreated with an IV bolus dose of ceftriaxone 100 mg/kg or an equivalent volume of saline (controls). 10 min following the drug injection the rats received a 5-min bolus dose of 50 mg/kg B with »20 µCi of 3H-B. The rats were killed 5 min after the end of the B infusion, and the brain blood vessels were flushed in situ. Brain B was determined by scintillation counting. Results were compared with two-way ANOVA. Results The mean serum B concentrations for the control and drug-treated groups at sacrifice were 618±73 and 535±43 µmol/L respectively (mean ±SD, p=0.006). Brain B concentrations were significantly higher in brain regions from the drug-treated rats than the controls (F=114.2, p<0.0001). In both groups there were significant differences in B concentrations between brain regions (F=9.5, p<0.0001). However, in both groups this was primarily accounted for by a higher concentration in the cerebellum, and the distribution of B between regions was not different between controls and ceftriaxone-treated rats. Discussion Inhibition of BBB PGP function by ceftriaxone significantly increased the acute influx of B into brain, but did not change the regional distribution relative to control conditions. The expression of PGP in the BBB increases with postnatal age. Further studies will be needed to address the question of whether there may be differences between brain regions in the rate of maturation of BBB PGP function.

• Hansen, Thor Willy Ruud; Tommarello, Steve & Watchko, Jon F. (1998). Inhibition of blood-brain barrier P-glycoprotein function by various drugs enhances acute bilirubin entry into brain. Full text in Research Archive Show summary

  Background Entry of B into brain is significantly increased in the absence of BBB PGP expression, while efflux is not affected (Watchko J et al, Pediatr Res 1997;41:186A). PGP may block the entry of amphipatic compounds, or enhance their efflux. PGP function is inhibited by a number of common drugs. We postulated that pretreatment with such drugs would increase the entry of B into brain. Materials and methods Young adult SPRD rats were anesthetized and pretreated with IV bolus doses of: verapamil (1 mg/kg; n=11), propanolol (0.15 mg/ kg; n=7), ceftriaxone (100 mg/kg; n=7), erythromycin (10 mg/kg; n=6), or rifampin (10 mg/kg; n=6). Controls (n=12) received saline. Ten min after the drug injection the rats received 50 mg/kg B over 5 min. They were sacrificed 5 min after the end of the B infusion. Brain bilirubin was measured by acid chlorform extraction. Results were compared with unpaired t-tests. Results The overall mean serum B concentration for the groups at sacrifice was 554±62 µmol/L (mean ±SD). Fortuitously there were significant differences between group mean serum B values. Therefore brain:serum B ratios (x1000) were calculated for all rats and used in the comparisons. Unbound B concentrations were not significantly different between any groups (overall mean±SD = 36±18 nmol/L). There were significant increases of brain:serum B ratio in all but the erythromycin group (see table; * denotes p<0.05 vs control). Discussion It has long been known that drugs which displace B from its albumin binding will increase brain B influx. Ceftriaxone has been reported to be a displacer of B. However, the lack of difference in unbound B concentrations between the groups suggests that displacement of B did not play a significant role in the present study. These findings show that a number of drugs known to inhibit PGP function will significantly increase the acute influx of B into brain. This further supports the role of PGP in modulating B entry into brain, and also raises new concerns regarding the use of drugs in jaundiced infants.

• Hansen, Thor Willy Ruud (1998). Senabort og tidligfødsel. Kristelig tidende. ISSN 0808-0879. 127(20), p. 14–14. Full text in Research Archive
• Hansen, Thor Willy Ruud (1998). Enkle måter for effektivisering av lysbehandling. Full text in Research Archive Show summary

