observed. These data indicate that administration of indomethacin in the early postnatal period may not only be unnecessary but also dangerous giving the risk for necrotizing enterocolitis. These new-born infants with mutations at the ROMK channel gene are often mildly hyperkalemic and acidotic during some weeks after birth and indomethacin administration may precipitate a menacing picture of oliguric renal failure and severe hyperkalemia, as in fact occurred in the case reported by Konrad et al. In my experience, in the immediate neonatal period all therapeutic efforts should be directed to correct dehydration and electrolytic imbalance. Continuous saline infusion may be needed to at-tain this aim. However, at 4 to 6 weeks of life, when massive urinary electrolyte losses have greatly abated and the biochemical profile is shifted from hyperkalemic metabolic acidosis to hypokalemic metabolic alkalosis, the patient may greatly benefit from the administration of indo-methacin. As stated by Konrad et al, patients with mutations at the ROMK channel gene are espe-cially sensitive to that drug, and doses well below 1 mg/kg per day may be sufficient to maintain plasma K levels within the normal range.
The comments made above may not be entirely valid when referring to cases of neonatal Bartter’s syndrome caused by mutations at gene coding for the NKCC2 transporter. In these instances massive renal sodium chloride-wasting, hypokalemia, and metabolic alkalosis may be already present at birth and indomethacin therapy may probably be started at the early neonatal period without especial risks. The article by Konrad et al opens new perspectives about the prenatal and postnatal management of patients with neonatal Bartter’s syndrome but only accumulated experience over the next few years shall fully establish the precise regimen of indomethacin administration for each genetic variety as well as the safe balance between clinical benefits and potential risks.
Juan Rodriguez-Soriano, MD Department of Pediatrics Hospital de Cruces and Basque
University School of Medicine 48903 Bilbao
Paı´s Vasco, Spain
REFERENCES
1. Bartter FC, Pronove P, Gill JR Jr, MacCardle RC. Hyperplasia of juxta-glomerular complex with hyperaldosteronism and hypokalemic alkalo-sis.Am J Med.1962;33:811– 828
2. Rodrı´guez-Soriano J. Bartter and related syndromes: the puzzle is al-most solved.Pediatr Nephrol.1998;12:315–327
3. Seyberth HW, Rascher W, Schweer W, Ku¨hl PG, Mehls O, Scha¨rer K. Congenital hypokalemia with hypercalciuria in preterm infants: a hy-perprostaglandinuric tubular syndrome different from Bartter syn-drome.J Pediatr.1985;107:694 –701
4. Konrad M, Leonhardt A, Hensen P, Seyberth HW, Ko¨ckerling A. Pre-natal and postPre-natal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes.Pediatrics.1999;103:678 – 683 5. Proesmans W. Bartter syndrome and its neonatal variant.Eur J Pediatr.
1997;156:669 – 679
Problems in Diagnosing Attention
and Activity
ABBREVIATIONS. AHP, attentional or hyperactivity problem; PROS, the Pediatric Research in Office Settings (PROS) Network; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Fourth Edition; ADHD, attention deficit/hyperactivity disorder.
I
n this month’sPediatrics electronic pagesis an im-portant report by Wasserman and associates en-titled “Identification of Attentional and Hyperac-tivity Problems in Primary Care: A Report From PROS and ASPN.” This extensive, valuable study describes how a sample of 401 primary care pedia-tricians and family practice physicians with a patient cohort of over 22 000 children found that 18.7% of them had behavioral difficulties and about half of these, or 9.2% of the total sample, showed evidence of attentional or hyperactivity problems (AHPs). An-other main conclusion of the project was that the diagnosis was not made more frequently with chil-dren from “disadvantaged backgrounds.” This com-mentary explores the third principal result of the work, that “primary care assessment of AHPs lacks standardization.”A great strength of the report is the large and diverse sample of children studied. If anyone needs proof of the value of the Pediatric Research in Office Settings (PROS) Network, here it is. It makes avail-able an enormous cohort of the general population. Instead of the generally skewed samples typically used in studies based at tertiary academic centers, the Network provides a more realistic cross section of children in the community. Questions of incidence and prevalence are among the issues that can be investigated more accurately in primary care than at referral centers.1
Another important conclusion of the report is that pediatricians can and do pick up a substantial num-ber of behavioral problems in their practices.2 Per-haps this detection is sometimes not as thorough as it should be, but it is probably not as negligent as some nonpediatric critics have claimed.3
One need not dwell at length on the methodologic issues in the study, because every such effort has them. The fact that the physician participants were volunteers may have meant that they were not a representative sample of their respective profes-sional groups. The authors’ statement that their study “found little support for the contention that primary care clinicians use AHPs to label children with social and family problems” should not be mis-read as indicating that family dysfunction does not lead to behavioral problems or to an increase in AHP diagnoses. The Pediatric Symptom Checklist collects parental impressions of possibly worrisome
behav-Received for publication Dec 2, 1998; accepted Dec 2, 1998.
