- Email: [email protected]
No gold at the ends of the glycemic rainbow
EDITORIALS
recommended thyroxine treatment. J Pediatr 1991;118:850-7. 4. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk PH, de Muinck Keizer-Schrams SMPF. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;136:292-7. 5. Fisher DA. The importance of early management in optimizing IQ in infants with congenital hypothyroidism. J Pediatr 2000;136:273-4. 6. Selva KA, Mandel SH, Rien L, Sesser D, Miyahira R, Skeels M, et al. Initial treatment of L-thyroxine in congenital hypothyroidism. J Pediatr 2002;141:786-92.
THE JOURNAL OF PEDIATRICS DECEMBER 2002 7. Penfold JL, Simpson DA. Premature craniosynostosis—a complication of thyroid replacement therapy. J Pediatr 1975;86:360-3. 8. Daneman D, Howard J. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. J Pediatr 1980;97:257-9. 9. American Academy of Pediatrics. Newborn screening for hypothyroidism: Recommended guidelines. Pediatrics 1993;91:1203-9. 10. Pinchera A, MacGillivray MH, Crawford JD, Freeman AG. Thyroid refractoriness in an athyreotic cretin fed soybean formula. N Engl J Med 1965;273:83-7.
11. Chorazy PA, Himelhoch S, Hopwood NJ, Greger NG, Postellon DC. Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature. Pediatrics 1995;96:148-50. 12. Bell DS, Ovalle F. Use of soy protein supplement and resultant need for increased dose of levothyroxine [review]. Endocr Pract 2001;7:193-4. 13. Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000; 283:2822-5. 14. Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333:1688-94.
No gold at the ends of the glycemic rainbow Children with type 1 diabetes mellitus (DM) are gravely threatened at both extremes of the glycemic spectrum. At one extreme, an excess of insulin relative to inadequate nutrient intake, or greater energy expenditure with exercise, can lead to severe hypoglycemia, seizures, coma, and death. At the other extreme, the metabolic decompensation of diabetic ketoacidosis (DKA) also can wreak havoc, including death and varying degrees of permanent neurologic impairment. The standardized mortality ratio in patients with DM who are younger than 20 years of age has been reported to be 2.3 (95% confidence interval, 1.9-2.9) and is highest in the very young (1–4 years of age) at 9.2 (95% CI, 5.4-14.7). DKA is 10 times as likely to be the cause of death as hypoglycemia, and cerebral edema compliReprint requests: Mark A. Sperling, MD, Professor, Department of Pediatrics/Endocrinology, 3705 Fifth Ave, Pittsburgh, PA 15213-2583.
J Pediatr 2002;141:754-6. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/18/130265 doi:10.1067/mpd.2002.130265
754
cating DKA is the most common cause of death and neurologic sequelae in children younger than 12 years of age.1 Hence, DKA complicated by cerebral edema remains the bane of physicians treating children with DM.2-4 Why do these complications occur and what can we do to avoid their devastating consequences? DKA DM
Diabetic ketoacidosis Diabetes mellitus
DKA represents the last line of defense in the body’s attempt to maintain homeostasis. The ultimate cause is lack of insulin, in association with marked increases in the stress hormones glucagon, epinephrine, cortisol, and growth hormone.5,6 Together, this hormonal milieu promotes glucose production but prevents its utilization, leading to hyperglycemia, osmotic diuresis, loss of glucose, water, electrolytes and anions, dehydration, and lactic acidosis. This same hormonal scenario promotes lipid breakdown as an alternate source of energy with formation of the keto acids betahydroxy-butyric and acetoacetic at rates that exceed their utiliza-
tion, thereby overwhelming buffering capacity and leading to marked metabolic acidosis. The clinical features result directly from these disturbances: polyuria, polydipsia, dehydration, weight loss, and deep-sighing Kussmaul respirations to excrete carbon dioxide in an attempt to balance acidosis. DKA occurs because the diagnosis of DM is not suspected and belatedly recognized at initial presentation, or because of deliberate and inadvertent omission of insulin, or because of sepsis and other severe stress in patients with established disease.5-7 Appropriate treatment with insulin, fluids, and electrolytes, and other specific and gen-
See related article, p 793. eral supportive measures correct metabolic acidosis without sequelae in almost 99% of cases. About one in 100 episodes of DKA in children result in cerebral edema.2-4 The ultimate cause of cerebral edema remains enigmatic.3-4 There may be more than one mechanism involved, including putative generation of idiogenic osmoles intracerebrally that promote retention of
EDITORIALS
THE JOURNAL OF PEDIATRICS
VOLUME 141, NUMBER 6 water during rehydration, decreased cerebral blood flow, and vascular thrombosis. The contribution of medical management, especially the rate and composition of fluid replacement therapy, remain controversial. The standards of care recommend protocols to replace fluid deficit over 48 hours, and the use of isotonic fluid to avoid too rapid a decline in serum osmolality. But, it is not proven that this approach is safer or reduces cerebral edema.1-4 In this issue of The Journal of Pediatrics, Marcin et al describe the factors associated with adverse outcomes in children in whom cerebral edema develops during treatment for DKA.8 The data set and cohort are the same as previously reported,2 and involve an analysis of apparent cerebral edema that occurred in 61 of 6977 hospitalizations for DKA during a 15-year period involving 10 major