  Gulsott er en av de vanligste kliniske ytringer hos nyfødte som krever tiltak fra vår side. Synlig gulsott fører til at vi tar prøver, og hvis bilirubin-nivået er over visse grenser starter vi behandling. Grunnen til at vi i det hele tatt bryr oss om dette, i og for seg helt normale fenomenet hos nyfødte, er at svært høye bilirubin-konsentrasjoner er forbundet med risiko for hjerneskade ("kjerneikterus") eller død. Den vanligste og enkleste behandling er lysbehandling (fototerapi). Når lys av bestemte bølgelengder treffer gul hud, vil det bilirubinet som treffes endre konfigurasjon slik at det går over fra å være fettløselig til å være vannløselig. Dette har to ønskelige resultater: 1)bilirubinet kan nå skilles ut uten å trenge konjugering i leveren, og 2)vannløselig bilirubin kan ikke trenge inn i hjernen. Erfaringen viser at lysbehandling ofte ikke gis så effektivt som man kunne ønske. Dette fører til at barnet blir liggende i lys lenger enn nødvendig, med de uheldige følgene det kunne tenkes å ha for interaksjonen mellom mor og barn. I det følgende vil jeg beskrive hva som skal til for å effektivisere lysbehandlingen. Effekten av lysbehandling er avhengig av flere faktorer. Bølgelengde: Bilirubinet omdannes mest effektivt av lys som er blått til blågrønt, mens hvitt lys er mindre effektivt og rødt lys er til liten nytte. I lyskasser med flere rør greier det seg med ett hvitt lysrør for å redusere ubehaget ved det blå lyset. Lysenergi: Jo høyere lysenergi som treffer huden, jo større blir dannelsen av vannløselig bilirubin. Lysenergien øker vi ved å ha rimelig "friske" lysrør og holde kort avstand mellom lysrørene og pasienten (35-50 cm). Ved lengre avstand avtar energien raskt. Bestrålt overflate: Effekten av lysbehandlingen øker også jo større hudoverflate vi bestråler. Hvis vi dekker innsiden av sengen med et hvitt laken eller annet reflekterende materiale og henger en hvit gardin rundt sengen og lyskassen, vil det reflekterte lyset føre til at vi får gitt lysbehandling på hudområder som ikke ville bli særlig bestrålt med bare lys ovenfra. Det er også viktig å holde tildekningen av barnet på et minimum: dekk kun øynene og klipp bleien ned til den minste nødvendige størrelsen. Fototerapiutstyr som er slik konstruert at det bare gir lysbehandling på et lite hudområde (lysmatte, lysvest, lysseng) er mindre effektivt samme hvor nett og pent det ser ut. Enterohepatisk sirkulasjon Bilirubin som blir skilt ut i tarmen men ikke blir fraktet videre ut med tarminnholdet, vil kunne suges opp igjen og bidra til at gulsotten holder seg. De barna som kommer inn hjemmefra med uttalt gulsott og som veier mindre enn fødselsvekten har ofte fått for lite morsmelk, og derfor har det ikke vært nok i tarmen til å frakte bilirubinet videre ("mangel-på-morsmelk-ikterus"). Disse kan ha nytte av å få rikelig morsmelktillegg i de første timene etter innleggelsen. Konklusjon Ved å følge disse retningslinjene vil man etter vår erfaring kunne redusere varigheten av lysbehandlingen betraktelig uten andre innvesteringer enn (kanskje) nye lysstoffrør og noen kritthvite lakener.

• Hansen, Thor Willy Ruud (1998). Ikterus hos nyfødte - basalvitenskap og klinikk. Full text in Research Archive Show summary

  Foredraget går gjennom den basalvitenskapelige kunnskap om hjerneskade ved gulsott hos nyfødte. Dette diskuteres i lys av de aktuelle retningslinjer for behandling av nyfødt-ikterus.

• Hansen, Thor Willy Ruud (1998). Historiske og dagsaktuelle perspektiver på behandling av gulsott hos nyfødte. Full text in Research Archive Show summary

  Foredraget tok for seg den historiske bakgrunnen for behandlingen av gulsott hos nyfødte. Utviklingen av de ulike behandlingsalternativene ble gjennomgått. Den basalvitenskapelige bakgrunn for vår nåværende kunnskap om mekanismene bak hjerneskaden ble gjennomgått. Den store spredningen i de retningslinjer som praktiseres i dagens behandling av iketrus ble satt inn i et nasjonalt perspektiv.

