DOI: 10.1542/neo.11-11-e613 2010;11;e613-e618 NeoReviews

Gorm Greisen of Neonatology

Historical Perspectives: Perinatal Profiles: Bent Friis-Hansen: A Danish Pioneer

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The Underpinnings ofNeonatal/Perinatal Medicine

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Perinatal Profiles: Bent Friis-Hansen:A Danish Pioneer of NeonatologyGorm Greisen, MD*

IntroductionBent Julius Friis-Hansen was theprime mover in developing neonatol-ogy as a pediatric field in Denmarkstarting in 1964. He had been a co-founder of the European Club ofPediatric Research in 1959, whichevolved into the European Societyfor Pediatric Research. He and hisAmerican colleagues Leo Stern andlater William Oh led the Interna-tional Perinatal Collegium, an infor-mal group of pioneers from bothsides of the Atlantic, through a seriesof biannual meetings from 1971 un-til he retired in 1990. (1)

An Immature andRebellious BoyFriis-Hansen was born in 1920 inSvendborg, a small town in SouthernFunen. The primary income of thetown came from shipping, and allfamilies had fathers and brothers onthe high seas. When the young Bentand his older brother were in kinder-garten, the woman who taught themto write decided that they should bein primary school, in grades 2 and 3,respectively. At that time, Bent wasonly 5 years old. He later wrote thathe probably was too immature for hisclass, which was the reason why hehad frequent conflicts with teachers.His dyslexia and problems with read-ing also may have contributed. Heoften shirked school, preferring thefree life of a young boy to school-work. When he started high school,staying quiet in class still was a prob-lem for him. His father died when hewas 16, and his mother and elder

brother moved to Copenhagen. Heremained in Svendborg, living withfriends of the family for the last yearof his high school. He wrote that theconflicts with teachers persisted. Al-though the head master often threat-ened to expel him from school, hegot his certificate, joined his motherin Copenhagen, and started thestudy of medicine.

To make it to his last examinationin January 1945, he missed a meetingof the resistance group of which hewas a member. Leaving the examina-tion room, he received a messagethat the Gestapo of the German oc-cupation forces had been informedabout the group and had taken themto prison. Four of them were laterexecuted. Friis-Hansen lived undercover until the liberation of Denmarkin May 1945.

Rapidly Into ResearchThe first year of clinical practice wasspent in Kolding, Western Denmark,doing internal medicine and surgery.Friis-Hansen already was engaged inresearch, publishing first on glucosetolerance of partially hepatectomizedrabbits, then on glucose tolerance inartificial diphtheria toxemia. Oneevening, a newborn was brought inwho had been found on the railwaytrack, presumably having been de-livered on the toilet of the train andfallen directly onto the tracks. Themother was found and reunited withher child. Friis-Hansen cited this eventas one of the sources for his life’swork in neonatology.

Back in Copenhagen and workingin the medical department of Fred-eriksberg Hospital, he published ongastric acid production after hista-

*Department of Neonatology, Rigshospitalet andUniversity of Copenhagen, Copenhagen, Denmark.

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mine stimulation in 12 febrile adultpatients in the ward. Perhaps becauseof his talent and energy and perhapsbecause of his service in the resistanceduring the war, the professor of sur-gery at Rigshospitalet, Erik Husfeldt,who himself had played a central rolein the resistance movement, medi-ated a contact with a blood bank inBoston. While Friis-Hansen preparedhimself by reading everything hecould find on blood transfusions, hewas informed that they had foundan American who, as Friis-Hansenwrites in his autobiography, hope-fully was a better qualified physician.As an alternative he was invited tojoin the team of the newly appointedprofessor in surgery at the Peter BentBrigham Hospital in Boston, the32-year-old Francis D. Moore. Friis-Hansen borrowed money and leftDenmark. On his arrival in Boston,he obtained a fellowship from theAmerican-Scandinavian Foundationand worked from 1948 to 1950 as aresearch fellow in surgery at Harvardin Dr Moore’s laboratory.