pediatric centers. In their original report, the authors focused on risk factors that predisposed children with DKA for cerebral edema.2 They identified predisposing factors to be a low partial pressure of arterial carbon dioxide and high serum urea nitrogen concentration at presentation, as well as those who were treated with bicarbonate as being at increased risk for cerebral edema. Each of these factors, and especially their combination, would suggest more severe, long-standing DKA before intervention. Thus, bicarbonate replacement is generally contra-indicated in patients with DKA except with circulatory failure and when pH is already <7.1 so that its use in children who had cerebral edema may reflect the severity of the acidosis rather than a direct effect of the bicarbonate replacement on causing or promoting cerebral edema. In the current report,8 the authors have focused on potential relationships between the outcome of the DKA-related cerebral edema and baseline clinical features and therapeutic interventions for the treatment of the cerebral edema rather than the DKA. In this cohort, 36 of the 61 subjects (59%) survived without sequelae; 17 (28%)
died or survived in a vegetative state; and 8 (13%) survived with mild-to-moderate neurologic disabilities. Factors associated with poor outcome included greater neurologic depression at recognition of cerebral edema, a high initial serum urea nitrogen concentration, and intubation with hyperventilation to a partial pressure of carbon dioxide of <22 mmHg. Once again, these factors reflect prolonged metabolic decompensation, so that both the occurrence of cerebral edema and its outcome may depend on duration and severity of untreated DKA. Only the hyperventilation may be modified. These overall results now are better than a previous, more selected series of 69 episodes of cerebral edema reported by Rosenbloom a decade ago.9 There, only 10 survived unscathed and 6 were mild-to-moderately disabled; 9 were severely disabled or vegetative; and 44, almost two thirds of the total, died. Early recognition and intervention was far more likely to result in favorable outcome; failure-to-treat was almost invariably associated with death or severe disability. It appears that physicians are now more alert to the possibility of cerebral edema and intervene more effectively. The results of another review of cerebral edema complicating DKA also confirm that patients with cerebral edema were significantly younger, had a 3-fold longer duration of DKA before treatment was instituted, and were more hyperglycemic at presentation.10 Thus, delay in diagnosing and treating DKA is related to the likelihood of cerebral edema, whereas anticipatory awareness and appropriate early interventions may improve prognostic outcome in those in whom cerebral edema does develop. Although the use of mannitol was not associated with improved outcomes in the current report, the variability of dose and timing of administration in relation to signs and symptoms of cerebral edema preclude definitive conclusions. Of greater interest is the association of poorer neurologic outcome with intubation and hyperventilation, consistent with a
growing body of evidence that hypocarbia contributes to decreased cerebral blood flow and cerebral ischemia. In a prospective, randomized trial for ventilatory management of acute traumatic brain injury, hyperventilation was associated with a less favorable outcome.8,11 However, in the current retrospective, nonrandomized series, it was not possible to distinguish between an adverse effect of hyperventilation treatment versus the underlying illness. Most unquantifiable remains individual susceptibility to the combined influences of severe metabolic decompensation in DKA. What can be done about this situation? The broad thread that unites both cerebral edema and poor neurologic outcome is the severity of longstanding DKA in children, particularly those younger than 10 years of age. Hence, avoidance of DKA should be a prime target in the education of physicians and patients. The simple procedure of dipstick testing of urine for glucose and ketones should be routine in children who appear ill without other apparent cause, or perhaps even with it, and especially if a history of weight loss and polyuria is elicited, ie, sought. Once DKA is diagnosed, prompt transfer of children to a center experienced in the management of childhood DKA and its complications is highly recommended and some may say mandatory. Emergency transfer of severely ill children to regional medical centers is now a well established part of extensive and sophisticated systems available in the United States. Finally, a consensus conference on the management of DKA would be of great value to standardize care among endocrinologists, intensivists, emergency department specialists, and other providers who usually manage these sick children. Such standardized protocols may also permit prospective randomized trials to evaluate questions such as hyperventilation, the use of bicarbonate, rates of fluid replacement and their composition, and other variables considered as contributors to the outcome of DKA. Given today’s 755
EDITORIALS
knowledge, children in developed countries should not die or suffer irreparable neurologic damage with DKA—it is likely avoidable in the majority of instances. Mark A. Sperling, MD Division of Endocrinology Children’s Hospital of Pittsburgh Pittsburgh, PA 15213
REFERENCES 1. Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin-dependent diabetes 1990-96. Arch Dis Child 1999;81:318-23.
