Development of the Reflux Finding Score for Infants

and Its Observer Agreement

Rachel J. van der Pol, MD1, Maartje M. J. Singendonk, MsC1, Astrid M. K€onig, MD, PhD2, Hans Hoeve, MD, PhD3,
Quinten Kammeijer, MD2, Bas Pullens, MD3, Erik van Spronsen, MD, PhD2, George Thomas, MD, PhD2,
Lenka Vermeeren, MD, PhD2, Marc A. Benninga, MD, PhD1, and Michiel P. van Wijk, MD, PhD1

Objective It is hypothesized that laryngeal edema is caused by laryngopharyngeal reflux (LPR) (ie, gastroesoph-
ageal reflux extending into the larynx and pharynx). The validated reflux finding score (RFS) assesses LPR disease in
adults. We, therefore, aimed to develop an adapted RFS for infants (RFS-I) and assess its observer agreement.
Study design Visibility of laryngeal anatomic landmarks was assessed by determining observer agreement. The
RFS-I was developed based on the RFS, the found observer agreement, and expert opinion. An educational tutorial
was developed which was presented to 3 pediatric otorhinolaryngologists, 2 otorhinolaryngologists, and 2 gastro-
enterology fellows. They then scored videos of flexible laryngoscopy procedures of infants who were either diag-
nosed with or specifically without laryngeal edema.
Results In total, 52 infants were included with a median age of 19.5 (0-70) weeks, with 12 and 40 infants, respec-
tively, for the assessment of the laryngeal anatomic landmarks and the assessment of the RFS-I. Overall interob-
server agreement of the RFS-I was moderate (intraclass correlation coefficient = 0.45). Intraobserver agreement
ranged from moderate to excellent agreement (intraclass correlation coefficient = 0.50-0.87).
Conclusion A standardized scoring instrument was developed for the diagnosis of LPR disease using flexible
laryngoscopy. Using this tool, only moderate interobserver agreement was reached with a highly variable intraob-
server agreement. Because a valid scoring system for flexible laryngoscopy is lacking up until now, the RFS-I and
flexible laryngoscopy should not be used solely to clinically assess LPR related findings of the larynx, nor to guide
treatment. (J Pediatr 2014;165:479-84).

L
aryngomalacia is the most common congenital anomaly of the larynx accounting for over 60% of all noninfectious stri-
dors in infancy.1 In infants with laryngomalacia, laryngeal edema is frequently seen during laryngoscopic examination. It
is commonly thought to be the result of gastroesophageal reflux (GER) extending into the larynx and pharynx: laryng-
opharyngeal reflux (LPR).2-6 However, evidence for this causality is lacking. It is hypothesized that a partial obstruction of the
airway because of laryngomalacia causes a negative intrathoracic pressure, facilitating LPR to occur, which in turn causes laryn-
geal edema. This subsequently leads to a vicious circle of increased obstruction, more LPR, and edema.7
In adults, LPR can reliably be detected using flexible laryngoscopy and a validated reflux finding score (RFS).8 In children,
evaluation of the larynx with flexible laryngoscopy might be hampered by the smaller anatomic landmarks and smaller endo-
scopes with lower image resolution. Furthermore, reflux patterns in infants differ significantly from those in adults as a result of
different feeding patterns and posture. In infants, common endoscopic findings suggested to be LPR-related are edema and
erythema of the arytenoids, postglottic and vocal fold edema, and erythema.9 Despite the abovementioned differences between
adults and infants, no specific scoring instrument exists for this age group.
Based on medical history, physical examination, and laryngoscopic findings, proton pump inhibitor (PPI) therapy is
commonly initiated when LPR-related laryngeal edema is suspected to be the cause of symptoms.10,11 Contrary to adults,
however, PPI therapy has been proven ineffective for classical GER symptoms in infants such as regurgitation and excessive
crying and are, thus, not approved by the Federal Drug Administration.12 Furthermore, no evidence is available for their
use in LPR-related symptoms in infants.
The aim of this study was to develop a scoring instrument to evaluate signs of LPR seen on flexible laryngoscopy in infants,
the RFS for infants (RFS-I) and to assess its inter- and intraobserver agreement.