Happy Postwar Daysin BostonMoore was a pioneer, using the newadvances of the physical sciences thathad produced radioactive isotopes ofhydrogen, sodium, and potassium.These achievements had made it pos-sible to study the fluid spaces of thehuman body in health and disease.Moore was particularly interestedin burns, but his laboratory hostedyoung researchers from many coun-tries who used this new methodologyin other applications. Moore wasan extraordinary leader. He had re-ported measurement of total bodywater using the indicator dilutionprinciple and intravenous adminis-tration of the nonradioactive isotopeof deuterium in the form of heavywater in Science in 1946. Moore hadshown that equilibrium takes place

within 1 hour. Moore also was agood host to a young and somewhatmiserable stranger from postwarDenmark. It became a happy time.

Heavy WaterFriis-Hansen joined a team of youngcolleagues who refined the fallingdrop method to measure the relativeabundance of heavy water. In princi-ple, a small drop of water obtained bydistillation of a sample of blood wasallowed to fall through a carefullytemperature-controlled column ofo-fluoro-toluene (Fig. 1). The grouprefined the method to an astonishingprecision of 0.0012 vol% deuterium/normal water in a blood sample of150 to 200 mL. (2) Bent Friis-Hansen’s wife once told me, how-ever, that this was not easy; one late

night, the instrument was thrownthrough the window into the street.

Friis-Hansen studied inpatients inthe Children’s Hospital in Boston,(3) and after his return to Copen-hagen, he studied inpatients first atRigshospitalet during his years as aresearch fellow of the professor ofpediatrics at Rigshospitalet, PrebenPlum, and later in Queen Louise’sChildren’s Hospital as “reservelæge”with professor Oluf Andersen. Themeasurements of deuterium in Co-penhagen were carried out at the de-partment of biologic isotope researchat the Institute of Zoophysiologyheaded by Professor Hans Ussing.The money for the very expensivedeuterium came from many sources.This work led to six publications anda Doctor of Medical Sciences thesis

Figure 1. The instrument used for determining the deuterium concentration in bodyfluids. By turning the handle from S1 to S2, a well-defined volume is pressed throughthe glass tubing and a small drop is formed at the end H. The rate of falling of the dropin the cylinder with o-fluoro-toluene is proportional to gravity, and gravidity isproportional to the concentration of heavy water. Reprinted with permission fromKeston et al. J Bio Chem. 1938.

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in 1956. Before, the only data avail-able had come from desiccation ofdead human fetuses and a few deadnewborns. Friis-Hansen showed thatthe total body water decreases from79% on the first day after birth to 58%at puberty. These numbers fit in per-fectly with desiccation data from thefetus and in vivo studies in adults(Fig. 2). He also showed that thedecrease in total body water is exclu-sively due to a decrease in extracellu-lar water, whereas intracellular wateris nearly constant from birth to pu-berty. These conclusions are still valid.Friis-Hansen was a tall man, and hisfriend and coauthor, Jørgen Vesterdal,later told me that often during thoseearly years, Friis-Hansen’s head disap-peared in clouds of heavy water.

Africa and NutritionIn 1957, Friis-Hansen again con-tacted Husfeldt. Husfeldt was bornin Indonesia, and after the war, hehad considerable international activ-ity based at the school of anesthesiaand intensive care in Copenhagenthat had been developed during thepolio epidemic during which hundredsof paralyzed patients were manuallyventilated until recovery. Husfeldthad become a World Health Organi-zation (WHO) advisor. Friis-Hansenwanted to go the Far East, but Hus-feldt advised him to go to Africa asan expert in nutrition. Friis-Hansensaid that he was not interested inAfrica and that he was not an expertin nutrition. Husfeldt told him thatnutrition was easy to learn and thatAfrica was unknown and, therefore,twice as interesting.

Friis-Hansen spent 1 year in theNorthern province of Northern Rho-desia (now Zambia) with a Scottishparasitologist, Fergus McCullough.He found widespread symptoms ofvitamin A deficiency in children (4)and devised plans for interventions.He wrote that the plans were lost

during the process of independencein the following years, but he re-mained active for WHO in childhoodnutrition, and Africa stayed in hismind.

