how low can we go…safely?: factors affecting intensive diabetes management

3
documentation of an impact of grade I IVH both with and without white matter injury. In conclusion, the study by Patra et al 4 has highlighted to the neonatal clinician that grade I to II IVH should not be disregarded in terms of neurodevelopmental consequences. Definitive neuroimaging with MRI in any infant with any grade of IVH before discharge would further assist in defining both the nature and extent of cerebral injury and/or impaired cerebral development. One key question for the future is, “Does low-grade IVH lead to adverse neurodevelopmental outcomes via white matter injury alone, or is there an addi- tional impact on neural progenitor cells limiting plasticity and development?” Regardless of the answer, our aim of continu- ing to reduce the incidence of IVH must be encouraged. Terrie E. Inder, MBChB, MD Associate Professor of Pediatrics, Neurology and Radiology St Louis Children’s Hospital Washington University St Louis, MO REFERENCES 1. Ancel PY, Livinec F, Larroque B, Marret S, Arnaud C, Pierrat V, et al. Cerebral Palsy Among Very Preterm children in relation to gestational age and neonatal ultrasound abnormalities: the EPIPAGE Cohort Study. Pedi- atrics 2006;117:828-35. 2. Horbar J. Vermont Oxford Network Database Summary 2004. 3. Sherlock RL, Anderson PJ, Doyle LW. Neurodevelopmental sequelae of intraventricular haemorrhage at 8 years of age in a regional cohort of ELBW very preterm infants. Early Hum Dev 2005;81:909-16. 4. Patra K, Wilson-Costello D, Taylor HG, Mercuri-Minich N, Hack M. Grades I to II intraventricular hemorrhage in extremely low birth weight infants: effects on neurodevelopment. J Pediatr 2006;149:169-73. 5. Savman K, Nilsson UA, Blennow M, Kjellmer I, Whitelaw A. Non- protein-bound iron is elevated in cerebrospinal fluid from preterm infants with posthemorrhagic ventricular dilatation. Pediatr Res 2001;49:208-12. 6. Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ. Maturation-depen- dent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 1998;18:6241-53. 7. Volpe JJ. Neurology of the Newborn. 4th edition. Philadelphia, PA: WB Saunders; 2001. 8. Dull C, Torbey MT. Cerebral vasospasm associated with intraventric- ular hemorrhage. Neurocrit Care 2005;3:150-2. 9. Lou HC. Perinatal hypoxic-ischemic brain damage and intraventricular hemorrhage: a pathogenetic model. Arch Neurol 1980;37:585-7. 10. Inder TE, Warfield SK, Wang HX, Huppi PS, Volpe JJ. Abnormal cerebral structure at term in premature infants. Pediatrics 2005;115:286-94. 11. Gressens P, Richelme C, Kadhim HJ, Gadisseux JF, Evrard P. The germinative zone produces the most cortical astrocytes after neuronal migra- tion in the developing mammalian brain. Biol Neonate 1992;62:4-24. 12. Vasileiadis GT, Gelman N, Han VK, Williams LA, Mann R, Bureau Y, Thompson RT. Uncomplicated intraventricular hemorrhage is followed by reduced cortical volume at near-term age. Pediatrics 2004;114:e367-72. 13. Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ. White matter injury in the preterm infant: a comparison between serial cranial sonographic and MR findings at term. Am J Neuroradiol 2003;24:805-9. 14. Inder TE, Wells S, Mogridge N, Spencer C, Volpe JJ. Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study. J Pediatr 2003;143:171-9. 15. Maalouf EF, Duggan PJ, Rutherford MA, Counsel SJ, Fletcher AM, Battin M, et al. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr 1999;135:351-7. 16. Woodward LJ, Anderson PA, Austin NC, Howard K, Inder TE. Cerebral abnormalities on neonatal magnetic resonance imaging and neuro- developmental outcomes in preterm infants. N Engl J Med 2006 (in press). HOW LOW CAN WE GO...SAFELY?: FACTORS AFFECTING INTENSIVE DIABETES MANAGEMENT A lthough there is little doubt that the Diabetes Con- trol and Complications Trial (DCCT) was a land- mark in the history of diabetes care, pediatric diabe- tes centers have been understandably cautious in adopting intensive management regimens. Diabetes centers eager to take this approach have seen a consistent decline in HbA1c among their patients but were also faced with an increased occurrence of severe hypoglycemic reactions. 1 However, in more recent years, hypoglycemia has been curtailed with the introduction of continuous subcutaneous insulin infusion (CSII) 2 and insulin analogues. 3 In addition, the flexibility that these advancements offer has been shown to decrease the perceived burden of diabetes care. 4 This enthusiasm for in- tensive diabetes management must be tempered, however, with the reality that this approach is more costly and may not be appropriate for every child. The DCCT enrolled more than 1400 subjects (195 were children) and is the largest study to examine whether strict blood glucose control could delay or prevent the long- term complications of type 1 diabetes. 5 Although the past 10 years have seen remarkable advancements in diabetes tech- nologies (continuous glucose sensors, insulin analogues, and so forth), the results of the DCCT were achieved with the same basic tools avail- able since the early 1980s (regular, neutral protamine Hagedorn [NPH], ultralente in- sulin, and self-moni- tored blood glucose). Even the insulin pump, which was used by about one third of the See related article, p 227 Reprint requests: Steven M. Willi, MD, Di- vision of Endocrinology/Diabetes, Chil- dren’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Suite 8C09, Philadelphia, PA 19104. E-mail: willi@email. chop.edu. J Pediatr 2006;149:154-6 0022-3476/$ - see front matter Copyright © 2006 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2006.06.002 154 Editorials The Journal of Pediatrics • August 2006

