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Tight Glycemic Control in Children — Is the Target in Sight? Michael S.D. Agus, M.D. Should a strategy of tight glycemic control with the use of intravenous insulin be used to normalize blood glucose concentration in critically ill children as part of their therapy? This approach significantly reduced morbidity, mortality, or both in two randomized, controlled trials involving children1,2 but not in a third, in which continuous glucose monitoring was performed.3 The patient populations differed among the three studies, with one involving children with severe burns, one involving children who were in the intensive-care unit (ICU) after cardiac surgery, and one involving children who were in the ICU for a variety of reasons. The intervention increased the rate of severe hypoglycemia across populations, except in the study that used continuous glucose monitoring.3 Hypoglycemia was not associated with a risk of neurocognitive disability in one 4-year follow-up study,4 but an association between hypoglycemia and mortality has been reported.5 Pediatric intensivists remain wary of the risks of severe hypoglycemia in protocols involving tight glycemic control.6 In this issue of the Journal, Macrae et al.7 report the results of a fourth randomized, controlled trial of tight glycemic control in children who have undergone cardiac surgery and in critically ill children without heart disease — the Control of Hyperglycaemia in Paediatric Intensive Care (CHiP) trial. The investigators enrolled 1369 critically ill children, at 13 pediatric ICUs in England, who were undergoing mechanical ventilation and receiving vasoactive medications; patients were randomly assigned to either tight glycemic control, with a blood glucose target of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per
168
liter) or conventional glycemic control, with a target of 180 to 216 mg per deciliter (10.0 to 12.0 mmol per liter). The primary outcome was the number of days alive and free from mechanical ventilation at 30 days. The investigators also assessed other critical care outcomes, as well as the number of days in the hospital and health care costs over a 12-month period. There was no significant between-group difference in the primary outcome, even when the outcome was analyzed in prespecified subgroups of children who had been admitted to the pediatric ICU after cardiac surgery and those who had been admitted for other reasons. This well-designed, well-executed trial is the first study of tight glycemic control in children to be conducted at more than two centers. Patients who had undergone cardiac surgery constituted 60% of the overall cohort, with surgical complexity scores similar to those in prior trials. In the non–cardiac-surgery subgroup, 73% of the patients had a predicted mortality of 5% or higher, and 19% had a predicted mortality of 15% or higher, rates that are indicative of an extremely ill non–cardiac-surgery cohort. Investigators achieved the target glucose control with an average blood glucose level of 107 mg per deciliter (5.9 mmol per liter) in the tightglycemic-control group, a level similar to that in two prior trials (an average of 112 mg per deciliter [6.2 mmol per liter] in one study,3 and 115 mg per deciliter [6.4 mmol per liter] among children >1 year of age and 86 mg per deciliter [4.8 mmol per liter] among children ≤1 year of age in the other study1). The blood glucose level in the conventional-glycemic-control group was
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
editorials
not as elevated as expected, at 114 mg per deciliter (6.3 mmol per liter), which was lower than the level in two prior trials (an average of 121 mg per deciliter [6.7 mmol per liter] in one study,3 and 148 mg per deciliter [8.2 mmol per liter] among children >1 year of age and 115 mg per deciliter among children ≤1 year of age in the other study1); the fact that hyperglycemia did not develop in a third of the included patients may have affected these means. Severe hypoglycemia, defined as a blood glucose level of less than 36 mg per deciliter (2.0 mmol per liter), occurred in 7.3% of the patients in the tight-glycemic-control group and 1.5% in the conventional-glycemic-control group. In two earlier trials,1,3 the rate of hypoglycemia was 25% in one and 4% in the other, in which continuous glucose monitoring was used. The rate of severe hypoglycemia in the general pediatric critical care population is in the range of 4 to 7%.8 Hypoglycemia was associated with increased mortality among the patients in the CHiP trial, as it was in a previous large study involving adults,9 although not in the previous single-center study involving children.1 There was also a remarkable difference that emerged over the course of the 1-year health care follow-up: in the subgroup of patients who had not undergone cardiac surgery, the average length of stay in the hospital up to 1 year was 13.5 days shorter with tight glycemic control than with conventional glycemic control, and the per-patient health care costs were $13,000 less in the tight-glycemic-control group. These differences were not due to early mortality. The use of renal-replacement therapies was significantly lower in the tight-glycemic-control group than in the conventional-glycemic control group, although renal function was not reported. The lack of benefit with respect to infection or survival in the CHiP trial appears to confirm data from the earlier two-center trial3 but contradicts findings from the single-center trial.1 One hopes that a combined analysis will be performed on data from the three trials that used similar strategies, involving more than 2300 cardiac surgical patients at 16 intensive care units.1,3,7 Such an analysis should consider the degree of hyperglycemia, insulin dose, age of the patients, and the incidence of hypoglycemia. Meanwhile, the preponderance of published data