The Neonatal Intensive CareUnit at RigshospitaletProfessor Trolle at the department ofobstetrics and professor Plum at thedepartment of pediatrics at Rigshos-pitalet in Copenhagen had agreedthat a dedicated person was neededto develop the new field of neona-tology. Thus, a department with aseparate medical and nursing staffand a separate budget was estab-lished in 1964, with Friis-Hansenas the head.

Rigshospitalet at the time was

state-owned and had a particular re-sponsibility for research and develop-ing highly specialized care for thesmall Danish nation (population:5 million). At the time, it had beenonly 54 years since Rigshospitalethad introduced the first pediatrichospital department in the country,and it was only during the preceding10 years that the country’s regionalhospitals had developed pediatric de-partments of their own.

Developing neonatology requiredpractical sense. Dr R. Cooke fromSouth Africa helped to start intensivecare of newborns and, in particular,mechanical ventilation. In 1967, thegroup first published the results ofassisted ventilation in 14 babies of28 to 37 weeks gestational age in

Figure 2. Total body water and intracellular and extracellular water during childhood.Each point represents the data from clinical investigation of a child admitted to thehospital in Boston or Copenhagen. The fetal values were taken from the literature andrepresent averages obtained by desiccation of dead fetuses. Reprinted with permissionfrom Friis-Hansen B. Changes in body water compartments during growth [thesis].Acta Paediatr Suppl. 1957;46(suppl 110):1–68.

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which 5 babies survived. (5) Friis-Hansen wrote: “No definite criteriawere used in the selection of infantsfor artificial ventilation. Initially, onlythose infants that were clinically mor-ibund and in gross respiratory andcirculatory collapse, were subjectedto this treatment.” The inspiratorypressures used ranged from 15 to40 cm H2O, and often negative pres-sure was used during expiration “toovercome the resistance in the nar-row naso-tracheal tube.” In an ad-dendum, he wrote, “Since the com-pletion of this study a further 18infants have been treated on the res-pirator with 9 survivals. The lowestweight of an infant that survived thetreatment being 1120 g.” The sur-vival rate for such babies only im-proved slightly (Table 1), untilGeorge Gregory presented his resultsusing continuous positive airwaypressure (CPAP) delivered by endo-tracheal tube at the InternationalPerinatal Collegium in August 1971.This principle was rapidly adopted atRigshospitalet, and results improved(Table 2). Soon, a high degree ofcentralization of preterm deliveriesto Rigshospitalet from all of EasternDenmark was achieved. Jens Kamperworked with Friis-Hansen in thisearly period, (6) published severalpapers, and wrote his thesis on treat-

ment of respiratory distress. Jens Ka-mper later moved to Odense, wherehe developed the “Scandinavian” ap-proach with early nasal CPAP.

The Family-orientedApproach“They pass the main entrance andthrough a wide door. It says ‘NEO-NATAL UNIT no admittance’. Thenthey now are in a small, warm passage.On one side is a kitchen, where a bigwoman is cleaning bottles, on the otherside are two narrow doors, each onewith a small glass window. Marie seesthat one leads to the unit with cots fornewborns and that the other leads tothe incubators.

“Marie and the nurse face astranger.

“Here we have a small one, threedays old, dehydrated with elevated bil-irubin.”

“Well yes, we will take care of that.”“The child disappears through the

door to the unit with cots. The doorcloses. After a moment Marie gets areceipt, a scrap of paper, a stencil thatreads:

“To Mrs—the word Nansen isadded in pencil—Your baby is nowadmitted to dept. GN, and has beengiven number GN 29—the number iswritten by hand—The children are ondisplay for you every day from 11.30 to12.00 AM. Furthermore the child maybe seen by the next of kin the first30 minutes of the visiting hours. En-

quiries by telephone are answered everyday between 8 AM and 8 PM. With kindregards.

“To Mrs Nansen it says. Her nameis Hansen—well, that does not matter.The nurse makes a sign, they musthurry back, there is nothing more to dohere. Marie gives her long stockings apull and silently they move as shadowsthrough the long white tubes back to thepost-natal ward.