From the 1Department of Pediatric Gastroenterology and

Nutrition, Emma Children’s Hospital, 2Department of
Otorhinolaryngology, Academic Medical Center,
GER Gastroesophageal reflux Amsterdam, The Netherlands; and 3Department of
ICC Intraclass correlation coefficient Otorhinolaryngology-Head and Neck Surgery, Erasmus
Medical Center, Rotterdam, The Netherlands
LPR Laryngopharyngeal reflux
The authors declare no conflicts of interest.
PPI Proton pump inhibitor
RFS Reflux finding score 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc.
RFS-I RFS for infants All rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2014.05.022

479
THE JOURNAL OF PEDIATRICS  www.jpeds.com
Methods
For the development of the RFS-I and the observer agreement
of the RFS-I, we randomly selected 52 infants under the age of
18 months from a database of laryngoscopic procedures per-
formed in the otorhinolaryngology department of the Aca-
demic Medical Center Amsterdam between 2006 and 2010.
For the development of the established RFS-I, 12 infants
without evidence of LPR-related laryngeal findings during
clinical flexible laryngoscopy were selected. To evaluate inter-
and intraobserver agreement of the RFS-I, 20 additional in-
fants with reported flexible laryngoscopy evidence of LPR
and 20 additional infants without any reported pathologic
findings were selected. Patients were excluded if 1 of the
following conditions were present: history of malformation
of the esophagus and/or history of surgery of the gastrointes-
tinal or pulmonary tract. The study was approved by the
medical ethics committee of the Academic Medical Center,
Amsterdam.
Development of the RFS-I
First, we selected anatomic landmarks (Figure 1) that could
potentially be included in the RFS-I. In patients without any
reported abnormalities during the original flexible
laryngoscopy, we evaluated the viability of the laryngo-
scopic detection of these landmarks by assessing inter- and
Figure 1. Anatomic landmarks (1 = epiglottis, 2 = aryepiglot-
tic fold, 3 = cuneiform cartilages, 4 = vocal cords, 5 = aryte-
noids, 6 = postcricoid region, 7 = piriform sinus).
480
Vol. 165, No. 3
intraobserver agreement. Two experienced pediatric
otorhinolaryngologists and 1 otorhinolaryngology resident
reviewed the anonymized video clips. Reviewers performed
their analysis blinded from symptom presentation and
independently from each other. Both visibility and aspect
of the selected landmarks were assessed. To determine
intraobserver agreement, all reviewers performed a second
evaluation of the video clips with a minimum interval of at
least 2 days after the first analysis. For intraobserver
agreement, the mean of the intraobserver scores of the 3
observers was used. The visibility of a specific landmark
was arbitrarily scored as ‘good’ if at least 1 of the inter- or
intraobserver scores, ranged between 0.61 and 1.00, and the
other accompanying inter- or intraobserver score was at
least 0.35. Landmarks were considered to be ‘fair to
moderate’ when both inter- or intraobserver score ranged
between 0.35 and 0.60. Values lower than those mentioned
above were considered invalid. Second, based on expert
opinion on pediatric laryngoscopy and based on items that
were included in the original RFS, items for the RFS-I were
selected.
Inter- and Intraobserver Agreement of the RFS-I
The 40 selected laryngoscopy video clips were scored by 3 pe-
diatric otorhinolaryngologists, 2 general otorhinolaryngolo-
gists, and 2 gastroenterology fellows (group 1, 2, and 3,
respectively) from 2 different centers. The participants were
first presented an educational tutorial that explained the
scoring items of the RFS-I and showed static images of all
different scoring options per scoring item. Next, reviewers
were presented the video clips in a randomized order. All re-
viewers evaluated these video clips independently, blinded
for the patient’s clinical profile and findings during the clin-
ical flexible laryngoscopy. In order to evaluate intraobserver
agreement, all reviewers were asked to perform a second rat-
ing of the laryngoscopic video clips at least 2 days after their
first assessment. Finally, observers where asked for comments
on video quality and any other comments they might have
after completing their review.
Statistical Analyses
Data were analyzed using IBM SPSS Statistics 19 (SPSS Inc,
Armonk, New York). For the analysis of the development
of the RFS-I, inter- and intraobserver agreement was deter-
mined for all selected landmarks using Fleiss kappa (kappa
further annotated as k). For the RFS-I, inter- and intraob-
server agreement was determined per scoring item of the
RFS-I and for all scoring items combined. For categorical
data, inter- and intraobserver agreement was calculated using
Cohen k (2 observers) and Fleiss k (>2 observers). For ordinal
data, weighted k and the intraclass correlation coefficient
(ICC) were used. Fleiss k was calculated by using a pre-
made syntax for SPSS (available from corresponding author).
For the assessment of the inter- and intraobserver agreement
of the RFS-I, we applied the arbitrary but common scale for k
and ICC values: 0.00 = no agreement, 0.01-0.20 = slight
agreement, 0.21-0.40 = fair agreement, 0.41-0.60 = moderate
van der Pol et al
September 2014 ORIGINAL ARTICLES