THE JOURNAL OF PEDIATRICS DECEMBER 2002 2. Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med 2001;344:264-9. 3. Dunger DB, Edge JA. Predicting cerebral edema during diabetic ketoacidosis. N Engl J Med 2001;344:302-3. 4. Muir A. Do doctors cause or prevent cerebral edema in children with diabetic ketoacidosis? Pediatr Diabetes 2000;1:209-16. 5. Sperling MA. Diabetic ketoacidosis. Pediatr Clin North Am 1984;31:591-610. 6. White NH. Diabetic ketoacidosis. Endocrinol Metab Clin North Am 2000; 29:657-82. 7. Morris AD, Boyle DIR, McMahon AD, Greene SA, MacDonald TM,
8.
9.
10.
11.
Newton RW. Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus. Lancet 1997;350: 1505-10. Marcin JP, Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, et al. Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. J Pediatr 2002;141:793-7. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990;13:22-33. Bello FA, Sotos JF. Cerebral edema in diabetic ketoacidosis in children. Lancet 1990;336:64. Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med 2002;347:43-53.
Randomized trials and recruitment tribulations: Rethinking the research enterprise In their article exploring Australian pediatricians’ attitudes toward randomized controlled trials (RCTs),1 Caldwell et al identify reasons why clinicians are disinclined to enroll their patients in clinical experiments. Many factors appear to influence pediatricians’ enrollment of patients in RCTs, including pediatricians’ assumptions about parental social class and attitudes about research, pediatricians’ own opinions about the treatments under study, and concerns for the doctor-patient relationship. A variety of misgivings dissuade Reprint requests: Richard C. Wasserman, MD, MPH, One S Prospect St, Burlington, VT 05401. E-mail: [email protected].
J Pediatr 2002;141:756-7. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/18/130359 doi:10.1067/mpd.2002.130359
756
some pediatricians from enrolling patients in any trials and lead others to enroll patients erratically and selectively. Unwillingness on the part of many pediatricians to enroll their patients in RCTs represents a challenge to the pediatric scientific community. Researchers’ mandates to provide the best evidence on which to base improvements in health care for children compels us to conduct more pediatric RCTs, and therefore to involve more children. The
See related article, p 798. ethical issues presented by children’s participation in trials are substantial, but far from insuperable. Many successful US models for broad participation in pediatric RCTs exist. In oncology the merger of several groups has formed the highly successful Children’s Oncology Group (http://www.childrensoncology-
group.org/). Rheumatology has the Pediatric Rheumatology Collaborative Study Group and the Pediatric Rheumatology Research Network; neonatology has the National Institute of Child Health and Human DevelopRCT
Randomized controlled trial
ment Neonatal Research Network and the Vermont Oxford Network, and, among pediatric primary care practitioners, the American Academy of Pediatrics Center for Child Health Research’s Pediatric Research in Office Settings is currently conducting its first RCT. These groups all have identified strategies for involving large groups of pediatricians in enrolling their patients in RCTs, and we have much to learn from their experience. In addition, site management organizations working with the pharmaceutical industry and
recommended thyroxine treatment. J Pediatr 1991;118:850-7. 4. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk PH, de Muinck Keizer-Schrams SMPF. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;136:292-7. 5. Fisher DA. The importance of early management in optimizing IQ in infants with congenital hypothyroidism. J Pediatr 2000;136:273-4. 6. Selva KA, Mandel SH, Rien L, Sesser D, Miyahira R, Skeels M, et al. Initial treatment of L-thyroxine in congenital hypothyroidism. J Pediatr 2002;141:786-92.