• Hansen, Thor Willy Ruud (1998). Holdninger til behandling av ekstrem prematuritet i ikke-nordiske land. Full text in Research Archive
• Hansen, Thor Willy Ruud (1998). Smerter hos nyfødte. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 118(27), p. 4270–4270. Full text in Research Archive
• Hansen, Thor Willy Ruud (1998). Tidlig diagnose av medfødt hørselstap. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 118(29), p. 4561–4561. Full text in Research Archive
• Watchko, Jon F.; Daood, Monica J. & Hansen, Thor Willy Ruud (1997). Brain bilirubin influx is increased in blood-brain barrier P-glycoprotein deficient null mutant mice. Full text in Research Archive Show summary

  P-glycoprotein (P-gp) is an ATP-dependent plasma membrane protein that blocks the cellular influx and/or increases the cellular efflux of a wide variety of unrelated amphipathic compounds. P-gp is constitutively expressed in many tissues including the endothelial cells of the blood-brain-barrier and is encoded for by the MDRla gene. Although P-gp expression is known to confer a multiple drug resistance phenotype to tumors that express it, an endogenous substrate for P-gp has not been defined. We hypothesizcd that bilirubin is a substrate for P-gp and that bilirubin transport across the blood-brain-barrier into the central nervous system would be increased in the absence of P-gp expression in brain endothelial capillary cells. We tested this hypothesis using adult MDRla null mutant transgenic mice (MDRla[-/-], Cell 77:491-502, 1994). Fifteen MDRla[-/-] P-gp null mutants and 15 wild type [+/+] mice of the same mixed genetic background were lightly anesthetized and 50 mg/kg of bilirubin infused through the tail vein. Ten or 60 min following infusion the animals were sacrificed, brain vasculature flushed with saline in situ, and brain bilirubin content and serum bilirubin levels determined. Brain bilirubin content (mean±SEM) was significantly higher in MDR la(-/-] P-gp deficient mice (10.6±1.4 ug/G [n=9]) as compared with wild type [+/+] mice (6.1±0.7 ug/G [n=gl) 10 min following infusion (P<0.05). Brain bilirubin content declined in both groups at the 60 min time point but was higher in MDRia[-/- ] mice (6.2±1.1 ug/G [n=61) as compared with the wild type [+/+] (3.0±0.5 ug/G [n=7]) (P<0.05). Brain bilirubin clearance, however, did not differ between groups (t½ 55 min). Serum bilirubin levels declined from 10 to 60 min but did not differ between MDR la [-/-] and [+/+] animals. We conclude that MDR1a[-/-] P-gp deficient mice have significantly higher brain bilirubin content compared with P-gp sufficient controls following an intravenous load of bilirubin. These data suggest that i) bilirubin is a substrate for P-gp and ii) the increased brain bilirubin content in MDRla[-/-] mice is due to enhanccd brain bilirubin influx rather than impaired efflux. We speculate that brain capillary endothelial cell P-gp expression provides a protective effect against bilirubin neurotoxicity by reducing brain bilirubin influx. Supported by the Magee-Womcns Health Foundation Research Fund

• Hansen, Thor Willy Ruud & Tommarello, Steve (1997). In vivo subcellular localization of 3H-bilirubin in rat brain. Full text in Research Archive Show summary