agreement, 0.61-0.80 = substantial agreement, 0.81-
0.99 = excellent agreement, and 1.00 = perfect agreement.
A k between 0.6 and 1.0 was considered to be valid for use
in research settings and/or clinical practice.
Results
Development of the RFS-I
The process of developing the RFS-I is shown in Figures 1
and 2. The first step in the development of the RFS-I was
the assessment of the anatomic landmarks, which showed
good visibility of the aryepiglottic fold and vocal cords.
The second step in the process of the development of the
RFS-I consisted of the selection of items based on the
items included in the original RFS, the visibility scores as
reported in Figure 2, and expert opinion. Vocal fold
edema is one of the adult RFS items. Based on expert
opinion, this was translated to visibility of the vocal cords
and was included in the RFS-I as such. Although the
aryepiglottic fold was scored to have good visibility, it was
not included in the RFS-I because it is not used in the
original RFS and was not considered discriminative for
laryngeal edema by expert opinion. Diffuse laryngeal
edema and endolaryngeal mucus, both items on the
original RFS, were selected by expert opinion and
included in the RFS-I. Other items on the adult RFS were
discussed, yet not included in the RFS-I because these
items would be too difficult to assess and/or they are
absent in infants with and without laryngeal edema.
Table I presents all items of the RFS-I, resulting in a total
RFS-I score ranging from 0-8.
Patients
Of the 52 included infants (median age: 19.5 [0-70] weeks),
indications for flexible laryngoscopy were stridor (75%),
obstructive sleep apnea syndrome, apparent life threatening
events, and swallowing problems. Age and sex were equally
distributed in the 2 groups. Inter- and intraobserver agree-
ment was not influenced by previous diagnosis of LPR on
the initial clinical flexible laryngoscopy.
Interobserver Agreement of RFS-I
All interobserver agreement data are shown in Table II. The
overall interobserver agreement of the total RFS-I score was
moderate (ICC = 0.45). Highest agreement was reached for
the visibility of the vocal cord (k = 0.44) and fair agreement
was reached for the presence of erythema or laryngeal edema
(k = 0.28) for all observers. The observers in group 3
showed highest interobserver agreement (ICC = 0.63).
Intraobserver Agreement of RFS-I
All intraobserver agreement data are shown in Table II.
Overall intraobserver agreement of the total score of the
RFS-I ranged from moderate to excellent (ICC = 0.42-0.87)
between the 3 groups. Agreement per scoring item showed
a wide variation between observers (k = 0.13-1.00).
Intraobserver agreement on all scorings items was
consistently highest in group 2.

Figure 2. Flowchart of development of the RFS-I. The left panel depicts the scores of the observer agreement of the anatomic
landmarks of the larynx. In the right panel the items of the RFS are presented. Based on the visibility of the anatomic landmarks of
the infant larynx and the adult RFS items for the RFS-I were selected through expert opinion.

