Attention Deficit Disorder

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COMMENTARIES

623

is associated with 80% survival or better, whereas

the other is associated with a survival rate at least

40% less than the better treatment. For example, if

extracorporeal membrane oxygenation treatment is

associated with 100% survival, as it was in this

trial, conventional treatment is associated with no

better than 60% survival. As the authors say,

“Con-clusions can be drawn from this study only if the

selection criteria really detect a group of patients

with high mortality risk.” By constructing a trial

whose results are analyzed in light of experience external to the trial, the authors, in effect, rely on historical controls, a procedure that can easily mis-lead.

How likely is the assumption that patients with

the entry criteria specified in this trial experience 40% mortality or worse on conventional treatment?

Although this is a question that can only be

an-swered definitively through inspection of results

from nonextracorporeal membrane oxygenation

us-ing nurseries, some of Bartlett et al’s data concern-ing the pool from which trial subjects were selected bears on this question.

In the course of the study, 50 infants weighing

more than 2 kg were admitted with respiratory

failure, defined as a requirement for intubation,

mechanical ventilation, and an FiO2 of 100% for 12

hours or more. Of these infants, 47 had also

expe-rienced the stress of transport. Yet, among the 34

of these infants who did not enter the trial and who

were treated conventionally, and who differed from

the trial infants only in not fulfilling the criteria listed in fig 1, there was not a single death.

The reader with experience of severely ill

neo-nates should look at the fig 1 criteria and determine

for him- or herself whether those criteria would be

sufficient, when superimposed on severe respiratory

failure as defined above, to change mortality from

0% to 40% or worse.

Does the result of the trial itself provide evidence

for the superiority of extracorporeal membrane

ox-ygenation? Had the results of Bartlett et al’s study emerged from a randomized clinical trial, a conven-tional analysis would be to use the Fisher-Irwin

test. This yields a one-tailed probability of .083,

which is not statistically significant. More impor-tantly, the inference from this statistical calcula-tion is only valid if the two treatment groups were

identical in all respects except treatment.

Unfor-tunately, the single infant who did not receive

ex-tracorporeal membrane oxygenation appears to

have been one of the sickest infants in the trial. He

or she had the lowest pH, the highest PC02, the

second lowest PaO2, shared the lowest birth weight

with one other patient, and entered the trial at the

most advanced age.

The data presented by Bartlett et al do not,

therefore, perform the function of a randomized

trial, which is to convince practitioners that

extra-corporeal membrane oxygenation is definitely

su-perior to conventional treatment. Simon3 has

pointed out that, despite a voluminous statistical literature on trials with adaptive treatment

assign-ments, they are little used in practice, mainly

be-cause they are generally unconvincing to clinicians.

In Simon’s words, “Any design that does not

pro-vide for a convincing test of the null hypothesis has little chance of being adopted for general use.”

The history of neonatology4 suggests that where

new treatments are concerned we would be wise to

cling to the null hypothesis until a well-conducted

experiment has convinced us otherwise. In the case

of extracorporeal membrane oxygenation, it

ap-pears that such an experiment has yet to be

per-formed.

NIGEL PANETH, MD, MPH

SYLVAN WALLENSTEIN, PhD G.H. Sergievsky Center

Divisions of Epidemiology and Biostatistics Department of Pediatrics

Columbia University and

New York State Department of Mental Hygiene

New York

REFERENCES

1. Zelen M: Play the winner rule and the controlled clinical

trial.J Am Stat Assoc 1969;64:131-146

2. Wei LI, Durham 5: The randomized play the winner rule in medical trials. J Am Stat Assoc 1978;73:840-843

3. Simon R: Adaptive treatment asalgnment methods and din-ical trials. Biometrics 1977;33:743-749

4. Silverman W: Retrolental Fibroplasia: A Modern Parable. New York, Grune & Stratton, Inc, 1980

Attention

Deficit

Disorder

In the article by Eichlseder (Pediatrics 1985;

76:176-184), a practicing pediatrician in West

Ger-many, reviews 1,000 cases of attention deficit

cbs-order seen in his office practice during a 10-year

period. Such a report is intriguing, not only because of the author’s sincerity and diligence in caring for

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624 PEDIATRICS

Vol.

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No. 4 October 1985

this

population, but also because his involvement

may serve as a potential model for the kind of

clinical studies that practicing pediatricians

else-where might be encouraged to undertake. However,

if other practicing pediatricians are to emulate

Ei-chlseder, they need to pay careful attention to

methodologic details if their observations are to be

meaningful. The following comments we hope will

serve as a gentle reminder of some of the pitfalls in clinical research in attention deficit disorder.

