....Beginning to See the Light

(1)

or provide a full explanation for a deficiency.

In-stead, evaluations of children need to be aimed at

deriving functional profiles, descriptive accounts of

strengths and weaknesses in multiple areas. One

then may relate that wide-angle view to the

expec-tations or demands made upon children at different

ages (or grades). The profile itself should be the

product of several different observers who vary in

professional background and diagnostic comfort.

To this end, pediatricians are becoming

increas-ingly involved in the administration and

interpre-tation of neurodevelopmental examinations. The

Pediatric Early Elementary Examination

(PEEX),3’4 whose early stages of creation are

de-scribed by Berninger and Colwell,2 has been

con-structed in such a way that physicians can

contnib-ute to the empiric description of a child’s functional

profile or array ofdevelopmental assets and deficits.

The PEEX does not generate a specific score label

or percentile rank. The description derived from

the PEEX is meant to be used in context, integrated

with historical data obtained from parents and

teachers, as well as assessments by psychologists

and/or other professionals, and findings from

standard neurologic and physical examinations. In

such a way, the pediatrician or pediatric nurse

clinician becomes part of a system of diagnostic

checks and balances. This enables the health

pro-vider to play a more meaningful role as a politically

neutral informed child advocate, to help

counter-balance economic and political conflicts of interest

that may exist in school systems, to temper any

strong diagnostic disciplinary biases, and to provide

longitudinal functional monitoring for children

whose early life failure has rendered them

exquis-itely vulnerable to lifelong maladjustment.

The immediate goal of assessment should be the

collaborative description of a child’s life struggle, a

therapeutically relevant set of empiric observations

instead of a numerical caricature or a simplistic

label.

REFERENCES

MELVIN D. LEVINE, MD

Division of Ambulatory Pediatrics

The Children’s Hospital Boston

1. Gittleman R: The role of the psychological tests for

differ-ential diagnosis in child psychiatry. J Am Acad Child

Psy-chiatry 1980;19:413

2. Berninger VW, Colwell SO: Relationships between neuro-developmental and educational findings in children aged 6 to 12 years. Pediatrics 1985;75:697-702

3. Levine MD, Meitzer U; Busch B, et al: The Pediatric Early

Elementary Examination: Studies of a neurodevelopmental

examination for 7- to 9-year-old children. Pediatrics

1983;71:894

4. Levine MD: The Pediatric Early Elementary Examination. Cambridge, MA; Educator’s Publishing Service, 1983

. . U

Beginning

to See the Light

I never made love by lantern shine I never saw rainbows in the wine

And now that your lips are burning mine

I’m beginning to see the light

-Duke Ellington

In March 1952, Mollison and Walker1 reported

the results of their prospective, randomized, con-trolled trial on the effect of exchange transfusion v

simple transfusion in infants with severe erythro-blastosis fetalis. They showed that exchange

trans-fusion led to significantly lower mortality and a

much lower incidence of fatal kernicterus. In the

interim, numerous published studies have

exam-med the relation between serum bilirubin levels in the neonatal period and the postmortem finding of

kernicterus or the presence of later, clinical,

bili-rubin encephalopathy. With few exceptions, the

design of these studies has made interpretation of their results hazardous, if not nugatory.2 We now

have a study from the National Institute of Child

Health and Human Development (NICHD)3 in

which the population is sufficiently large and the

study design sufficiently rigorous to permit actual, if tentative, conclusions concerning the effect of a

different intervention (phototherapy) upon the im-mediate and later outcome of jaundiced newborn infants. If for nothing else, I congratulate the in-vestigators on their design and execution of this

study. We are beginning to see the light.

The results are overdue-it is 8 years since the

last infant was enrolled-but most welcome. Our delight is tempered, however, by the realization that so far, at least, the study has answered none of the questions it was originally designed to answer. In fact, the questions themselves are not entirely clear.