THE JOURNAL OF PEDIATRICS DECEMBER 2002 7. Penfold JL, Simpson DA. Premature craniosynostosis—a complication of thyroid replacement therapy. J Pediatr 1975;86:360-3. 8. Daneman D, Howard J. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. J Pediatr 1980;97:257-9. 9. American Academy of Pediatrics. Newborn screening for hypothyroidism: Recommended guidelines. Pediatrics 1993;91:1203-9. 10. Pinchera A, MacGillivray MH, Crawford JD, Freeman AG. Thyroid refractoriness in an athyreotic cretin fed soybean formula. N Engl J Med 1965;273:83-7.
11. Chorazy PA, Himelhoch S, Hopwood NJ, Greger NG, Postellon DC. Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature. Pediatrics 1995;96:148-50. 12. Bell DS, Ovalle F. Use of soy protein supplement and resultant need for increased dose of levothyroxine [review]. Endocr Pract 2001;7:193-4. 13. Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000; 283:2822-5. 14. Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333:1688-94.
No gold at the ends of the glycemic rainbow Children with type 1 diabetes mellitus (DM) are gravely threatened at both extremes of the glycemic spectrum. At one extreme, an excess of insulin relative to inadequate nutrient intake, or greater energy expenditure with exercise, can lead to severe hypoglycemia, seizures, coma, and death. At the other extreme, the metabolic decompensation of diabetic ketoacidosis (DKA) also can wreak havoc, including death and varying degrees of permanent neurologic impairment. The standardized mortality ratio in patients with DM who are younger than 20 years of age has been reported to be 2.3 (95% confidence interval, 1.9-2.9) and is highest in the very young (1–4 years of age) at 9.2 (95% CI, 5.4-14.7). DKA is 10 times as likely to be the cause of death as hypoglycemia, and cerebral edema compliReprint requests: Mark A. Sperling, MD, Professor, Department of Pediatrics/Endocrinology, 3705 Fifth Ave, Pittsburgh, PA 15213-2583.
J Pediatr 2002;141:754-6. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/18/130265 doi:10.1067/mpd.2002.130265
754
cating DKA is the most common cause of death and neurologic sequelae in children younger than 12 years of age.1 Hence, DKA complicated by cerebral edema remains the bane of physicians treating children with DM.2-4 Why do these complications occur and what can we do to avoid their devastating consequences? DKA DM
Diabetic ketoacidosis Diabetes mellitus
DKA represents the last line of defense in the body’s attempt to maintain homeostasis. The ultimate cause is lack of insulin, in association with marked increases in the stress hormones glucagon, epinephrine, cortisol, and growth hormone.5,6 Together, this hormonal milieu promotes glucose production but prevents its utilization, leading to hyperglycemia, osmotic diuresis, loss of glucose, water, electrolytes and anions, dehydration, and lactic acidosis. This same hormonal scenario promotes lipid breakdown as an alternate source of energy with formation of the keto acids betahydroxy-butyric and acetoacetic at rates that exceed their utiliza-
tion, thereby overwhelming buffering capacity and leading to marked metabolic acidosis. The clinical features result directly from these disturbances: polyuria, polydipsia, dehydration, weight loss, and deep-sighing Kussmaul respirations to excrete carbon dioxide in an attempt to balance acidosis. DKA occurs because the diagnosis of DM is not suspected and belatedly recognized at initial presentation, or because of deliberate and inadvertent omission of insulin, or because of sepsis and other severe stress in patients with established disease.5-7 Appropriate treatment with insulin, fluids, and electrolytes, and other specific and gen-
See related article, p 793. eral supportive measures correct metabolic acidosis without sequelae in almost 99% of cases. About one in 100 episodes of DKA in children result in cerebral edema.2-4 The ultimate cause of cerebral edema remains enigmatic.3-4 There may be more than one mechanism involved, including putative generation of idiogenic osmoles intracerebrally that promote retention of
EDITORIALS
THE JOURNAL OF PEDIATRICS
VOLUME 141, NUMBER 6 water during rehydration, decreased cerebral blood flow, and vascular thrombosis. The contribution of medical management, especially the rate and composition of fluid replacement therapy, remain controversial. The standards of care recommend protocols to replace fluid deficit over 48 hours, and the use of isotonic fluid to avoid too rapid a decline in serum osmolality. But, it is not proven that this approach is safer or reduces cerebral edema.1-4 In this issue of The Journal of Pediatrics, Marcin et al describe the factors associated with adverse outcomes in children in whom cerebral edema develops during treatment for DKA.8 The data set and cohort are the same as previously reported,2 and involve an analysis of apparent cerebral edema that occurred in 61 of 6977 hospitalizations for DKA during a 15-year period involving 10 major pediatric centers. In their original report, the authors focused on risk factors that predisposed children with DKA for cerebral edema.2 They identified predisposing factors to be a low partial pressure of arterial carbon dioxide and high serum urea nitrogen concentration at presentation, as well