“Marie tells herself again andagain that this is best as it happened.The responsibility had become tooheavy.

“But she cannot rid herself of thethought that she carries a small certif-icate of death in her pocket.” (FromWinter’s Children by Dea TrierMørch, 1976—my translation).

This book was one of the roots ofchange. The psychologists GrettyMirdal and Hanne Munch, both in-terested in parent-child interaction,became agents of change. Friis-Hansen invited them into the unitfor their fieldwork and by his respect-ful curiosity and openness, earnedtheir affection. The head nurse,Gerda Christensen, and later LonePetri and Jean Paul Guilbert all tookthese ideas further to what is now aculture of care.

Brain DamageWith rapidly evolving neonatal inten-sive care allowing survival of ever-smaller babies, the problem of brain

Table 1. MechanicalVentilation ofNewborns*

Birthweight (g)Survivors/Total Infants

<1,000 1/31,001 to 1,500 4/221,501 to 2,000 7/292,001 to 2,500 16/292,500 23/45Total 51/128

*Department of Neonatology at Rigshospi-talet until 1969

Table 2. The Effect of Introducing CPAP/PEEP byEndotracheal Tube

April 1966 toAugust 1971

August 1971 toAugust 1972

August 1972 toJune 1973

Number of infants 193 59 56CPAP/PEEP (%) 0 80 100Mortality (%) 61 51 23

CPAP�continuous positive airway pressure, PEEP�positive end-expiratory pressure

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injury and survival of handicappedchildren became a prime concern forFriis-Hansen.

Niels A. Lassen had measured ce-rebral blood flow (CBF) in adult pa-tients with radioactive krypton in1955 and with xenon in 1965, andCopenhagen was an internationalcenter for CBF research. Hans C.Lou had interest in pediatric neurol-ogy and was newly employed in thedepartment of neonatology when hereported CBF data in eight newbornswith Lassen and Friis-Hansen in1977. (7) The article focused on thesurprisingly low values of CBF,which were as low as 20 mL/100 gper minute, less than one third ofnormal adult values and much lessthan the values routinely obtained innewborn lambs, the most popularanimal model in perinatal research atthe time. A link was made to the lowsystolic blood pressure. In the nextarticle, data from 19 newborns wereincluded, (8) and the correlationbetween CBF and blood pressurebecame highly significant. The focusin this article was on the impair-ment of autoregulation and the riskof hypertension-induced cerebralhemorrhage. This shift in focus wasdue to the fact that intraventricularhemorrhage (IVH) was “put onthe agenda” by the publication byLu Ann Papile in 1978, which de-scribed detection of IVH by com-puted tomography scan. It had comeas a great surprise to most neonatol-ogists that 40% of all very low-birthweight infants developed IVHand that most were asymptomaticand survived.

Rigshospitalet had an obstetric ul-trasonography unit where Jens Banghad performed the first intrauterinetransfusions. Friis-Hansen proposedthat I borrow their equipment andtry it for diagnosing IVH by cranialultrasonography. There I was in 1980,6 months after my entry into the

unit, starting a prospective study onIVH. In 1982, he took me in as hisresearch fellow, partly because I had abachelor’s degree in computing,useful in taking the CBF studiesfurther.

During these years, the intentionin the unit was to aim for slight hy-perventilation for preterm infants tostabilize autoregulation and protectagainst IVH. (9) Many years later,years after Friis-Hansen was pen-sioned, data from the regional regis-try of cerebral palsy showed that thisgood intention had caused a localepidemic of cerebral palsy in very pre-term infants, (10) another exampleof the risks of ambitious neonatol-ogy.

MentoringIn addition to Jens Kamper, Friis-Hansen also mentored Gunnar EgAndersen, who did his thesis workon screening for familial hypercho-lesterolemia; Peter Wimberley, whoworked on hemoglobin F-oxygenbinding; myself on cerebral bloodflow; Ole Pryds also on cerebralblood flow; and Lotte Skov on cere-bral near-infrared spectroscopy.Furthermore, Henrik Sardemannand May Olufson published manyarticles on the infants of drug-addicted mothers, Finn Ebbesen onhyperbilirubinemia, Henrik Verderon prediction of respiratory distresssyndrome, and Jens Hertel on themetabolic response of diabeticmothers.