  Background B is a well known cause of neurotoxicity, but our understanding of the mechanisms underlying toxicity is incomplete. No information was available on the subcellular localization of B in vivo. Materials/methods Young SPRD rats (100-200g) were anesthetized with fentanyl/droperidol/ midazolam sc and 50 mg/kg B (containing 200µCi [3H]B) was infused iv over 5 min. Rats were sacri- ficed at 10 (n=7) and 30 (n=8) min after the start of the infusion, and the brain vasculature was flushed in situ with icecold saline. Brain were homogenized in 0.32M sucrose using a glass-Teflon homogeni- zer, followed by subcellular fractionation in sucrose gradients. Fractions were removed in aliquots of 2 mL, and the protein content of each fraction was determined. 10 mL of scintillation cocktail was added to each fraction for scintillation counting. Serum B concentration was determined in serum obtained immediately prior to sacrifice, and the specific activity of B was determined for each rat by scintillation counting of duplicate 10 µL serum samples. Data from the subcellular fractions were contrasted using nonparametric analysis of variance. Results Serum B concentrations were 529±78 and 394±42 µmol/L (mean±SD) at 10 and 30 min respectively. There were significant differences between B concentrations in subcellular fractions at both time points (KW=35.8, p<0.0001 at 10 min, KW=43.2, p<0.0001 at 30 min). At both time points the B concentration was highest in the myelin fraction followed by the super- natant (possibly representing cytoplasm), while the synaptosomes had the lowest B concentration. Myelin B concentration (237±110 pmol/mg protein at 10 min) was higher than synaptosomal (23±9 pmol/mg protein at 10 min) by a factor of 10. The distribution between fractions did not change over time (data not shown). Conclusion In the presence of an intact blood-brain barrier B entering the brain appears to achieve the highest concentrations in membranes and cytoplasm of brain cells. Although this does not prove that the basic mechanism of B neurotoxicity is necessarily associated with these fractions, knowing the concentrations of B associated with the different subcellular compartments may be of value in designing and evaluating studies of the effects of B on basic cellular functions.

• Hansen, Thor Willy Ruud & Tommarello, Steve (1997). Phenobarbital does not affect bilirubin metabolism in rat brain. Full text in Research Archive Show summary

  Background Previous (incomplete) data suggested that P might modify B metabol- ism in brain1,2. This is potentially important, as P is still in use for treatment of hyper- bilirubinemia. Materials/methods We have studied the clearance of B from brain following pretreatment of young adult SPRD rats with P 75 mg/kg ip daily for 7 days, controls received solvent only (n=8 in each group). On day 8 rats were anes- thetized and 50 mg/kg B was infused iv over 5 min. Rats were sacrificed after 60 min, the brain vasculature flushed in situ, and brain B determined by acid chloroform extraction. Serum B at sacrifice was determined by a diazo method. Results As ex- pected following P treatment, serum B was slightly lower in P-treated vs control rats (126±32 vs 140±21 µmol/L, p=0.3). Brain B values were also lower in the P-treated rats (0.52±0.08 vs 0.44±0.06 nmol/g, p=0.044). As the lower brain B values in P- treated rats could be due entirely to lower serum B values, we compared the brain: serum B ratios in the two groups and found these to be identical (0.0037). Conclusion P does not directly affect metabolism of B in rat brain. The 60 min time point for sacrifice represents at least 3 half-lives of B in brain, thus brain B concen- tration at this time is a good proxy for clearance. We speculate that P treatment may be neither helpful nor harmful relative to the neurotoxic effects of B in infants with already established jaundice. 1Burgess GH, Brown LAS, Pediatr Res 1987;21:804A 2Allen JW, Hansen TWR, Pediatr Res 1996;39:56A

• Hansen, Thor Willy Ruud; Mathiesen, Siri B. W.; Østvold, Anne Carine & Walaas, Sven Ivar (1997). Bilirubin inhibits casein kinase 2 by a non-competitive mechanism. Full text in Research Archive Show summary