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documentation of an impact of grade I IVH both with andwithout white matter injury.

In conclusion, the study by Patra et al4 has highlightedto the neonatal clinician that grade I to II IVH should not bedisregarded in terms of neurodevelopmental consequences.Definitive neuroimaging with MRI in any infant with anygrade of IVH before discharge would further assist in definingboth the nature and extent of cerebral injury and/or impairedcerebral development. One key question for the future is,“Does low-grade IVH lead to adverse neurodevelopmentaloutcomes via white matter injury alone, or is there an addi-tional impact on neural progenitor cells limiting plasticity anddevelopment?” Regardless of the answer, our aim of continu-ing to reduce the incidence of IVH must be encouraged.

Terrie E. Inder, MBChB, MDAssociate Professor of Pediatrics, Neurology and Radiology

St Louis Children’s HospitalWashington University

St Louis, MO

REFERENCES1. Ancel PY, Livinec F, Larroque B, Marret S, Arnaud C, Pierrat V, et al.Cerebral Palsy Among Very Preterm children in relation to gestational ageand neonatal ultrasound abnormalities: the EPIPAGE Cohort Study. Pedi-atrics 2006;117:828-35.2. Horbar J. Vermont Oxford Network Database Summary 2004.3. Sherlock RL, Anderson PJ, Doyle LW. Neurodevelopmental sequelaeof intraventricular haemorrhage at 8 years of age in a regional cohort ofELBW very preterm infants. Early Hum Dev 2005;81:909-16.4. Patra K, Wilson-Costello D, Taylor HG, Mercuri-Minich N, Hack M.

Grades I to II intraventricular hemorrhage in extremely low birth weightinfants: effects on neurodevelopment. J Pediatr 2006;149:169-73.5. Savman K, Nilsson UA, Blennow M, Kjellmer I, Whitelaw A. Non-protein-bound iron is elevated in cerebrospinal fluid from preterm infantswith posthemorrhagic ventricular dilatation. Pediatr Res 2001;49:208-12.6. Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ. Maturation-depen-dent vulnerability of oligodendrocytes to oxidative stress-induced deathcaused by glutathione depletion. J Neurosci 1998;18:6241-53.7. Volpe JJ. Neurology of the Newborn. 4th edition. Philadelphia, PA:WB Saunders; 2001.8. Dull C, Torbey MT. Cerebral vasospasm associated with intraventric-ular hemorrhage. Neurocrit Care 2005;3:150-2.9. Lou HC. Perinatal hypoxic-ischemic brain damage and intraventricularhemorrhage: a pathogenetic model. Arch Neurol 1980;37:585-7.10. Inder TE, Warfield SK, Wang HX, Huppi PS, Volpe JJ. Abnormalcerebral structure at term in premature infants. Pediatrics 2005;115:286-94.11. Gressens P, Richelme C, Kadhim HJ, Gadisseux JF, Evrard P. Thegerminative zone produces the most cortical astrocytes after neuronal migra-tion in the developing mammalian brain. Biol Neonate 1992;62:4-24.12. Vasileiadis GT, Gelman N, Han VK, Williams LA, Mann R, BureauY, Thompson RT. Uncomplicated intraventricular hemorrhage is followedby reduced cortical volume at near-term age. Pediatrics 2004;114:e367-72.13. Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ. White matterinjury in the preterm infant: a comparison between serial cranial sonographicand MR findings at term. Am J Neuroradiol 2003;24:805-9.14. Inder TE, Wells S, Mogridge N, Spencer C, Volpe JJ. Defining thenature of the cerebral abnormalities in the premature infant: a qualitativemagnetic resonance imaging study. J Pediatr 2003;143:171-9.15. Maalouf EF, Duggan PJ, Rutherford MA, Counsel SJ, Fletcher AM,Battin M, et al. Magnetic resonance imaging of the brain in a cohort ofextremely preterm infants. J Pediatr 1999;135:351-7.16. Woodward LJ, Anderson PA, Austin NC, Howard K, Inder TE.Cerebral abnormalities on neonatal magnetic resonance imaging and neuro-developmental outcomes in preterm infants. N Engl J Med 2006 (in press).