Definition of the disorder represents one of the

most critical issues in the investigation of neuro-psychiatric disorders in children. Eichlseder began

accumulating his series of patients prior to the

publication of Diagnostic and Statistical Manual of

Mental Disorders (DSM III) criteria and, thus, had

to retrieve his clinical records and determine

whether the children satisfied the inclusion and

exclusion criteria of this widely accepted nosology.

The DSM III criteria are currently undergoing

re-vision, but the current terminology considers the

diagnosis of attention deficit disorder if the child has both inattention and impulsivity. Each of these

symptoms is diagnosed if, on the basis of history

from either the parent or teacher, the child exhibits three of five designated criteria for inattention and three of six for impulsivity. Dr Eichlseder does not

follow this convention but, instead, employs as his

diagnostic criteria: “One or more symptoms

indic-ative of the core features of attention deficit and impulsivity were accepted as sufficient for a diag-nosis.”

This definition is at variance with what profes-sionals in the United States are using to diagnose

attention deficit disorder, and all but makes it

impossible to compare Dr Eichlseder’s study with

others. We would strongly encourage others who

are considering clinical studies of attention deficit disorder in their own patients to employ generally

accepted criteria for diagnosis.

Concomitant with the need for rigorous diagnos-tic criteria for attention deficit disorder is the need

to differentiate conduct disorders (or what the

re-vised DSM III criteria will refer to as “ODD,

Op-positional Defiant Disorder”) from attention deficit disorder. Although the terminology is still in flux, operationally, most clinicians and investigators

have used the prevailing DSM III criteria of

“Con-duct Disorder Socialized,” and “Conduct Disorder

Unsocialized,” each with an “Aggressive” and

“Non-aggressive” component. In discussing his

population, Eichlseder notes that: “The primary

presenting symptoms were attention deficit and the

ensuing academic difficulties and/or conduct

prob-lems arising from the impulsive behavior.” In fact,

current evidence suggests that these should be

dif-ferentiated from attention deficit disorder, rather

than as in Eichlseder’s formulation in which the

disorders are synonymous.

The consequences of such a nonstandardized

ap-proach to diagnosis and differentiation of attention

deficit disorder from conduct disorders can be

ob-served in the prevalence of pharmacotherapy.

Ei-chlseder believes that 95% of those children he

reports should be treated with stimulants (although

for a variety of reasons 87% were, in fact, given

stimulants). Most clinicians and investigators

would find this an extraordinarily high percentage

of children with attention deficit disorder who

re-quire pharmacotherapy.

Assessment of pharmacotherapy represents

an-other major issue that anyone engaged in clinical

studies of children with attention deficit disorder

must address. The clinician investigator is

inter-ested in the child’s performance both in school and

at home, with the term “performance” connoting a

number of different facets of the child’s life. Thus, performance in school represents academic achieve-ment (in reading, mathematics, written language),

classroom behavior, behavior in nonacademic areas

(such as recess and lunchroom), acceptance by

peers, and self-concept. Performance at home rep-resents interaction with parents and siblings, rela-tionships with friends, participation in after-school activities, facility with homework, and willingness to participate in family responsibilities (cleaning

own room, chores). The clinician investigator

de-pends upon the reports of others to assess the

effects of pharmacotherapy, primarily reports from

the child’s parents and his or her various teachers, reports that may include the results of standardized

cognitive and achievement tests. It is customary to

use rating scales, the psychometric properties of

which have been well accepted in the assessment of

“performance.”

A

variety of such instruments are available for

both parents and teachers. They include those

de-veloped by Conners (Conners Parent-Teacher

rat-ing scale), Achenbach (Child Behavior Check List),

and ourselves (Yale Children’s Inventory and

Teacher Behavior Rating Scales). The usual

pro-cedure is for the parents or teacher to complete the rating scale after the child has received medication for a specified period and compare the results with the same rating scale filled out for a previous

base-line period. The use of standardized rating scales

allows comparison with the results of other

inves-tigators, which is an important consideration. The

assessment procedure employed by Dr Eichlseder

is subjective, relatively nonspecific, and does not

provide enough details to allow such comparison

with other studies. It would, thus, be considered

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COMMENTARIES 625 inadequate by current investigational standards.