  Background B has been shown to inhibit several phosphorylation systems. As protein phosphorylation plays a key role in the regulation of many neuronal processes, this effect of B may be an important contributor to its well known neurotoxicity. Thus far the effects of B had been examined in phosphorylation systems with substrate consensus sequences consisting of basic amino acids. In order to evaluate the importance of the substrate characteristics for B effects. We have examined the effects of B on CK2, which preferentially phosphorylates a sequence of acidic residues. Materials/methods The nuclear protein Pl and the synthetic CK-2 peptide substrate were phosphorylated by CK -2 in the presence (or absence) of 0-320 µM B. The results were quantitated by gel electrophoresis (Pl) or filtration (peptide) and Cerenkov counting. Results B inhibited phosphorylation of both substrates by CK.2. Half-maximal inhibition of Pl phosphorylation was achieved at appr. 1 00 gM B. Kinetic analysis of B effects on phosphorylation of the peptide showed appr.70% reduction of Vmax without obvious effects on Km. Similarly, with ATP as substrate Vmax was reduced by 33%. These results are compatible with a noncompetitive mechanism of inhibition. Discussion T'hese results are consistent with the interpretation that inhibitory effects of B on protein/peptide phosphorylation are not dependent upon specific substrate properties. In particular the effects of B appear not to depend on the charge of the consensus sequence, since B was as potent against the CK-2 peptide containing multiple aspartates as previously found with PKA and substrates containing arginines. It therefore appears likely that the inhibitory effects of B on protein/peptide phosphorylation reactions is related to properties of the protein kinases. B is known to bind to lysine, i.a. on albumin and ligandin. We speculate that B binding to lysine, an invariant presence in subdomain II of the protein kinase family, may be important for the effects of B on protein phosphorylation systems.

• Hansen, Thor Willy Ruud (1997). The clinical and pathological features of kernicterus and what we do to prevent it. Full text in Research Archive
• Hansen, Thor Willy Ruud; Roseth, Svein; Fonnum, Frode & Walaas, Sven Ivar (1997). Bilirubin inhibits glutamate and dopamine uptake in isolated presynaptic vesicles. Full text in Research Archive Show summary

  Bilirubin is a well known neurotoxic agent and has been shown to affect neurotransmitter metabolism in nerve terminals. However, the level and mechanism of such effects are not clear. Here we show for the first time that bilirubin (B) directly affects neurotransmitter metabolism in isolated presynaptic vesicles. Materials and methods: Presynaptic vesicles (PC) were isolated from rat brains by centrifugation in sucrose gradients. PV (0.02 mg protein) were preincubated for 15 min at 30C +/- B (0-100 micromol/L), followed by addition of either 1mM L[3H]glutamate (G) or 83 nM [3H]dopamine (D) with 2 mM ATP. Incubation was continued for 3 min and stopped by adding ice-cold 0.15 M KCl, followed by filtration through Millipore HAWP filters. These were washed again x2 with 0.15 M KCl before scintillation counting. Effects on delta-pH were investigatd by measuring the uptake of [14C]methylamine in the presence of 4 mM MgSO4, 140 mM KCl, 25 microM methylamine, 20 microgram PV protein, and 2 mM ATP. After incubation for 2-10 min at 30 or 0C (+/- 100 micorM B), the reaction was stopped by adding 0.15M ice-cold KCl. Non-specific uptake of methylamine was measured by adding 200 nM of the specific ATPase inhibitor Bafilomycin A. REsult: B inhibited vesicular uptake of both G and D starting at 75 micromol/L B (p<0.01). The uptake of methylamine was not affected by B. The efects of B on PV uptake of neurotransmitters disappeared when the amount of proetin in the incubate was quadrupled. Discussion: ÅPV uptake of neurotransmitters occurs through transport proteins in the vesicular membrane, and is driven iether by delta-pH (D) or the mebrane potential (G). The near identical effects of B on the uptake of these transmitters argues against direct effects on the membrane potential. The lack of B effects on methylamine uptake suggests that neither uncoupling of protons nor inhibition of ATPase are likely mechanisms for the B effect. Our data are therefore compatible with an interaction between B and transport proteins in the PV membrane. The ability to block B effects by increasing the protein:B ratio supports this interpretation.