seems to indicate that tight glycemic control should not be used as standard treatment for children who have undergone cardiac surgery. In the CHiP trial, the non–cardiac-surgery patients appeared to differ importantly from cardiac-surgery patients, with a higher predicted mortality, and in prior data, these patients also had a higher rate and severity of hyperglycemia.10 Although the improved 1-year health care outcomes in the non–cardiac-surgery patients is compelling, it remains impossible to determine best practice for the child who requires critical care for reasons other than cardiac surgery or burns until either a meta-analysis of several trials is performed on an individual-data level or until data from an ongoing large, multicenter trial (ClinicalTrials.gov number, NCT01565941) are accrued. Future clinical trials should use the most advanced technology to reduce the incidence, severity, and duration of adverse events, most saliently, hypoglycemia. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From Boston Children’s Hospital and Harvard Medical School — both in Boston. 1. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin
therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009;373:547-56. 2. Jeschke MG, Kulp GA, Kraft R, et al. Intensive insulin therapy in severely burned pediatric patients: a prospective randomized trial. Am J Respir Crit Care Med 2010;182:351-9. 3. Agus MSD, Steil GM, Wypij D, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012;367:1208-19. 4. Mesotten D, Gielen M, Sterken C, et al. Neurocognitive development of children 4 years after critical illness and treatment with tight glucose control: a randomized controlled trial. JAMA 2012;308:1641-50. 5. Faustino EV, Bogue CW. Relationship between hypoglycemia and mortality in critically ill children. Pediatr Crit Care Med 2010;11:690-8. 6. Hirshberg EL, Sward KA, Faustino EV, et al. Clinical equipoise regarding glycemic control: a survey of pediatric intensivist perceptions. Pediatr Crit Care Med 2013;14:123-9. 7. Macrae D, Grieve R, Allen E, et al. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med 2014;370:107-18. 8. Rake AJ, Srinivasan V, Nadkarni V, Kaptan R, Newth CJ. Glucose variability and survival in critically ill children: allostasis or harm? Pediatr Crit Care Med 2010;11:707-12. 9. The NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012;367:1108-18. 10. Srinivasan V, Spinella PC, Drott HR, Roth CL, Helfaer MA, Nadkarni V. Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children. Pediatr Crit Care Med 2004;5:329-36. DOI: 10.1056/NEJMe1313770 Copyright © 2014 Massachusetts Medical Society.
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
169
n e w e ng l a n d j o u r na l
of
m e dic i n e
edi t or i a l s
Tight Glycemic Control in Children — Is the Target in Sight? Michael S.D. Agus, M.D. Should a strategy of tight glycemic control with the use of intravenous insulin be used to normalize blood glucose concentration in critically ill children as part of their therapy? This approach significantly reduced morbidity, mortality, or both in two randomized, controlled trials involving children1,2 but not in a third, in which continuous glucose monitoring was performed.3 The patient populations differed among the three studies, with one involving children with severe burns, one involving children who were in the intensive-care unit (ICU) after cardiac surgery, and one involving children who were in the ICU for a variety of reasons. The intervention increased the rate of severe hypoglycemia across populations, except in the study that used continuous glucose monitoring.3 Hypoglycemia was not associated with a risk of neurocognitive disability in one 4-year follow-up study,4 but an association between hypoglycemia and mortality has been reported.5 Pediatric intensivists remain wary of the risks of severe hypoglycemia in protocols involving tight glycemic control.6 In this issue of the Journal, Macrae et al.7 report the results of a fourth randomized, controlled trial of tight glycemic control in children who have undergone cardiac surgery and in critically ill children without heart disease — the Control of Hyperglycaemia in Paediatric Intensive Care (CHiP) trial. The investigators enrolled 1369 critically ill children, at 13 pediatric ICUs in England, who were undergoing mechanical ventilation and receiving vasoactive medications; patients were randomly assigned to either tight glycemic control, with a blood glucose target of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per
168
liter) or conventional glycemic control, with a target of 180 to 216 mg per deciliter (10.0 to 12.0 mmol per liter). The primary outcome was the number of days alive and free from mechanical ventilation at 30 days. The investigators also assessed other critical care outcomes, as well as the number of days in the hospital and health care costs over a 12-month period. There was no significant between-group difference in the primary outcome, even when the outcome was analyzed in prespecified subgroups of children who had been admitted to the pediatric ICU after cardiac surgery and those who had been admitted for other reasons. This well-designed, well-executed trial is the first study of tight glycemic control in children to be conducted at more than two centers. Patients who had undergone cardiac surgery constituted 60% of the overall cohort, with surgical complexity scores similar to those in prior trials. In the non–cardiac-surgery subgroup, 73% of the patients had a predicted mortality of 5% or higher, and 19% had a predicted mortality of 15% or higher, rates that are indicative of an extremely ill non–cardiac-surgery cohort. Investigators achieved the target glucose control with an average blood glucose level of 107 mg per deciliter (5.9 mmol per liter) in the tightglycemic-control group, a level similar to that in two prior trials (an average of 112 mg per deciliter [6.2 mmol per liter] in one study,3 and 115 mg per deciliter [6.4 mmol per liter] among children >1 year of age and 86 mg per deciliter [4.8 mmol per liter] among children ≤1 year of age in the other study1). The blood glucose level in the conventional-glycemic-control group was