According to one of the principal investigators, in

a discussion of the preliminary report,4 “. . . the

request from the National Research Council was for us to examine the safety ofphototherapy. Would

children undergoing phototherapy hemolyze,

(2)

COMMENTARIES 793 velop cancer, or fail to grow? . . . “ Yet, curiously,

we find no mention of the question of safety in the

description3 of the following official study objec-tives: “(1) Is phototherapy effective in preventing brain injury from hyperbilirubinemia, when

em-ployed to lower serum bilirubin levels?, and (2) “Is phototherapy as effective as exchange transfusion at predetermined serum bilirubin levels for pre-venting brain damage from neonatal

hyperbiliru-binemia?”

NICHD statisticians performed a power analysis to determine the sample size required to demon-strate any difference between the phototherapy and control groups (if such a difference indeed existed). This analysis was based on the prevalence of

hear-ing loss, dyskinesia, and mental retardation in (pre-viously) nonjaundiced infants and the relative risk

that might be detectable in a hyperbilirubinemic group. (Relative risk (for a disease) = incidence in exposed persons/incidence in nonexposed persons. For this study, relative risk (for hearing loss etc) = incidence in control (more jaundiced) babies/mci-dence in phototherapy (less jaundiced) babies.) The defects for which relative risks were calculated, however, were those of classic kernicterus-extra-pyramidal motor disturbances, sensorineural hear-ing loss, and mental retardation (not further de-fined). This is curious, because the studies pub-lished over the last 15 years that are most influen-tial in persuading us that a more subtle form of

bilirubin encephalopathy might exist suggest that, if neurodevelopmental handicap is detectable, it is most likely to manifest itself less dramatically as cognitive dysfunction-specifically, abnormalities of behavior, expression and reception, and fine motor development. The incidence of such subtle

problems is likely to be substantially greater than those listed in their table 2 (page 390), particularly as about 66% of the patients followed had birth

weight less than 2 kg. Extensive follow-up

exami-nations have already been performed, including Bayley Infant Development Scales. We hope that

the large size of the population followed (about 1,200 infants) will permit important differences to be detected.

No power analysis was performed for the possible detection of kernicterus at autopsy. This is strange, because kernicterus has been the pathologic marker most often used, in recent studies, to evaluate the usefulness of measured albumin binding of

biliru-bin. If “prevention of brain injury from hyperbili-rubinemia” was, indeed, the important question to be answered, then the pathologic finding of kernic-terus might, at least, be considered as one indication of such injury. Perhaps the low mortality and low incidence of pathologic kernicterus anticipated

would have required an unattainable sample size to show significant differences.

Did phototherapy affect the incidence of

kernic-terus as diagnosed at autopsy? It appears the

in-vestigators were faced with a dilemma (see the conclusions in reference 4): Kernicterus was found

at autopsy in four infants; three were control

in-fants and one was assigned to the phototherapy group. Due to an error, although randomly assigned

to the phototherapy group at 21 hours, this infant did not receive phototherapy until 43 hours of life (table 7, page 425). After only one hour of photo-therapy, an exchange transfusion was performed. The study protocol was breached, but what to do with this infant? Should the infant be included in

the phototherapy group (to which he was, in fact, assigned) or simply eliminated from further consid-eration? As he received virtually no phototherapy,

it might not seem unreasonable to include him in the control group. so assigned, we find that of 37 infants in that group for whom autopsy was

per-formed, four (10.8%) had kernicterus v none of the infants in the phototherapy group

(P

= .033, Fisher

exact test). If we simply exclude this infant, the

P

value for the exact test is .081, and, if he is included in the phototherapy group, the

P

value becomes

.20.

We wish to avoid concluding that phototherapy

reduces the risk of pathologic kernicterus, if it does

not (a type 1 error). Neither do we wish to conclude that phototherapy is not beneficial if, indeed, it is (a type 2 error). The question is not easily resolved but is discussed in some detail by Sackett and Gent.5 (I am grateful to Dr John C. Sinclair for his advice and for bringing this reference to my

atten-tion. Central to the issue is the nature of the study-was this an “explanatory trial” or a “man-agement trial”? Space does not permit an analysis of these terms, discussed by Sackett and Gent,5 but

my impression is that this trial was a mixture.) The NICHD authors do not discuss this important ques-tion (other than to say that the number of infants was too small to allow conclusions to be drawn), but there are several reasons why their cautious interpretation of the data is, probably, appropriate.