• Hansen, Thor Willy Ruud (1997). P-glycoprotein and bilirubin in the brain - is there a connection? Full text in Research Archive
• Hansen, Thor Willy Ruud (1997). For mange nyfødte lysbehandles? Kanskje, og kanskje ikke! Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. p. 95–96. Full text in Research Archive Show summary

  FOR MANGE NYFØDTE LYSBEHANDLES? KANSKJE, OG KANSKJE IKKE! Alf Meberg beskriver de endringer han har foretatt i lysbehandlingsopplegget ved sin avdeling, og peker på betydelige ressursbesparelser som følge av dette. Dessverre er ikke disse besparelsene kvantitert, og er kanskje ikke så store hvis ikke avståelsen fra fototerapi samtidig var ledsaget av tidligere utskrivelse av mor/barn fra fødeavdelingen? Når man leser Meberg's innlegg kan man få inntrykk av at det sentrale pooeng i min artikkel (1) var å "peke på ... at for mange friske fullbårne barn lysbehandles for fysiologisk ikterus". Da må jeg dessverre ha uttrykt meg uklart, eller Meberg må ha lest min artikkel med selektive øyne. Det jeg trodde å ha påpekt, var at den store spredningen i behandlingsretningslinjer viser hvor utilstrekkelig vår kunnskap er. Jeg prøvde videre å argumentere for at nettopp denne mangelen på eksakt kunnskap gjorde det betenkelig å forandre etablerte retningslinjer ved dekret, snarere enn med basis i en vitenskapelig studie. Det er mitt klare inntrykk av at Dag Bratlid i sin lederartikkel støtter opp om nettopp dette synspunktet (2). De hittil mest brukte norske retningslinjer for fototerapi (som vel i parentes bør tilskrives Per H. Finne, og ikke Dag Bratlid) er i noen grad validert gjennom mange års bruk. Således er det såvidt jeg kjenner til ikke beskrevet tilfelle av kjerneikterus så lenge retningslinjene er fulgt. Med unntak av en studie av norske rekrutter, der det påvises en sammenheng mellom varighet av hyperbilirubinemi og nedsatt intelligens (3), er det imidlertid ikke utført studier i et norsk materiale som spesifikt undersøker på "myke" nevrologiske problemer eller adferdsmessige funksjonsforstyrrelser i relasjon til grad av ikterus. Inntil slike studier er utført, kan man derfor ikke engang med sikkerhet si at den praksis vi hittil har fulgt er trygg! I dette lys fortoner det seg betenkelig å innføre nye retningslinjer som innebærer høyere behandlingsgrenser fra de første levedøgn, og derfor potensielt lengre varighet av eksponering for høyere bilirubinverdier. Den andre grunnen til at jeg finner de endringene Alf Meberg har gjennomført i Tønsberg betenkelige, er at de innføres uten noen planer om en vitenskapelig kontrollert studie. Dette var nok gangbart da de opprinnelige norske retningslinjene ble innført, men burde ikke være det i dag når man tar i betraktning vår tids krav til bevisbasert medisin. Jeg har den største respekt for Alf Meberg, som er en av våre dyktigste og driftigste barneleger, men jeg er redd han denne gangen har hoppet på et tog som gikk forbi uten helt å ha oversikt over hvor reisen fører. I det norske barnemedisinske miljø er det Dag Bratlid og i all ubeskjedenhet undertegnede som har forsket seriøst på bilirubintoksisitet, i hvert fall i de siste par generasjoner. Som det vil fremgå av min artikkel (1) og av Bratlid's leder (2) er vi enige om å advare mot innføring av nye, uprøvede retningslinjer slik det nå skjer ved flere norske barneavdelinger. Det er interessant at disse advarslene overses eller bagatelliseres av såpass mange i det norske barnemedisinske miljø.