Development of the Reflux Finding Score for Infants and Its Observer Agreement 481
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 165, No. 3

gists and gastroenterology fellows. It does show, however,

Table I. Scoring items of RFS-I
Findings Score
Erythema and laryngeal edema 0 = absent
2 = postcricoid region
4 = diffuse
Vocal cord visibility 0 = absent
2 = present
Endolaryngeal mucus 0 = absent
2 = present
Quality Assessment
Observers where asked for their comments after completing
their reviews. On quality of video clips, a median of 4 (1-
17) video clips where scored as being of ‘bad quality’ and
21 (11-24) video clips of ‘moderate quality.’ By the observers,
the poor quality of video clips was most often thought to be
inherent to flexible laryngoscopy. Despite the tutorial, ob-
servers mentioned having difficulties interpreting the scoring
item ‘endolaryngeal mucus.’
Discussion
To date, no gold standard exists for the detection of LPR dis-
ease in infants, and this is the first study attempting to find an
objective diagnostic tool. As flexible laryngoscopy is
commonly used to diagnose LPR disease in a clinical setting,
we developed a score for flexible laryngoscopy: the RFS-I.
This score is based on the validated adult RFS, inter- and in-
traobserver agreement of infant laryngeal landmarks and
expert opinion. Disappointingly, the RFS-I showed only
moderate interobserver agreement and a highly variable in-
traobserver agreement and is, therefore, not a valid tool for
further use in research settings or clinical practice.
We hypothesized that experienced observers would have a
better inter- and intraobserver agreement than less experi-
enced observers. In fact, we were not able to demonstrate
such a pattern because there was no difference in scoring be-
tween experienced observers and general otorhinolaryngolo-
that this scoring tool is not influenced by experience and
that it was successfully deployed to a broader range of clini-
cians in this study.
Of the separate RFS-I items, laryngeal erythema/edema
showed the lowest observer agreement. In a previous systematic
review of pediatric studies, arytenoid, postglottic and vocal fold
edema, and erythema have been correlated with the presence of
LPR.9 Although we incorporated these items in the RFS-I, we
were unable to show them to be objective or reproducible.
This could probably be explained by the highly heterogeneous
definitions of LPR disease and edema, as well as the age of chil-
dren (0-17 years) in the studies included in this review.
It is often speculated that laryngeal edema is caused by
LPR, but no convincing evidence is available to support
this theory.13 Edema, which is frequently observed in infants
with laryngomalacia could also be related to mechanical or
neuromuscular causes.14 PPI therapy is frequently prescribed
for infants thought to have LPR related symptoms. However,
despite PPIs being extremely effective in blocking acid pro-
duction in both adults and infants, they neither reduce the
number of GER events nor the occurrence of symptoms in
infants with classic GER disease.15 The use of PPI is, thus,
doubtful for infants suspected to have LPR related symp-
toms, because the relation between LPR disease and laryngeal
findings of LPR are unclear.
Adult studies investigating LPR disease seem to be incon-
sistent in describing the exact relationship between laryngeal
findings and LPR disease as well. Less than 40% of the adults
with larynogoscopically diagnosed LPR disease has GER dis-
ease confirmed by esophageal pH-impedance, though the
latter only shows that a condition is present, which theoret-
ically predisposes for LPR disease.16 Adult patients with a
positive score on the reflux symptom index, a validated ques-
tionnaire assessing LPR-related symptoms,17 and a positive
score on the RFS had a high likelihood of excellent improve-
ment on PPI therapy according to a nonblinded and noncon-
trolled study.18

Table II. Inter- and intraobserver agreement per item, per group
Interobserver agreement Intraobserver agreement
Total Group 1 Group 2 Group 3 Group 1 Group 2 Group 3
Erythema/hyperemia/laryngeal edema (ICC/k) 0.28 0.21 0.30 0.39 0.70 0.57 0.36
0.50 0.66 0.14
0.33
Vocal cord visibility (k) 0.44 0.37 0.48 0.73 0.57 0.68 0.79
0.50 0.66 0.41
0.28
Endolaryngeal mucus (k) 0.26 0.35 0.80 0.24 0.90 1.00 0.54
0.13 0.75 0.28
0.60
Total score (ICC) 0.45 0.51 0.51 0.63 0.87 0.84 0.73
0.51 0.80 0.50
0.42

ICC, intraclass correlation coefficient.