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
editorials
not as elevated as expected, at 114 mg per deciliter (6.3 mmol per liter), which was lower than the level in two prior trials (an average of 121 mg per deciliter [6.7 mmol per liter] in one study,3 and 148 mg per deciliter [8.2 mmol per liter] among children >1 year of age and 115 mg per deciliter among children ≤1 year of age in the other study1); the fact that hyperglycemia did not develop in a third of the included patients may have affected these means. Severe hypoglycemia, defined as a blood glucose level of less than 36 mg per deciliter (2.0 mmol per liter), occurred in 7.3% of the patients in the tight-glycemic-control group and 1.5% in the conventional-glycemic-control group. In two earlier trials,1,3 the rate of hypoglycemia was 25% in one and 4% in the other, in which continuous glucose monitoring was used. The rate of severe hypoglycemia in the general pediatric critical care population is in the range of 4 to 7%.8 Hypoglycemia was associated with increased mortality among the patients in the CHiP trial, as it was in a previous large study involving adults,9 although not in the previous single-center study involving children.1 There was also a remarkable difference that emerged over the course of the 1-year health care follow-up: in the subgroup of patients who had not undergone cardiac surgery, the average length of stay in the hospital up to 1 year was 13.5 days shorter with tight glycemic control than with conventional glycemic control, and the per-patient health care costs were $13,000 less in the tight-glycemic-control group. These differences were not due to early mortality. The use of renal-replacement therapies was significantly lower in the tight-glycemic-control group than in the conventional-glycemic control group, although renal function was not reported. The lack of benefit with respect to infection or survival in the CHiP trial appears to confirm data from the earlier two-center trial3 but contradicts findings from the single-center trial.1 One hopes that a combined analysis will be performed on data from the three trials that used similar strategies, involving more than 2300 cardiac surgical patients at 16 intensive care units.1,3,7 Such an analysis should consider the degree of hyperglycemia, insulin dose, age of the patients, and the incidence of hypoglycemia. Meanwhile, the preponderance of published data
seems to indicate that tight glycemic control should not be used as standard treatment for children who have undergone cardiac surgery. In the CHiP trial, the non–cardiac-surgery patients appeared to differ importantly from cardiac-surgery patients, with a higher predicted mortality, and in prior data, these patients also had a higher rate and severity of hyperglycemia.10 Although the improved 1-year health care outcomes in the non–cardiac-surgery patients is compelling, it remains impossible to determine best practice for the child who requires critical care for reasons other than cardiac surgery or burns until either a meta-analysis of several trials is performed on an individual-data level or until data from an ongoing large, multicenter trial (ClinicalTrials.gov number, NCT01565941) are accrued. Future clinical trials should use the most advanced technology to reduce the incidence, severity, and duration of adverse events, most saliently, hypoglycemia. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From Boston Children’s Hospital and Harvard Medical School — both in Boston. 1. Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin
therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009;373:547-56. 2. Jeschke MG, Kulp GA, Kraft R, et al. Intensive insulin therapy in severely burned pediatric patients: a prospective randomized trial. Am J Respir Crit Care Med 2010;182:351-9. 3. Agus MSD, Steil GM, Wypij D, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012;367:1208-19. 4. Mesotten D, Gielen M, Sterken C, et al. Neurocognitive development of children 4 years after critical illness and treatment with tight glucose control: a randomized controlled trial. JAMA 2012;308:1641-50. 5. Faustino EV, Bogue CW. Relationship between hypoglycemia and mortality in critically ill children. Pediatr Crit Care Med 2010;11:690-8. 6. Hirshberg EL, Sward KA, Faustino EV, et al. Clinical equipoise regarding glycemic control: a survey of pediatric intensivist perceptions. Pediatr Crit Care Med 2013;14:123-9. 7. Macrae D, Grieve R, Allen E, et al. A randomized trial of hyperglycemic control in pediatric intensive care. N Engl J Med 2014;370:107-18. 8. Rake AJ, Srinivasan V, Nadkarni V, Kaptan R, Newth CJ. Glucose variability and survival in critically ill children: allostasis or harm? Pediatr Crit Care Med 2010;11:707-12. 9. The NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012;367:1108-18. 10. Srinivasan V, Spinella PC, Drott HR, Roth CL, Helfaer MA, Nadkarni V. Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children. Pediatr Crit Care Med 2004;5:329-36. DOI: 10.1056/NEJMe1313770 Copyright © 2014 Massachusetts Medical Society.
n engl j med 370;2 nejm.org january 9, 2014
The New England Journal of Medicine Downloaded from nejm.org on May 19, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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