Address correspondence and reprint requests to William B. Carey, MD, 511 Walnut Ln, Swarthmore, PA 19081-1140.
iors, but does not separate challenging normal vari-ations from behavioral dysfunction and does not yield clinical diagnoses.
The study’s predominant finding, that “primary care assessment of AHP lacks standardization,” should be of concern to all us. Only about half of the clinicians studied (53.5%) used school reports in ar-riving at their diagnoses, and only 38.3% used the
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Fourth Edition4 criteria. This neglect of available information and standards can be variously interpreted. It could possibly mean that pediatric residents do not receive adequate training in a well-established diagnostic technique. Another explana-tion might be that even well-trained general and subspecialty pediatricians are being so overwhelmed by excessive pressures and concerns from parents and schools5and by the time constraints imposed by managed care regulations that they have abandoned lessons learned in their residencies. Some may be tempted to use an inappropriate trial of methyl-phenidate as a diagnostic test. However, a major alternative interpretation, briefly suggested by these authors, could be that the basic problem lies in the inadequacy of the current attention deficit/hyperac-tivity disorder (ADHD) diagnosis itself. This com-mentary urges the view that the lack of standardiza-tion and the confusion reflected by this study has been generated primarily by the nebulous official definition of ADHD.
In an effort to clarify the uncertainties about the diagnosis and treatment of ADHD, the National In-stitutes of Health convened a Consensus Develop-ment Conference on November 16 –18, 1998, in Bethesda, Maryland. The printed statement issued at the end of that conference6acknowledged that “the disorder has remained controversial in many public and private sectors.” It recognized that “we do not have an independent valid test for ADHD, and there are no data to indicate that ADHD is due to a brain malfunction.” Recommendations of the panel in-cluded the requirement for “further efforts to vali-date the disorder,” that “basic research is needed to better define ADHD,” and that “a more consistent set of diagnostic procedures and practice guidelines is of utmost importance.” At the press briefing after the conference, when the report was presented to the public, the one panel member in primary care pedi-atrics acknowledged that “the diagnosis is a mess.” Only 1 of the 31 invited speakers had been asked to respond formally to the question, “Is ADHD a valid disorder?”7A brief summary of those comments and the suggested remedies follows.
ADHD is defined by theDSM-IVas consisting of 6/9 inattention or 6/9 hyperactivity/impulsivity symptoms for 6 or more months, present from before the age of 7 years, with impairment in 2 or more settings, and not attributable to other conditions. Additional common assumptions about ADHD are: that the behaviors are clearly distinguishable from normal; that it constitutes a neurodevelopmental dis-ability; that it is relatively uninfluenced by the envi-ronment; and that this disability can be adequately diagnosed by brief questionnaires. All these
assump-tions and some others should be challenged because of the weakness of the empirical support. The current criteria allow for a lumping together under one all-encompassing label of a diverse collection of normal but troublesome variations of temperament, prob-lems in cognition, child-environmental dissonances, behavioral adjustment issues, and neurologic imma-turities.
A wide variety of observers appear to be in agree-ment about the existence of a small group of readily recognizable “hyperkinetic” children, about 1% to 2% of the population, whose pervasive, disorganized high activity and extremely short attention spans are so marked as to be the clinical problem by them-selves, not just as risk factors for other problems in adjustment.8 Even for them, however, there is usu-ally no certainty as to the source of the troublesome behaviors.9The discussion here is concerned with the problems in the diagnostic terminology of ADHD as applied to the other 5% to 10% or more of American children, who were surely most of the children being evaluated in the study by Wasserman et al.