Cohen k (2 observers).
Fleiss k (>2 observers).
Group 1 = 3 pediatric otorhinolaryngologists.
Group 2 = 2 general otorhinolaryngologists.
Group 3 = 2 gastroenterology fellows.

482 van der Pol et al

September 2014
In this study, we found moderate interobserver variability
of the RFS-I, which is likely to be the result of 1 or more of
several factors. First, it is inherent to the infant larynx that de-
tails of the larynx are less visible compared with adults, purely
because of size of the anatomic landmarks. Directly related is
the fact that smaller endoscopes produce images with less
optimal resolution. Second, observers in this study annotated
that the limited visibility of details on the examination videos
may be inherent to infants being awake and agitated. Flexible
laryngoscopy, at least in our hands, is performed in an awake
patient in order to study the larynx dynamically. Third, the
observers in our study mentioned having difficulties inter-
preting endolaryngeal mucus. This item, which was derived
from the adult RFS, could have influenced the moderate
outcome of the overall observer variability.
For the assessment of the items included in the RFS-I, it is
conceivable that images from anesthetized infants may suffice.
Although it is frequently recommended to perform flexible
laryngoscopy in infants,19 it could be hypothesized that exam-
ination of the infant larynx with direct laryngoscopy during
general anesthesia may provide a better agreement of the
RFS-I. However, the gain of better perception of details,
must outweigh the impact for the need for general anesthesia.
To test the association between LPR disease and laryngeal
aberrations one would ideally be able to perform a random-
ized controlled double blinded intervention trial in infants
with LPR using objective and reproducible means of detect-
ing LPR. The sensitivity and specificity of this method can
then be calculated in hindsight based on outcome data.
We have now shown that flexible laryngoscopy using the
RFS-I is not suitable for this purpose. Several other studies
have been performed to come up with normative data for
pharyngeal and proximal esophageal pH and pH-
impedance values in adults.20-24 However, debate still re-
mains on pathologic pH cut-off values, position of the pH
sensor and interobserver variability of pharyngeal
impedance measurements.24-26 In infants, no validated
questionnaires or normal values of pharyngeal pH or pH-
impedance are available for detecting LPR disease. Data in
infants are unlikely to resemble adult data because physio-
logic LPR is more likely to occur as frequent regurgitation
without any other symptoms or complications is present
in the majority of infants.27 Therefore, the first step ahead
should be to perform studies aiming to find a objective
and reproducible diagnostic approach for infants suspected
to have LPR disease. n
Submitted for publication Oct 22, 2013; last revision received Apr 21, 2014;
accepted May 12, 2014.
Reprint requests: Rachel J. van der Pol, MD, Department of Pediatric
Gastroenterology and Nutrition, Emma Children’s Hospital/Academic Medical
Center, Meibergdreef 9, C2-312, 1105 AZ Amsterdam, The Netherlands.
E-mail: r.j.vanderpol@amc.nl
References
1. Edmondson NE, Bent JP, Chan C. Laryngomalacia: the role of gender
and ethnicity. Int J Pediatr Otorhinolaryngol 2011;75:1562-4.
Development of the Reflux Finding Score for Infants and Its Observer Agreement
ORIGINAL ARTICLES
2. Carr MM, Nguyen A, Poje C, Pizzuto M, Nagy M, Brodsky L. Correla-
tion of findings on direct laryngoscopy and bronchoscopy with presence
of extraesophageal reflux disease. Laryngoscope 2000;110:1560-2.
3. El-Serag HB, Gilger M, Kuebeler M, Rabeneck L. Extraesophageal asso-