HOW LOW CAN WE GO. . .SAFELY?: FACTORS AFFECTING INTENSIVEDIABETES MANAGEMENT

A lthough there is little doubt that the Diabetes Con-trol and Complications Trial (DCCT) was a land-mark in the history of diabetes care, pediatric diabe-

tes centers have been understandably cautious in adoptingintensive management regimens. Diabetes centers eager totake this approach have seen a consistent decline in HbA1camong their patients but were also faced with an increasedoccurrence of severe hypoglycemic reactions.1 However, inmore recent years, hypoglycemia has been curtailed with theintroduction of continuous subcutaneous insulin infusion(CSII)2 and insulin analogues.3 In addition, the flexibility thatthese advancements offer has been shown to decrease theperceived burden of diabetes care.4 This enthusiasm for in-tensive diabetes management must be tempered, however,with the reality that this approach is more costly and may notbe appropriate for every child.

The DCCT enrolled more than 1400 subjects (195were children) and is the largest study to examine whether

strict blood glucose control could delay or prevent the long-term complications of type 1 diabetes.5 Although the past 10years have seen remarkable advancements in diabetes tech-nologies (continuousglucose sensors, insulinanalogues, and so forth),the results of the DCCTwere achieved with thesame basic tools avail-able since the early1980s (regular, neutralprotamine Hagedorn[NPH], ultralente in-sulin, and self-moni-tored blood glucose).Even the insulin pump,which was used byabout one third of the

See related article, p 227

Reprint requests: Steven M. Willi, MD, Di-vision of Endocrinology/Diabetes, Chil-dren’s Hospital of Philadelphia, 34th Streetand Civic Center Boulevard, Suite 8C09,Philadelphia, PA 19104. E-mail: [email protected].

J Pediatr 2006;149:154-6

0022-3476/$ - see front matter

Copyright © 2006 Mosby Inc. All rightsreserved.

10.1016/j.jpeds.2006.06.002

154 Editorials The Journal of Pediatrics • August 2006

intensively treated DCCT subjects, was only chosen by 8children at the time of randomization. Rather than technol-ogy, this trial placed its emphasis on the importance ofimproved education of patients and frequent contact with askilled diabetes treatment team. The close temporal relationbetween the publication of the DCCT’s results and theachievement of these goals in the clinical setting,6 despite theabsence of significant technological advancement, suggeststhat the adoption of a multidisciplinary diabetes treatmentmodel is the single most significant predictor of improveddiabetes outcomes. In the “pay for performance” days thatseem destined to come, we can anticipate even greater pres-sures to achieve more aggressive blood glucose targets. Effec-tive application of diabetes technologies, offers the hope forimproved achievement of these lower glycemic targets with-out severe hypoglycemia.

In this issue of The Journal, Springer et al7 examine thenumerous factors associated with the achievement of optimaldiabetes control in children with type 1 diabetes. They foundthat a number of factors (for example, age and diabetesduration) contributed, but low socioeconomic status (SES)was the single strongest predictor of poor diabetes outcome.This question was also recently examined in a study of 155children at the Oregon Health Sciences Center.8 Similarly,the authors found that older age and longer diabetes durationpredicted poorer diabetes outcomes but also found that sin-gle-parent households and a reduced number of blood glucosechecks (a marker of compliance) had the same effect. Theseauthors were careful to exclude patients in their first year afterdiagnosis but concluded little with regard to SES. Othermarkers of compliance and diabetes self-management skills(for example, frequency of diabetes clinic visits) have also beenshown to predict HbA1c.9 At least one report suggests thatincreasing the frequency of visits beyond DCCT recommen-dations can facilitate the achievement of even better control.10

Springer’s finding that most children with good com-pliance who are regularly in contact with a competent treat-ment team can achieve HbA1c targets is not unique. Yet, thisstudy has a number of significant implications toward thefuture of type 1 diabetes treatment. Although their study wassomewhat limited by its relatively homogeneous, affluent co-hort, the authors clearly found a strong association betweendiabetes outcome (specifically HbA1c) and SES. It is unclearwhat particular aspects of high socioeconomic status predictedbetter outcomes, but the authors were careful to control fordifferences in sex, age, diabetes duration, insulin pump use,and body mass index. It seems likely that patients with lowSES may struggle with the financial burdens of diabetes care.The relative paucity of subjects with low SES in theircohort may have limited their ability to identify whetherthe use of CSII (which costs approximately $1800 per yearmore than insulin injections)6 might have mitigated someof these differences.