• Hansen, Thor Willy Ruud (1997). Mer lys? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 117, p. 411–411. Full text in Research Archive Show summary

  Mer lys? But what am I? An infant crying in the night: An infant crying for the light: And with no language but a cry. Alfred, Lord Tennyson, i In Memoriam, 1850 Kravet om "Mer lys!" skal ha vært Goethe's siste ord før han døde. Selv om man kanskje kan få inntrykk av det, ligger det ikke noe slikt krav bak mitt engasjement i denne saken, i hvert fall ikke noe krav om mer fototerapi. Det er forsåvidt heller ikke riktig at jeg "anbefaler" dagens norske retningslinjer for fototerapi. Snarere håper jeg det fremgår av min artikkel og mitt tilsvar til Alf Meberg's første innlegg at jeg uten videre erkjenner den tynne vitenskapelige bakgrunnen for disse retningslinjene. Jeg kan bare ikke se at det er noe fremskritt å hente et annet sett retningslinjer (med like tynt vitenskapelig underlag) fra en annen populasjon, uten å ha noen ambisjoner om å underkaste dette en kritisk vitenskapelig studie. På dette punktet får vi vel konstatere at Alf Meberg og jeg for tiden er enige om å være uenige på kollegialt vennskapelig basis. Men kanskje vi kunne bli enige om å legge opp til en studie der man fokuserte både på "harde" og "myke" bilirubin-sekveler? Det kunne kanskje resultere i retningslinjer med et mer solid fundament.

• Mreihil, Khalaf; Hansen, Thor Willy Ruud & Nakstad, Britt (2019). Phototherapy for Neonatal Jaundice. Studies of photoisomer formation and clinical practice. Reprosentralen, UiO. ISSN 9788283775068. Full text in Research Archive
• Hankø, Erik & Hansen, Thor Willy Ruud (2008). Bilirubin and Brain Toxicity. Universitetet i Oslo. ISSN 9788280727336. Full text in Research Archive Show summary

  Despite improvements in detection and treatment of neonatal jaundice, there has been an apparent resurgence of bilirubin-induced brain damage. Unresolved issues concerning bilirubin-induced brain damage include the mechanisms by which bilirubin enters the brain and the molecular mechanisms by which bilirubin exerts its toxicity. These issues were the basis for the experimental studies performed in this thesis in pediatrics. <br><br> In the first paper (paper I) we hypothesized that treatment with drugs known to inhibit the membrane transport protein phospho-glycoprotein (P-gp) would increase the entry of bilirubin into the brain of young adult Spraque-Dawley rats. In these in vivo experiments brain bilirubin content was examined after the iv injection of a P-gp inhibitor and bilirubin. In the remaining studies (paper II, III and IV) we used human NT2-N neurons to elucidate bilirubin-induced apoptotic and necrotic cell death in vitro. A specific caspase-3 inhibitor (zDEVD.fmk), a general caspase inhibitor (zVAD.fmk) and/or the NMDA receptor antagonist MK-801 were used to further explore the apoptotic cell death pathways involved. <br><br> We conclude that drugs known to inhibit P-gp increased the entry of bilirubin into the brain. We speculate whether such drugs may increase the risk of bilirubin-induced brain damage in newborns. Delayed apoptotic cell death predominated over necrotic cell death in human NT2-N neurons after exposure to low and moderate bilirubin concentrations. Both caspase dependent- and NMDA receptor mediated mechanisms, are involved in bilirubin-induced apoptosis. These mechanisms appear to be at least in part distinct, and concurrent inhibition of both pathways with a pancaspase inhibitor and MK-801 provided synergistic protection. Our results should encourage further studies to elucidate the nature of bilirubin-induced apoptosis in vivo.

• Hansen, Thor Willy Ruud (2003). Bruk av diagnose- og prosedyrekoder i nyfødtmedisinen - effekter av innsatsstyrt finansiering (ISF). Senter for helseadministrasjon. Full text in Research Archive
• Meberg, Alf; Bratlid, Dag; Cheetham, Nina Bøhle; Hansen, Thor Willy Ruud; Holt, Jan & Reigstad, Hallvard [Show all 10 contributors for this article] (2001). Nasjonal plan for nyfødtmedisin. Rapport fra et utvalg oppnevnt av Statens helsetilsyn på oppdrag fra Sosial- og helsedepartementet. [Mangler utgivernavn]. Full text in Research Archive

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