Journal of Peviatlogy (208) 28, 7-6 e 1 2088 Nav Paling Gr A gs red OS SHS $30 ORIGINAL ARTICLE Surfactants: past, present and future ‘HL Halliday'? ‘Department of Child Heath, Queen's University of Bef, Bla, Northern treland and “Perinatal Seine, Regional Neonatal Unit, Royal Maternity Hospital, Belfast, Northern feland |r 1929 Kurt von Neen pene experiments sagging the pases pulmonary surfactant ant is lexan te nebo’ fist beth Aims 25 yes ner, Richard Pate, jb Cements and Chris Mack, ce woking on the foc of nee son te ngs, cot othe Understanding ofthe pyslag of pulmonary surfactant, abot 5 yeas leer Mary Elen Ary and Jee Mead pulse camining evden that pee ness dhng of halle membrane dese (spiro srs syndrome, RDS) had 2 eng of pulmonary src. Theft of bull sytec (pre) scat to pret RDS wee pbb soon afer Patrick Bsier Kenny (sn of Preset Jehn F Kenna) de ‘ofthis serie fe matmen a son, Tse tals wee sucess were, Goran Enoming and gt Roberton in he ery 1975 dso hat natural satan containing pons) ete fit in mae rt motel of RDS, Soon afer his Fret Was shoe tha a natal srftant vas ako ete in an nme ab mel ‘Working ith him mas Testo Fjivar who 2 yeas a, ting sorta wok at pe by pl os he ange bt as ize messi nga mask, pang epson api culos © CPAP he shaved prone. Uta, dey of surah nebula fren ete, Siac eet ‘os fen na mud of been epic done bt nly fans wth meconium epi een ten aough ng an sor fut ese pry elt mate mgt ang fant, A suecan pol be upon ey veament nd PAP s ‘ops or oy ptr fins Ber ett my ip il rs fo ths ifn sever, 2 of neh praeee Als as of cna hng divas. Nverbves sui thy bas een amr contrition w ee the pee nes ding he pat 3 yn Journal of Perna O18 28, S47-S5; dot 101037920850 Keywords: surfactant: respirator dies stone; preterm infant hyaline membrane dase history, chronic hung dase ton, pas the enna arc eprint spars 10 prea infans wth RDS ts ofall evista. Ding he 985 ther wee ace nian bal sf may ile ata an yet sufi, destin eat nui sks snd ound moray. Suse natu surat woe be ‘spor the pee see pros Ree the eben a number ordi il cooing dent aur tic ution Connerly sain suns mey have sindar fica but ae sme ae tat a an ut wel wed ADS wih an inal e210 ig se cn than bovine suit ad in a ti dv of 1002 Boe and acne suas hae at en corn lf popilss Ye exy nee st sco with saat pin i as en compre her commerciale mural and tte sofas a, The ao ican may be se tan he er rtf see surat but de 0 ence os oper ir stl til plies a it ey at ap fr cel we. nun of ober nex siete suas he en etl animal modo in test of al th ARTS it Be thee Benno mos of nee of nal RDS. tr Pioneers of surfactant research Von Neergaard, Pattle, Clements and Macklin 1 have chosen 1929 as the stat date for tis presentation on the history of surfactant administration in the treatment of neonatal respiratory distress sdrome (RDS). in 1929 Kut von Neergaard, a Gennan-hom physiologist working in Switzerland, evacuated ait from an isolated porcine lang which he thn filed with an isotonic um solution ‘to eliminate surface tension ofthe artiste interfaces" Von Neergaard then performed pressure-volume curses during expansion ofthe hungs with air and tii, From these experiments he was able to conclude three things (2) "Surface tension is responsible forthe greater part of total ung, recoil compared to tse elastic. (2) °4 lower surface tension would be wsefl forthe respiratory mechanism because without it pulmonary retraction might, ‘acome so pret as to interfere with adequate expansion” and (3) ‘Surface tension as foree counteracting the first breath of the newly bom should be investigated further.” ‘spn Di al, el Vane, Roa Nay Ho, Gwen Ro lit 712 (4, rte le emi: hala ack Unfortunately, von Neergaanl didnot fllow his cm adhice so it was left to Peter Gruenwald, a pathologist in New York, toc Surfactants: past, present and future HL Halli repeat these experiments with the lungs of stillborn infants some 18 years later In 1947 Gruenwald stated “the resistance to aeration is due to surface tension which counteracts the entrance of air’ and he also showed that surface active subsancis reduced the pressure ned for lung aeration 11s perhaps noteworthy that Peter Gruenvald later taught Mary Ellen Avery, In the 1950s Richard Pattle (Figure 1) was working with nerve gases in England when he made an unexpected discovery. Pate wes a physicist working at « Ministy of Defence laboratory at Porton Dawn when he noted that nerve gases caused pollonary ‘edema foam in the rabbits he was studying. These bubbles remained stable for many hours. The usuel anioaming agents ‘were ineffective and Pattle surmised that ‘the air bubbles must be covered with a unique substance from the lining layers of the alveoli which made them so stable’ He also spectated that ‘absence of the lining substance may sometimes be one cf the difficulties with which a premature baby has to contend At almost the same time John Clements (Figure 2) working at the US Amy Chemical Center in Elgewood, Marland was performing quantitative studies using a modified Wilhelmy balance. Clements was a physiologist with no patcular interest in the respiratory system until he was assigned the task of finding cout how nerve gases damage the lungs. In 1957, he published an article reporting the surface tension of films from the lungs of rats, cats and dogs.’ Together with Chris Macklin, a pathologist working with phesgene in Canadian chemical warfare laboratories in 1954°” it is remarkable how they and Pattle came to the same conclusions independently and within a few months ofeach oer, Cleary some good came from studies in three countries of the adverse effects of nerve gases on the lungs. Avery and Mead The next step was to show that hyaline membrane disease (HMD) of the newborn was caused by abnormal surface tension in the Tangs. In the late 1950s May Ellen Avery (Figure 1) was esearch fellow in Jere Meads Inboratory in Boston with Clement Smith as her clinical supervisor. Mel Avery was so imprest with Clements 1957 article that she vised him in Edgewood to an more about the surface fim balance and adapt it to study extracts from the Tangs of infants who had died soon after bith. In 1959, along with Jere Mead, she published a seminal article demonstrating that FHMD, later known as RDS, was due to lack of sufactant® The lang of babies dying of MD had mean surface tension of about 30dmes om" compared to about 8dmes em" for those who died of other causes. Avery and Mead conludd “hyaline memirane disease s associated with the absence or the ate appearance of some sustances which inthe normal subject renders the intemal surface capable of attaining a low surface tension when the hang volume is decreased’ Despite knowledge ofthe cause of RDS ouraal of Perinaiooay Figure 1 fichan Patle and May Elen Avery IBA Foundation nxstng, 1968 Figure 2 jon Ceres early as 1958, progres in developing a cure was proceeing slowly ‘until a significant event took place. Patrick Bouvier Kenney, the son of President Jol F Kennedy and Jacqueline Bouvier Kennedy was born at 34 to 35 weeks’ sgstation on 7 August, 1963. His birth took place in Ots Air Fore Base Hespital following an emergency Cesarean section and he weighed. about 1860 . Soon alter bint he was transfered toFigure 3 Pick Hennal’s deat 1965 pla he splight on rspneoy dss syne (RDS), Boston Children’s Hospital where he did 2 days Inter of HMD (Figure 3) An obituary in the New York Times noted that at that time all that could be done for vietim of hyaline membrane disease is to monitor the infant's blood chemistry and 0 try to beep it near normal levels. Thus, the battle for the Kennedy baby was lost only because medical sence has not yet advance far enough to accomplish as quickly as necessary what the body could do by isl in is ov time,’ Patrick Kennedy’ death from HAD increased public awareness of the disease and stimulated further esearch into is treatment. Within a. ew years two trials reporting the use of synthetic surfactants to treat RDS had been published” First synthetic surfactant trials Unfortunately, the results of these studies were largely negative both had used nebutizddipalmitoyphosphatidlchotine (DPPC), and there were no disaemible beneficial clinical eflects.™ The results of the study by Jacqueline Chu ef af," conducted in ngapore, kt the suhors so disilusioned that they enti article ‘Neonatal Pulmonary Ischemia’ implying that the underlying cause of RDS was law pulmonary blood flow than a primary surfactant deficiency, We know now that phespholipids lower surface tension on their own otto, but they need proteins to allow the rapid spreading and adsorption that are necessary for efficacy ft vo. Furthermore, nebulization is not an effective method of delivering surfactant to the always Animal studies with natural surfactants few yeas later in Stockholm, Goran Enhoming, an obstetrician, and Beng! Robertson, pediatric pathologist (Figure 4), showed that preterm rabbits treated with natural surfactant didnot die as expected soon aler birth." After one year Later, in 1973, they showed that pharyngeal deposition rather than trachea instillation of natural surfactant was also effective" and more than 30 years Surlaants:ps, present and future pare & igure 4 (a) Goran Enoming (sti). (9) Beng Roberson (pint potholes) Ie, this is stil not an established method of surfactant administration in the newbor. Aer 5 years Forest Adams and his colleagues in California demonstrat the beneficial effets cf 2 natural bovine surfactant on the lungs of preterm lambs" One of his co-authors was Tetsuro Fujisara from Japan who ams’ laboratory in Califomia was then working in First clinical trials with a natural surfactant Before Adams could hegin studies with human babies, Fujiwara hhad retumed to Japan and in 1980 published a seminal article in the Lancet giving the results of administration of modified bovine surfactant (Surfactant-TA) to 10 preterm infants Fujiwara’ infants were relatively mature with a mean gestation of about 30 weeks and a mean birth weight of over 1500 g, Within a short time the mean arterial oxygen tension had increased from about 45torr to 210 torr (Figure 5) and chest radiographs also improve!” Nine ofthe 10 infants developed patent ductus “Journal of Periatoley