We are not told why the protocol was breached,

and we are left with the distinct implication that this was, in fact, the only such case. But in a study

that involved 1,339 infants, 15 clinical investiga-tors, and, presumably, many pediatric residents, the suggestion that this represented the only

contre-temps strains our credulity. Rather, the discovery that the protocol was breached in this particular infant is suggestive of a “diagnostic-suspicion bias.”5 The finding of kernicterus in this infant, undoubtedly led to an intensive review of the

at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news

(3)

pital record. It is unlikely that similar reviews were

done for all other infants for whom autopsy had

been performed, preventing other possible

irregu-larities from being detected. Furthermore, 28% of

the infants who died in the nursery did not come

to autopsy. This is unavoidable, perhaps, but

con-founds interpretation of the results.6 Finally, when

a conclusion of “significance” or “nonsignificance”

depends on the outcome of a single subject, a

con-servative interpretation of the data is certainly

appropriate.

The findings are nevertheless intriguing. No

in-fant who received phototherapy (as planned)

de-veloped kernicterus; four other infants did.

Exclud-ing the “miscast” infant completely produces a

P

= .081. Thus, there is an 8% chance of being wrong if

we assert that a true difference exists between the

two groups. Unfortunately, this question can only

be resolved by repeating the study with three to

four times the number of infants having autopsies

performed-something that is unlikely to be

achieved.

The clinical information on the four infants who

died with kernicterus is surprisingly sparse. The

course of three of the four infants includes the

diagnosis of “respiratory distress syndrome” with

no mention of its severity. Nor is there any

infor-mation regarding the presence or absence of

meta-bolic acidosis, hypercarbia, hypoalbuminemia,

hy-pothermia, hypoxia, or sepsis (more detailed

infor-mation can be found in Brown et al4). According to

the study design, many of these risk factors were

used to determine the level at which infants would

receive an exchange transfusion-a belief that has

yet to be substantiated by adequate evidence.

Although effective in preventing

hyperbilirubi-nemia in infants with birth weight less than 2 kg,

and in controlling hyperbilirubinemia in larger

in-fants, phototherapy, as used in this study, did not

prevent exchange transfusions among infants with

hemolytic disease. The investigators suggest that

this was related to the late initiation of

photother-apy. Another possible explanation is that the dose

was too low. The average irradiance received by

infants in this study was approximately 7 W/cm2/

nm in the 400 to 500 nm range. Tan7 has shown

that saturation is not reached until doses four to

five times greater are used. In uncontrolled studies,

using blue lights above and below the mattress,

Ebbesen8 was able to reduce the number of repeat

exchange transfusions and to reduce the maximum

serum bilirubin concentration in infants with Rh

hemolytic disease.

The observations on the relationship between

serum bilirubin levels and caloric intake are of

interest and are consistent with findings of other

studies in adults, infants, and animals. Neverthe-less, it must be recognized that infants in this study were not randomly assigned to one or another

ca-loric regimen, nor is there any indication why some infants received fewer calories than others. Sick

babies commonly cannot be fed. The reason for their inability to tolerate calories also may have contributed to an elevated serum bilirubin level. Of course, fluid intake and caloric intake are closely

related. Thus, although fluid and caloric intake

were analyzed separately, we cannot be confident

that they exert independent effects. It is, neverthe-less, interesting that phototherapy appeared to be ineffective at fluid intakes of less than 60 mL/kg/

24 h.