as those who were treated with bicarbonate as being at increased risk for cerebral edema. Each of these factors, and especially their combination, would suggest more severe, long-standing DKA before intervention. Thus, bicarbonate replacement is generally contra-indicated in patients with DKA except with circulatory failure and when pH is already <7.1 so that its use in children who had cerebral edema may reflect the severity of the acidosis rather than a direct effect of the bicarbonate replacement on causing or promoting cerebral edema. In the current report,8 the authors have focused on potential relationships between the outcome of the DKA-related cerebral edema and baseline clinical features and therapeutic interventions for the treatment of the cerebral edema rather than the DKA. In this cohort, 36 of the 61 subjects (59%) survived without sequelae; 17 (28%)
died or survived in a vegetative state; and 8 (13%) survived with mild-to-moderate neurologic disabilities. Factors associated with poor outcome included greater neurologic depression at recognition of cerebral edema, a high initial serum urea nitrogen concentration, and intubation with hyperventilation to a partial pressure of carbon dioxide of <22 mmHg. Once again, these factors reflect prolonged metabolic decompensation, so that both the occurrence of cerebral edema and its outcome may depend on duration and severity of untreated DKA. Only the hyperventilation may be modified. These overall results now are better than a previous, more selected series of 69 episodes of cerebral edema reported by Rosenbloom a decade ago.9 There, only 10 survived unscathed and 6 were mild-to-moderately disabled; 9 were severely disabled or vegetative; and 44, almost two thirds of the total, died. Early recognition and intervention was far more likely to result in favorable outcome; failure-to-treat was almost invariably associated with death or severe disability. It appears that physicians are now more alert to the possibility of cerebral edema and intervene more effectively. The results of another review of cerebral edema complicating DKA also confirm that patients with cerebral edema were significantly younger, had a 3-fold longer duration of DKA before treatment was instituted, and were more hyperglycemic at presentation.10 Thus, delay in diagnosing and treating DKA is related to the likelihood of cerebral edema, whereas anticipatory awareness and appropriate early interventions may improve prognostic outcome in those in whom cerebral edema does develop. Although the use of mannitol was not associated with improved outcomes in the current report, the variability of dose and timing of administration in relation to signs and symptoms of cerebral edema preclude definitive conclusions. Of greater interest is the association of poorer neurologic outcome with intubation and hyperventilation, consistent with a
growing body of evidence that hypocarbia contributes to decreased cerebral blood flow and cerebral ischemia. In a prospective, randomized trial for ventilatory management of acute traumatic brain injury, hyperventilation was associated with a less favorable outcome.8,11 However, in the current retrospective, nonrandomized series, it was not possible to distinguish between an adverse effect of hyperventilation treatment versus the underlying illness. Most unquantifiable remains individual susceptibility to the combined influences of severe metabolic decompensation in DKA. What can be done about this situation? The broad thread that unites both cerebral edema and poor neurologic outcome is the severity of longstanding DKA in children, particularly those younger than 10 years of age. Hence, avoidance of DKA should be a prime target in the education of physicians and patients. The simple procedure of dipstick testing of urine for glucose and ketones should be routine in children who appear ill without other apparent cause, or perhaps even with it, and especially if a history of weight loss and polyuria is elicited, ie, sought. Once DKA is diagnosed, prompt transfer of children to a center experienced in the management of childhood DKA and its complications is highly recommended and some may say mandatory. Emergency transfer of severely ill children to regional medical centers is now a well established part of extensive and sophisticated systems available in the United States. Finally, a consensus conference on the management of DKA would be of great value to standardize care among endocrinologists, intensivists, emergency department specialists, and other providers who usually manage these sick children. Such standardized protocols may also permit prospective randomized trials to evaluate questions such as hyperventilation, the use of bicarbonate, rates of fluid replacement and their composition, and other variables considered as contributors to the outcome of DKA. Given today’s 755
EDITORIALS
knowledge, children in developed countries should not die or suffer irreparable neurologic damage with DKA—it is likely avoidable in the majority of instances. Mark A. Sperling, MD Division of Endocrinology Children’s Hospital of Pittsburgh Pittsburgh, PA 15213
REFERENCES 1. Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin-dependent diabetes 1990-96. Arch Dis Child 1999;81:318-23.