1. The supposedly abnormal ADHD symptoms are not clearly distinguishable from normal tempera-ment variations. Temperatempera-ment research reminds us that half of any population of children are more active and half are less attentive than average. Many children with these traits are completely normal or just annoying to their caregivers with-out becoming dysfunctional.10Dysfunction in the child’s social behavior or school performance re-sults neither from the number of these risk factors present nor from extreme ratings in any of them but when any number of them induces a “poor fit” with the particular environment and reactive problems in the child.11 No solid empirical data support the current use of 6/9 of the activity or inattention behaviors as defining a true “cutpoint” where normal leaves off and abnormal begins.12 2. There is no clear evidence that the ADHD
symp-toms are related to brain malfunction. The ADHD behaviors are generally assumed to be largely or entirely attributable to a neurodevelopmental dis-ability. TheDSM-IVdoes not say so but the jour-nals and textbooks do.13 We know that various brain insults like lead poisoning, fetal alcohol syn-drome, traumatic brain injury, and low birth weight may lead to increased activity and de-creased attention span. Some preliminary brain imaging studies have shown inconsistent differ-ences in children with the ADHD diagnosis but there is no proof to date that they are deviations. No consistent pathologic changes or structural, functional, or chemical marker is found with the current ADHD diagnosis despite extensive searches with sophisticated techniques.14Meanwhile, differ-ences in brain function have been documented in healthy children with nothing more than normal temperament variations (eg, frontal electroencepha-logram asymmetries).15 Therefore, any new proce-dures purporting to establish a brain abnormality as the basis for ADHD must not just use any random controls but individuals with exactly the same traits
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as the subjects except for the behavioral dysfunction. And care must be exercised to distinguish cause from result and coincidence. Genetic contributions to normal diversities in temperament16and coping patterns17have been established, and must be born in mind when claims are made for a genetic basis for the clinical diagnosis of ADHD.
3. The role of the environment and interactions with it is generally neglected in considerations of the cause of ADHD, which is typically regarded as being all in the child. However, there is evidence that the environment can produce18 or at least worsen19 the ADHD symptoms, as it does for other problems in adjustment. Beside the predis-posing traits in the child something else is needed in the family, neighborhood, school, or elsewhere, like intolerance of those traits or various psycho-social stressors, to produce the behavior problem. 4. The diagnostic questionnaires now in use for ADHD are highly subjective and impressionistic. The small numbers of items place much of the responsibility not only for reporting the behavior but also for making clinical judgments as to devi-ation in the eye of the beholder. Varidevi-ations in experience, tolerance, or criteria used among par-ents and teachers are not allowed for. Such scales probably measure caregiver discomfort as much as they do the actual behavior of the child. 5. The most important factors predisposing to the
dysfunction in the majority of children getting the ADHD label today is probably not the high activ-ity and low persistence but low adaptabilactiv-ity20and cognitive disabilities,21especially working memo-ry.22
6. The assumption that children not fitting into the modern classroom have defective brains lacks an evolutionary perspective. These traits may have been highly adaptive in primitive times in a world full of predators and in our own times in some situations outside the classroom.23
7. The small practical usefulness and possible harm from the ADHD label should not be overlooked. Some clinicians maintain that the ADHD label represents progress in that it takes the blame off of parents and schools, helps such children get needed services, and justifies the use of medica-tion. However, the label has limited practical value to teachers, psychologists, and physicians in that it offers no description of the individual’s particular problems and strengths and no sugges-tions for specific management other than medica-tion. It involves an overly simple analysis of the complex phenomenon of attention. It may be mis-leading as to the true nature of the child’s prob-lems, such as abnormal environmental influences. The label may be stigmatizing and harmful in a variety of ways in the future. Finally, this over-simplification and lumping together of various complex conditions into one diagnosis is sure to be an impediment to scientific research.
Several steps are possible to find a theoretical so-lution to this confusing situation and to establish
evidence-based criteria that can standardize practice in the area of AHPs and ADHD:
1. When theDSM-Vis assembled, the system should finally acknowledge the existence and clinical im-portance of normal temperament differences. No longer should they be ignored, trivialized, or pathologized. Temperament variations are fre-quently annoying to parents and teachers but do not necessarily make the child dysfunctional without other factors. The important quality of adaptability should be understood for its central position in be-havioral adjustment. Adequate recognition should be given to the power of these interactions to affect the behavioral adjustment of children. Neither envi-ronmental nor biological determinism explains all children’s problems.