ciations of gastroesophageal reflux disease in children without neuro-
logic defects. Gastroenterology 2001;121:1294-9.
4. Matthews BL, Little JP, Mcguirt WF, Koufman JA. Reflux in infants with
laryngomalacia: results of 24-hour double-probe pH monitoring. Oto-
laryngol Head Neck Surg 1999;120:860-4.
5. Halstead L. Gastroesophageal reflux: a critical factor in pediatric subglot-
tic stenosis. Otolaryngol Head Neck Surg 1999;120:683-8.
6. Bibi H. The prevalence of gastroesophageal reflux in children with tra-
cheomalacia and laryngomalacia. Chest 2001;119:409-13.
7. Landry AM, Thompson DM. Laryngomalacia: disease presentation,
spectrum, and management. Int J Pediatr 2012;2012:753526.
8. Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the
reflux finding score (RFS). Laryngoscope 2001;111:1313-7.
9. May JG, Shah P, Lemonnier L, Bhatti G, Koscica J, Coticchia JM.
Systematic review of endoscopic airway findings in children with
gastroesophageal reflux disease. Ann Otol Rhinol Laryngol 2011;
120:116-22.
10. Hicks DM, Ours TM, Abelson TI, Vaezi MF, Richter JE. The prevalence
of hypopharynx findings associated with gastroesophageal reflux in
normal volunteers. J Voice 2002;16:564-79.
11. Barron JJ, Tan H, Spalding J, Bakst AW, Singer J. Proton pump in-
hibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr
2007;45:421-7.
12. Chen IL, Gao WY, Johnson AP, Niak A, Troiani J, Korvick J, et al. Proton
pump inhibitor use in infants: FDA reviewer experience. J Pediatr Gas-
troenterol Nutr 2012;54:8-14.
13. Hartl TT, Chadha NK. A Systematic Review of Laryngomalacia and acid
reflux. Otolaryngol Head Neck Surg 2012;147:619-26.
14. Thompson DM. Abnormal sensorimotor integrative function of the lar-
ynx in congenital laryngomalacia: a new theory of etiology. Laryngo-
scope 2007;117:1-33.
15. Van der Pol RJ, Smits MJ, van Wijk MP, Omari TI, Tabbers MM,
Benninga MA. Efficacy of proton-pump inhibitors in children with
gastroesophageal reflux disease: a systematic review. Pediatrics 2011;
127:925-35.
16. De Bortoli N, Nacci A, Savarino E, Martinucci I, Bellini M, Fattori B,
et al. How many cases of laryngopharyngeal reflux suspected by laryn-
goscopy are gastroesophageal reflux disease-related? World J Gastroen-
terol 2012;18:4363-70.
17. Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the re-
flux symptom index (RSI). J Voice 2002;16:274-7.
18. Eherer AJ, Habermann W, Hammer HF, Kiesler K, Friedrich G, Krejs GJ.
Effect of pantoprazole on the course of reflux-associated laryngitis: a
placebo-controlled double-blind crossover study. Scand J Gastroenterol
2003;38:462-7.
19. Yellon RF, Borland LM, Kay DJ. Flexible fiberoptic laryngoscopy in chil-
dren: effect of sitting versus supine position. Int J Pediatr Otorhinolar-
yngol 2007;71:1293-7.
20. Sun G, Muddana S, Slaughter JC, Casey S, Hill E, Farrokhi F, et al. A new
pH catheter for laryngopharyngeal reflux: normal values. Laryngoscope
2009;119:1639-43.
21. Dobhan R, Castell DO. Normal and abnormal proximal esophageal acid
exposure: results of ambulatory dual-probe pH monitoring. Am J Gas-
troenterol 1993;88:25-9.
22. Bove M, Ruth M, Cange L, M ansson I. 24-H pharyngeal pH monitoring
in healthy volunteers: a normative study. Scand J Gastroenterol 2000;35:
234-41.
23. Andersson O, Ylitalo R, Finizia C, Bove M, Magnus R. Pharyngeal reflux
episodes at pH 5 in healthy volunteers. Scand J Gastroenterol 2006;41:
138-43.
24. Zerbib F, Roman S, Bruley Des Varannes S, Gourcerol G, Coffin B,
Ropert A, et al. Normal values of pharyngeal and esophageal 24-hour
pH impedance in individuals on and off therapy and interobserver
reproducibility. Clin Gastroenterol Hepatol 2013;11:366-72.
483
THE JOURNAL OF PEDIATRICS  www.jpeds.com Vol. 165, No. 3