THE JOURNAL OF PEDIATRICS DECEMBER 2002 2. Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med 2001;344:264-9. 3. Dunger DB, Edge JA. Predicting cerebral edema during diabetic ketoacidosis. N Engl J Med 2001;344:302-3. 4. Muir A. Do doctors cause or prevent cerebral edema in children with diabetic ketoacidosis? Pediatr Diabetes 2000;1:209-16. 5. Sperling MA. Diabetic ketoacidosis. Pediatr Clin North Am 1984;31:591-610. 6. White NH. Diabetic ketoacidosis. Endocrinol Metab Clin North Am 2000; 29:657-82. 7. Morris AD, Boyle DIR, McMahon AD, Greene SA, MacDonald TM,
8.
9.
10.
11.
Newton RW. Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus. Lancet 1997;350: 1505-10. Marcin JP, Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, et al. Factors associated with adverse outcomes in children with diabetic ketoacidosis-related cerebral edema. J Pediatr 2002;141:793-7. Rosenbloom AL. Intracerebral crises during treatment of diabetic ketoacidosis. Diabetes Care 1990;13:22-33. Bello FA, Sotos JF. Cerebral edema in diabetic ketoacidosis in children. Lancet 1990;336:64. Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med 2002;347:43-53.
Randomized trials and recruitment tribulations: Rethinking the research enterprise In their article exploring Australian pediatricians’ attitudes toward randomized controlled trials (RCTs),1 Caldwell et al identify reasons why clinicians are disinclined to enroll their patients in clinical experiments. Many factors appear to influence pediatricians’ enrollment of patients in RCTs, including pediatricians’ assumptions about parental social class and attitudes about research, pediatricians’ own opinions about the treatments under study, and concerns for the doctor-patient relationship. A variety of misgivings dissuade Reprint requests: Richard C. Wasserman, MD, MPH, One S Prospect St, Burlington, VT 05401. E-mail: [email protected].
J Pediatr 2002;141:756-7. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/18/130359 doi:10.1067/mpd.2002.130359
756
some pediatricians from enrolling patients in any trials and lead others to enroll patients erratically and selectively. Unwillingness on the part of many pediatricians to enroll their patients in RCTs represents a challenge to the pediatric scientific community. Researchers’ mandates to provide the best evidence on which to base improvements in health care for children compels us to conduct more pediatric RCTs, and therefore to involve more children. The
See related article, p 798. ethical issues presented by children’s participation in trials are substantial, but far from insuperable. Many successful US models for broad participation in pediatric RCTs exist. In oncology the merger of several groups has formed the highly successful Children’s Oncology Group (http://www.childrensoncology-
group.org/). Rheumatology has the Pediatric Rheumatology Collaborative Study Group and the Pediatric Rheumatology Research Network; neonatology has the National Institute of Child Health and Human DevelopRCT
Randomized controlled trial
ment Neonatal Research Network and the Vermont Oxford Network, and, among pediatric primary care practitioners, the American Academy of Pediatrics Center for Child Health Research’s Pediatric Research in Office Settings is currently conducting its first RCT. These groups all have identified strategies for involving large groups of pediatricians in enrolling their patients in RCTs, and we have much to learn from their experience. In addition, site management organizations working with the pharmaceutical industry and