Another pitfall to be avoided is that of being so

enamored of our own favorite theory or therapy

that we fail to consider other approaches,

exempli-fled

in this context by Eichlseder’s belief in the

efficacy of stimulant therapy. Clearly, like the ex-cellent clinician he obviously is, he recognized the

importance of other management techniques and:

“used environmental manipulation, social and

to-ken reinforcement, reward, punishment, extinction, and time out.” Yet, despite this and other evidence

that a variety of management procedures were

em-ployed, Eichlseder attributes his success to

phar-macotherapy, when, in reality, his approach

prob-ably more accurately represents a pediatric

equiv-alent of what Satterfield and Satterfield’ have

termed “multimodality therapy.”

Finally, the clinician investigator should inves-tigate only what is reasonable within the context of

his or her own practice. Such a recommendation

seems self-evident but would preclude a great deal

of time and energy being expended on projects that

can only be accomplished within the framework of

a large multidisciplinary study. For example,

long-term follow-up of children with attention deficit

disorder demands resources beyond what an

mdi-vidual practitioner can devote to studies of this

kind. Studies such as those of Weiss and her

associates2 require personnel to locate and then

contact each subject and contrast with the

well-intentioned but apparently inadequate follow-up

described by Dr Eichlseder.

We believe it is possible for the practicing pedia-trician to engage in the kind of clinical research studies described by Dr Eichlseder. However, if he

or she is to make a significant contribution, the

clinician investigator must incorporate into the

study design the methodology of state-of-the-art clinical research.

REFERENCES

SALLY E. SHAYWITZ, MD BENNETT A. SHAYWITZ, MD Departments of Pediatrics, Neurology,

and the Yale Child Study Center

Yale University School of Medicine New Haven, Connecticut

1. Satterfield JH, Satterfield BT, Cantwell DP: Three-year multimodality treatment study of 100 hyperactive boys. J Pediatr 1981;98:650-655

2. Weiss G, Hechtman L, Milroy T, Penman T: Psychiatric status of hyperactives as adults: A controlled prospective 15-year follow-up of 63 hyperactive children. J Child Psy-chiatry 1985;24:211-220

Vitamin

E-How

Much

Is Too

Much?

For many years a treatment in search of a disease,

vitamin E (a-tocopherol) is now being prescribed

widely and in large doses to small premature

in-fants. The possibility of reducing the incidence of

severe retrolental fibroplasia,’ intraventricular

hemorrhage, and even the mortality of these tiny

babies5 has, quite understandably, excited the

in-terest of those responsible for their care.

Although concern about potential toxicity has

been expressed,6’7 Hittner and co-workers4

recom-mend that infants weighing less than 1,500 g at

birth who require oxygen receive intramuscular

in-jections of a water miscible preparation of

d,l-a-tocopherol on days 1, 2, 4, and 6 of life as well as

oral a-tocopherol in a dosage of 100 mg/kg/d.5

Using this regimen, these workers report that they

have not (or have rarely) encountered plasma

to-copherol levels in excess of 3.5 mg/dL.8’9 This has

not been our experience, however, and if plasma

levels are indeed related to vitamin E toxicity, the widespread use of relatively high doses of vitamin

E (in the absence of rigorous control of plasma

levels) could be hazardous.

Our experience with the use of oral vitamin E

indicates that serum levels are frequently elevated to potentially toxic levels on recommended dosages.

At the James Whitcomb Riley Hospital for

Chil-dren 78 infants weighing less than 1,500 g at birth

received 100 mg/kg/d of Aquasol E (divided into

four doses) from day 1 of life and were followed

with weekly or semiweekly plasma determinations

during a 6-month period. In the 78 infants, 557

plasma vitamin E levels were measured. No

intra-venous vitamin E was administered within seven

days of any vitamin E level. Elevated plasma

con-centrations were very common (Table). Of the 557

levels obtained during vitamin E supplementation, 211 (38%) were greater than 3.5 mg/dL, whereas 72

(13%) exceeded 5.5 mg/dL. Although oral

supple-mentation was discontinued when the level

ex-ceeded 3.5 mg/dL, concentrations often remained

above 3.5 mg/dL for several days or exceeded 3.5

mg/dL again when Aquasol E supplementation was

reinstituted at a reduced dosage of 25 or 50 mg/kg/

d. Because of similar experience at the Hershey

Medical Center, the daily dosage was reduced to 50

mg/kg/d.

To discuss the potential adverse effects of

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1985;76;623

Pediatrics

SALLY E. SHAYWITZ and BENNETT A. SHAYWITZ