2. A revised ADHD diagnosis would be more tena-ble if it were limited to those 1% to 2% of the population who are truly extremely “hyperkinet-ic,” that is, so objectively and pervasively hyper-active and nonpersistent that these traits are the problem itself. A categorical diagnosis of ADHD based on vague descriptions such as “often talks excessively” should be replaced with clearer, more reliable criteria.
3. The other 5% to 10% of the child population now being labeled with ADHD would best be diag-nosed as having either: a) annoying but normal temperament traits without dysfunction in social or school adjustment; b) adjustment disorders re-lated to individual-environment interactions, of-ten involving a poor fit; or c) a variety of other problems stemming from other causes largely in the environment like parental conflict and social disorganization or in the individual child such as learning disabilities and chronic illness.
4. Any diagnosis or suggestion of brain malfunction should be based only on some objective evidence of it.
5. Until a clearer diagnostic system evolves, children will be better served by the use of comprehensive functional assessments, consisting of separate evaluations of strengths and liabilities in the sev-eral areas of adjustment: social relations, task per-formance, self-relations, internal status, and cop-ing patterns.
avail-able to improve the criteria may be via the appropri-ate DSM-V Workgroup (Disorders Usually First Diagnosed During Infancy, Childhood, or Ado-lescence). The DSM-IV members of this group con-sisted of 12 psychiatrists, 4 psychologists, and no pediatricians—in other words nobody in ongoing direct contact with primary care issues. A major col-laborative effort is needed to relieve practitioners, children, their parents, teachers, and the general public from the present confusion.
William B. Carey, MD Division of General Pediatrics Children’s Hospital of Philadelphia Philadelphia, PA
REFERENCES
1. Carey WB. On doing clinical research in office practice.Pediatrics.1978; 62:424 – 425
2. Horowitz SM, Leaf PJ, Leventhal JM, Forsyth B, Speechley KN. Identi-fication and management of psychosocial and developmental problems in community-based, primary care pediatric practices.Pediatrics.1992; 89:480 – 485
3. Costello EJ, Edelbrock C, Costello AJ, Dulcan MK, Burns BJ, Brent D. Psychopathology in pediatric primary care: the new hidden morbidity.
Pediatrics.1988;82:415– 424
4. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV).Washington, DC: American Psychiatric Association; 1994 5. Diller LH.Running on Ritalin. A Physician Reflects on Children, Society, and
Performance in a Pill.New York, NY: Bantam; 1998
6. National Institutes of Health Consensus Development Conference Statement.Diagnosis and Treatment of Attention Deficit Hyperactivity Dis-order (ADHD).Bethesda, MD: National Institutes of Health; November 18, 1998
7. Carey WB. Is ADHD a valid disorder? Invited paper presented at NIH Consensus Development Conference on Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder; November 16, 1998; Bethesda, MD. Longer version in press
8. Rutter ML. Motivation and delinquency. In: Nebraska Symposium on Motivation, XXXXIV.Lincoln, NE: University of Nebraska Press; 1997:73 9. Taylor E. Syndromes of attention deficit and overactivity. In: Rutter ML, Taylor E, Hersov L, eds.Child and Adolescent Psychiatry.3rd ed. Oxford, UK: Blackwell Scientific; 1994:294
10. Thomas A, Chess S, Birch HG.Temperament and Behavior Disorders in Children.New York, NY: New York University Press; 1968
11. Carey WB, McDevitt SC.Coping With Children’s Temperament. A Guide for Professionals.New York, NY: Basic Books; 1995
12. Levy F, Hay DA, McStephen M, Wood C, Waldman I. Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study.J Am Acad Child Adolesc Psychiatry.1997;36: 737–744
13. Tannock R. Attention deficit hyperactivity disorder. Advances in cog-nitive, neurobiological, and genetic research.J Child Psychol Psychiatry.