Bent Friis-Hansen had a goodsense of humor and was a good men-tor. Once asked how he could keepyoung researchers moving, he an-swered that he didn’t know becausehe found it difficult to keep movinghimself. He was inspiring, not direc-tive. He would quietly lead the wayby questions.

The Tough Piece of ToffeeA requirement for providing up-to-date neonatal care was to be able toimplement the many medical andtechnological advances of neonatol-ogy, which required funding. The100% public hospital sector in Den-mark was run extraordinarily re-strictively during the 1970s and1980s. This led to an overall set-back in health-care spending inDenmark from being on the top inEurope to sinking to the bottom.Friis-Hansen managed to maintainand improve economic support.His wife compared his strategy to-ward hospital directors to chewinga tough piece of toffee: “Chew,wait, and chew.”

A Final Word on His PortraitFriis-Hansen’s portrait was paintedwhen he retired at 70 years of age(Fig. 3). At this age, he was markedby Parkinson disease and macular de-generation, two illnesses that af-fected him increasingly for the 12years until his death in 2002. Thepainting depicts his facial expressionvery well: distant and respectful butcurious. Friis-Hansen was not well-liked by medical students. They did

Figure 3. Bent Julius Friis-Hansen.A portrait by Viggo Kragh Hansen, 1980.

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not easily understand him. His ques-tions at examinations were feared.However, his younger colleagues, aswell as other staff, were affectionatetoward him.

Despite his illnesses, he grew oldin a way that one could only respectand admire. He was cared for until hedied by his wife Bente in their oldhouse and beautiful garden north ofCopenhagen. When I visited himduring his last years, he would pa-tiently, but not too attentively, listento my explanations and then ask thecentral question. A long series ofDanish pediatricians will pause whenhis name is mentioned and feel grate-ful, and he won many friends abroad.

References1. Swyer PR. The international perinatalcollegium: an historical overview. SeminPerinatol. 1996;20:162–1632. Schloerb PR, Friis-Hansen BJ, EdelmanIS, Solomon AK, Moore FD. The measure-ment of total body water in the human subjectby deuterium oxide dilution; with a consider-ation of the dynamics of deuterium distribu-tion. J Clin Invest. 1950;29:1296–3103. Friis-Hansen BJ, Holiday M, StapletonT, Wallace WM. Total body water in chil-dren. Pediatrics. 1951;7:321–3274. Friis-Hansen B, Mc Cullough F. VitaminA deficiency in African children in NorthernRhodesia. J Pediatr. 1962;60:114–1215. Cooke R, Friis-Hansen B, Lunding M.Respiratory failure in the newborn. ActaPaediatr Scand. 1967;56:498–5086. Kamper J, Baekgaard P, Peitersen B,Christiansen PM, Tygstrup I, Friis-Hansen

B. [Treatment of respiratory distress syn-drome with continuous positive airwaypressure]. Ugeskr Laeger. 1973;135:2207–22117. Lou HC, Lassen NA, Friis-Hansen B.Low cerebral blood flow in hypotensiveperinatal distress. Acta Neurol Scand. 1977;56:343–3528. Lou HC, Lassen NA, Friis-Hansen B.Impaired autoregulation of cerebral bloodflow in the distressed newborn infant. J Pe-diatr. 1979;94:118–1219. Lou HC, Phibbs RH, Wilson SL, Greg-ory GA. Hyperventilation at birth may pre-vent early periventricular haemorrhage.Lancet. 1979;8286:140710. Topp M, Ulldall P, Greisen G. Cere-bral palsy births in Eastern Denmark1987–90: implications for neonatal care.Paediatr Perinatol Epidemiol. 2001;15:271–277

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DOI: 10.1542/neo.11-11-e613 2010;11;e613-e618 NeoReviews

Gorm Greisen of Neonatology

Historical Perspectives: Perinatal Profiles: Bent Friis-Hansen: A Danish Pioneer

 

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