Another critical factor that limits the generalizability oftheir results is the relative availability of pediatric diabetesservices in urban Connecticut versus much of the UnitedStates. For their 667 patients, they have two physicians and

six nurse practitioners, which yields a patient-to-practitionerratio of less than 85:1, compared with a ratio of greater than150:1, as would be calculated from manpower data from theDCCT.11 The increasing number of pediatric patients withdiabetes, the emergence of type 2 diabetes in children, and thelimited number of skilled pediatric endocrinologists and nursepractitioners dedicated to the care of children with diabetescombine to make these ratios difficult to achieve across thecountry. Recent estimates from the Centers for Disease Con-trol suggest that more than 200,000 children in the UnitedStates are affected by diabetes, with only 633 full time equiv-alents (FTE) of clinical pediatric endocrinologists (many ofwhom provide a limited amount of diabetes care).

Hypoglycemia is the major limiting factor to the imple-mentation of intensive glycemic control. A variety of ingeniousdevices with the potential to improve control and decrease mor-bidity (including CSII and continuous glucose monitoring sys-tems) have only recently been introduced at a select number ofpediatric institutions on a large scale. The linking of thesecompact devices represents an “artificial pancreas,” which has thepotential to revolutionize diabetes care in the very near future.Perhaps because of the novelty of these devices and the com-plexity of their implementation in children, technology has onlyslowly made its way into pediatric diabetes practices. The ad-vanced age of pediatric endocrinologists in this country (medianage, 52.8 years; data from American Medical Association Mas-terfile, 2003) may play a role as well. A survey of the diabetesliterature will show that except for the noteworthy efforts of theDiabetes Research in Children Network (DirecNet, of whichYale is a constituent), the application of advanced technologieshas been largely limited to adults and older children in goodcontrol with few behavioral issues and strong family supportsystems. However, recent reports have suggested that very youngchildren12 and those with limited diabetes management skills10

have the most to gain from a technological approach to intensivetreatment.

Therefore, the reader should not interpret the results ofSpringer et al7 to imply that disadvantaged families are notworthy of the best efforts of a diabetes treatment team. Rather,it may be access to these specialized services, which was notsystematically evaluated in this report, that presents the majorobstacle for many families (and perhaps disproportionately thoseof low SES) to overcome. The shorter duration of diabetes inblack and Hispanic children (and presumably those of low SES)in this report remains unexplained, and, in fact, might reflect ahigher rate of attrition from care for these families who arestretched beyond their means by intensive treatment.

Despite the fact that intensive diabetes managementhas been shown to be cost-effective (even over the shortterm),13 reimbursement for diabetes care remains poor. As aresult, the vast majority of pediatric diabetes treatment teamsare situated at large academic medical centers, which limitstheir availability. Unless manpower limitations in pediatricdiabetes care can be overcome, these trends are unlikely tochange. More creative strategies to disseminate needed ser-vices (such as telemedicine)14 have been developed primarilyin countries with socialized medicine, but are currently being

Editorials 155

piloted in the United States. These strategies seem destined tofail in a medical system such as ours, which does not reim-burse health care providers for the time devoted to dataanalysis without the patient being present.

Steven M. Willi, MDDirector, Diabetes Center for Children

Children’s Hospital of PhiladelphiaAssociate Professor of Pediatrics

University of PennsylvaniaPhiladelphia, PA

REFERENCES1. Bulsara MK, Holman CD, Davis EA, Jones TW. The impact of adecade of changing treatment on rates of severe hypoglycemia in a popula-tion-based cohort of children with type 1 diabetes. Diabetes Care2004;27:2293-8.2. Willi SM, Planton J, Egede L, Schwarz S. Benefits of continuoussubcutaneous insulin infusion in children with type 1 diabetes. J Pediatr2003;143:796-801.3. Alemzadeh R, Berhe T, Wyatt, DT. Flexible insulin therapy withglargine insulin improved glycemic control and reduced severe hypoglycemiaamong preschool-aged children with type 1 diabetes mellitus. Pediatrics2005;115:1320-4.4. Fox L, Buckloh LM, Smith SD, Wysocki T, Mauras N. A randomizedcontrolled trial of insulin pump therapy in young children with type 1diabetes. Diabetes Care 2005;28:1277-81.5. Diabetes Control and Complications Trial Research Group. Effect ofintensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus.J Pediatr 1994;125:177-88.