1998;39:65–99
14. Zametkin AJ, Ernst M, Silver R. Laboratory and diagnostic testing in child and adolescent psychiatry: a review of the past 10 years.J Am Acad Child Adolesc Psychiatry.1998;37:464 – 472
15. Fox NA, Rubin KH, Calkins SD, et al. Frontal activation asymmetry and social competence at four years of age.Child Dev.1995;66:1770 –1784 16. Plomin R, Owen MJ, McGuffin P. The genetic basis of complex
behav-iors.Science.1994;264:1733–1739
17. Mellins CA, Gatz M, Baker L. Children’s methods of coping with stress: a twin study of genetic and environmental influences.J Child Psychol Psychiatry.1996;37:721–730
18. Tizard B, Hodges J. The effect of early institutional rearing on the development of eight year old children.J Child Psychol Psychiatry.1978; 19:99 –118
19. Biederman J, Milberger S, Faraone SV, et al. Impact of adversity on functioning and comorbidity in children with attention-deficit hyperac-tivity disorder.J Am Acad Child Adolesc Psychiatry.1995;34:1495–1503 20. Barkley RA. Attention-deficit hyperactivity disorder.Sci Am.1998;279:
66 –71
21. Levine MD. Attention and dysfunctions of attention. In: Levine MD, Carey WB, Crocker AC, eds.Developmental-Behavioral Pediatrics.3rd ed. Philadelphia, PA: Saunders; 1999: chap 52
22. Denckla MB. Biological correlates of learning and attention: what is relevant to learning and attention-deficit hyperactivity disorder?J Dev Behav Pediatr.1996;17:114 –119
23. Jensen PS, Mrazek D, Knapp PK, et al. Evolution and revolution in child psychiatry: ADHD as a disorder of adaptation.J Am Acad Child Adolesc Psychiatry.1997;36:1672–1679
24. Diagnostic and Statistical Manual for Primary Care (DSM-PC) Child and Adolescent Version. Elk Grove Village, IL: American Academy of Pediatrics; 1994
Inhaled Nitric Oxide: A Premature
Remedy for Chronic Lung Disease?
ABBREVIATIONS. NO, nitric oxide; iNO, inhaled nitric oxide; cGMP, cyclic guanosine monophosphate; BPD, bronchopulmo-nary dysplasia; sGC, soluble guanylate cyclase.
N
itric oxide is the wonder drug of the ’90s. When Furchgott and Zawadski1reported in 1980 that the endothelial lining of arteries was the source of an important messenger of vascu-lar smooth muscle relaxation, who would have guessed that the messenger would turn out to be a noxious free radical gas contained in cigarette smoke? Identification of nitric oxide (NO) as the endothelial-derived mediator of vascular smooth muscle relaxation2,3 launched a remarkably rapid and rewarding series of discoveries regarding regu-lation of vascular tone, followed by prompt transfer of this knowledge to the successful treatment of hu-man disease.NO first achieved celebrity status when it was namedScience Magazine’s“Molecule of the Year” in 1992.4 In that year came the news that NO is the world’s leading cause of penile erection,5an obser-vation that spawned the development and distribu-tion of Viagra as an effective remedy for erectile dysfunction.6More accolades for NO came with the recent award of the Nobel Prize in Medicine to three American scientists whose pioneering research paved the way for NO’s ascent to fame and fortune in a world where so many gases are regarded as mere pollutants. Now people everywhere are saying “yes” to “NO.”
One of the most exciting developments in new-born medicine in the last decade has been the suc-cessful delivery of inhaled nitric oxide (iNO) to treat infants with persistent pulmonary hypertension,7–9a condition that commonly causes cyanosis from insuf-ficient blood flow to the lungs. Patients with this life-threatening disorder often have an overgrowth of smooth muscle in their pulmonary circulation as-sociated with increased vascular resistance that leads to systemic hypoxemia caused by shunting of de-oxygenated blood from the right atrium through the
Received for publication Dec 28, 1998; accepted Dec 28, 1998.
Address correspondence to Richard D. Bland, MD, Department of Pediat-rics, University of Utah School of Medicine, 50 North Medical Dr, Salt Lake City, UT 84132.
PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad-emy of Pediatrics.
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DOI: 10.1542/peds.103.3.664
1999;103;664
Pediatrics
William B. Carey
Problems in Diagnosing Attention and Activity
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