25. Habesoglu M, Habesoglu TE, Gunes P, Kinis V, Toros SZ, Eriman M, et al.
How does reflux affect laryngeal tissue quality? An experimental and histo-
pathologic animal study. Otolaryngol Head Neck Surg 2010;143:760-4.
26. Koufman JA. The otolaryngologic manifestations of gastroesophageal
reflux disease (GERD): a clinical investigation of 225 patients using
ambulatory 24-hour pH monitoring and an experimental investigation
of the role of acid and pepsin in the development of laryngeal. Laryngo-
scope 1991;101:1-78.
27. Campanozzi A, Boccia G, Pensabene L, Panetta F, Marseglia A,
Strisciuglio P, et al. Prevalence and natural history of gastroesoph-
ageal reflux: pediatric prospective survey. Pediatrics 2009;123:779-
83.

50 Years Ago in THE JOURNAL OF PEDIATRICS

Pulmonary Arterial Pressure Changes in Human Newborn Infants from
Birth to 3 Days of Age
Emmanouilides GC, Moss AJ, Duffie ER, Adams FH. J Pediatr 1964;65:327-33

S ome clinical “facts” are uncontested; for example that pulmonary artery pressure and resistance fall in the first few
days after birth. Nonetheless, in the early 1960s, this was suspected but not firmly known and Emmanouilides et al
figured it out. How? By performing umbilical artery catheterizations on sleeping healthy newborns with 5F nasogastric
tubes, passing them to the thoracic descending aorta and into the pulmonary artery via the ductus arteriosus. Pressure
recordings and oximetry were used to define catheter location and provide study measurements. Elegant graphs
showed the decline of pulmonary artery pressure and resistance day by day as well as the intrinsic variability of the
rate of decline. Parental consent was obtained, but in this era institutional review boards did not uniformly exist.
As arresting as the narrative of this paper are the references, which highlight contemporary investigations in newborns
and in the laboratory that tease out elements of the transitional circulation and the physiology behind the new diag-
nosis of persistent pulmonary hypertension of the newborn. It is perhaps no accident that the authors of this paper,
and the key references, produced the first truly authoritative textbooks in the field of pediatric cardiology.
The contrast between the investigative era of this study and today are striking. One wonders if institutional review
board approval could be obtained; morbidity to the study subjects is not reported. Nonetheless, families trusted the
study physicians and one assumes that the families believed the knowledge obtained from the study would benefit
many children other than their own, which it has. The skill of the investigators was high, performing bedside cathe-
terizations without waking sleeping infants and without fluoroscopic guidance, recording physiologic data, and ob-
taining oximetry data with equipment far inferior and slower than contemporary devices.
The lesson I take from rereading this seminal paper is to leave no piece of knowledge in medicine unexamined. The
knowledge came from somewhere: pioneering efforts that might now be considered unethical, medical mistakes that
under scrutiny led to revisions in technique, and, perhaps most important, imaginative thinking about how to use
existing tools to answer clinical questions deemed critical. Today, pulse oximetry and echocardiography can provide
similar (though less accurate) data; nonetheless, we interpret these studies based on “what we already know.” Well, 50
years ago, we did not know for sure the time course of change in pulmonary artery pressure.

Samuel S. Gidding, MD
Nemours Cardiac Center
A. I. DuPont Hospital for Children
Wilmington, Delaware
http://dx.doi.org/10.1016/j.jpeds.2014.02.058

484 van der Pol et al