6. Tamborlane WV, Bonfig W, Boland E. Recent advances in treatmentof youth with type 1 diabetic: better care through technology. Diabetic Med2001;18:864-70.7. Springer D, Dzieura J, Tamborlane WV, Steffen AT, Ahearn J H,Vincent M, Weinzimer SA. Optimal control of type 1 diabetes in youthreceiving intensive treatment. J Pediatr 2006;149:227-32.8. Urbach SL, LaFranchi S, Lambert L, Lapidus JA, Daneman D, BeckerTM. Predictors of glucose control in children and adolescents with type 1diabetes mellitus. Pediatr Diabetes 2005;6:69-74.9. Kaufman FR, Halvorson M, Carpenter S. Association between diabetescontrol and visits to a multidisciplinary pediatric diabetes clinic. Pediatrics1999;103:948-51.10. Wysocki T, Harris MA, Wilkinson K, Sadler M, Mauras N, WhiteNH. Self-management competence as a predictor of outcomes of intensivetherapy or usual care in youth with type 1 diabetes. Diabetes Care2003;26:2043-7.11. Diabetes Control and Complications Trial Research Group. Resourceutilization and costs of care in the diabetes control and complications trial.Diabetes Care 1995;18:1468-78.12. Jeha GS, Karaviti LP, Anderson D, Smith EO, Donaldson S, McGirkTS, Haymond MW. Continuous glucose monitoring and the reality ofmetabolic control in preschool children with type 1 diabetes. Diabetes Care2004;27:2881-6.13. Beck JK, Logan KJ, Hamm RM, Sproat SM, Musser KM, EverhartPD, et al. Reimbursement for pediatric diabetes intensive case management:a model for chronic diseases? Pediatrics 2004;113:47-50.14. Montori VM, Helgemoe PK, Guyatt GH, Dean DS, Leung TW,Smith SA, Kudva TC. Telecare for patients with type 1 diabetes andinadequate glycemic control: a randomized controlled trial and meta-analysis.Diabetes Care 2004;27:1088-94.

NO THE EVIDENCE: WHAT HAVE MEASUREMENTS OF EXHALED NITRICOXIDE GOT TO OFFER?

The relationship between the measurement of exhalednitric oxide (FeNO) and pediatric investigators hasgone from the heady excitement of the early flirta-

tions to a more solid and permanent relationship, perhaps lesssuperficially exciting, requiring harder work, but ultimatelymore realistic. The initial nitric oxide studies were largelycross-sectional or, at best, very-short-term longitudinal,1,2 butwere sufficient to suggest that here was something that addeda new dimension to the management of asthma.

A sea change in asthma management was long overdue.The importance of asthma as an inflammatory disease (at leastin older children and adults, not necessarily in infants andpreschool children) has long been appreciated, but even recentconventional guidelines3 instruct us to treat airway inflamma-tion with potent and potentially toxic anti-inflammatoryagents,4 without ever measuring inflammation at all! It isunimaginable that a cardiologist would fail to measure bloodpressure while prescribing antihypertensives, but that is ex-actly the situation in which we now find ourselves.

Initial studies in adults clearly demonstrated thatasthma could be better managed if a measure of inflammationwas used. Perhaps the best study showed that using inducedsputum eosinophils to titrate the dose of inhaled corticoste-roids resulted in fewer exacerbations without any increase inthe dose of inhaledmedication when com-pared with a groupmanaged convention-ally.5 A number of pe-diatric studies haveshown that FeNO canbe used to titrate thedose of inhaled ste-roids, leading to a bet-ter outcome,6 and topredict relapse aftercessation of inhaledcorticosteroids.7 A low

See related article, p 220

Reprint requests: Professor AndrewBush, Department of Paediatric Respira-tory Medicine, Royal Brompton Hospital,Sydney Street, London SW3 6NP,UK. E-mail: [email protected].

J Pediatr 2006;149:156-8

0022-3476/$ - see front matter

Copyright © 2006 Mosby Inc. All rightsreserved.

10.1016/j.jpeds.2006.05.035

156 Editorials The Journal of Pediatrics • August 2006