No one will be surprised to learn that, in most circumstances, phototherapy is a simple and effec-tive means of preventing or controlling hyperbili-rubinemia in the newborn, and we are reassured that it causes no immediate harm. The ease with which phototherapy is used and its apparent safety has, in fact, removed much of the clinical decision making from the treatment of hyperbilirubinemia

in the low-birth-weight infant. This may not be rational and it certainly is not scientifically com-forting, but it is a fact. For the last 10 years, we

have not performed a single exchange transfusion

for hyperbilirubinemia in a low-birth-weight-infant unless it was associated with severe hemolytic

dis-ease. Rising bilirubin levels in these infants are

controlled by individually tailored doses of

photo-therapy. (Tailoring of the dose is achieved by such

refined methods as using two or even three lights

and placing the light source as close as possible to

the infant.) Nevertheless, we have yet to discover whether the surviving infants in the present study

benefited from this intervention, or perhaps

suf-fered some (as yet) unidentified complications. Finally, the efficacy of a single dose of tin-pro-toporphyrin in obliterating physiologic jaundice in

newborn rhesus monkeys by inhibiting heme

oxygenase#{176} raises the sobering possibility of our stamping out a disease before we have had time to study it fully. Therapeutic blue light is actually a

part of the visible spectrum we see in that natural

wonder, the rainbow. But over that rainbow lurks

a Tin Man.

Acknowledgment

(4)

M. JEFFREY MAISELS, MB, BCH Department of Pediatrics

The Milton S. Hershey Medical Center The Pennsylvania State University Hershey

COMMENTARIES 795

REFERENCES

1. Mollison PL, Walker W: Controlled trials of the treatment of hemolytic disease of the newborn. Lancet 1952;1:429-433 2. Maisels MJ: Clinical studies of the sequelae of

hyperbiliru-binemia, in Levine RL, Maisels MJ (eds)

Hyperbilirubine-mia in the Newborn (Report of the 85th Ross Conference

on Pediatric Research, September 1983). Columbus, OH, Ross Laboratories, pp 26-38

3. National Institute ofChild Health and Human Development randomized, controlled trial of phototherapy for neonatal hyperbiiirubinemia. Pediatrics 1985;75(Suppi):381-441

4. Brown AK, Kim MH, Bryla D: Report on the NIH

cooper-ative study of phototherapy: Efficacy of phototherapy in controlling hyperbilirubinemia and preventing kernicterus, in Levine RL, Maisels MJ (eds) Hyperbilirubinemia in the

Newborn (Report of the 85th Ross Conference on Pediatric Research, September 1983). Columbus, OH, Ross Labora-tories, pp 55-63

5. Sackett DL, Gent M: Controversy in counting and attrib-uting events in clinical trials. N Engi J Med 1979;301:1410-1412

6. Department of Clinical Epidemiology and Biostatistics, McMaster University Health Sciences Centre: How to read clinical journals: III. To learn the clinical course and prog-nosis of disease. Can Med Assoc J 1981;124:869

7. Tan KL: The pattern of bilirubin response to phototherapy for neonatal hyperbilirubinemia. Pediatr Res

1982;16:670-674

8. Ebbesen F: Superiority of intensive phototherapy-blue double light-in rhesus haemolytic disease. Eur J Pediatr 1979;130:279-284

9. Cornelius CE, Rodgers PA: Prevention of neonatal hyper-bilirubinemia in rhesus monkeys by tin-protoporphyrin. Pe-diatr Res 1984;18:728

EVALUATION

OF INTENSIVE

CARE

. . . .

the warning to [those] using and interpreting data on neurological

handicap in relation to neonatal intensive care and other perinatal factors is

that it is necessary to wait long enough for the diagnosis to become stable and for all cases of cerebral palsy to be ascertained. I suggest that five years of age

would be appropriate, and not too long after the date of birth to cease being

useful.

Submitted by Student

From Stanley F: Using cerebral palsy data in evaluation of neonatal intensive care: A warning. (Dev

Med Child Neurol 1982;24:93-94).

(5)

1985;75;792

Pediatrics

M. JEFFREY MAISELS