NEWS & VIEWS PAEDIATRIC ENDOCRINOLOGY
Tight glycaemic control in criticaiiy iii chiidren Greet Van den Berghe and Dieter iVIesotten
A new triai has shown that targeting a biood giucose ievei of 4.0-7.0 mmoi/i in criticaiiy iii chiidren has some benefits, inciuding a reduced incidence of kidney faiiure, shortened duration of hospital stay and lowered health-care costs. iHowever, the chosen short-term primary end point was unaffected, which iimits the appiicabiiity of the findings. Van den Berghe, G. & Mesotten, D. Nat. Rev. Endocrinol. 10,196-197 (2014); published online 18 February 2014; doi:10.1038/nrendo.2014.16
The Control of Hyperglycaemia in Paediatric Intensive Care (CHiP) trial had the ambitious goal to assess in multiple centres whether 'tight glycaemic control' (TGC) with insulin titrated to a blood glucose target of 4.0-7.0 mmol/1 reduces morbidity and mortality of critically ill children in a costeffective manner compared with tolerating blood glucose levels up to 12.0 mmol/1.' The primary end point was the number of days alive and free from ventilator support assessed within 30 days of randomization. This primary end point was unaffected by whether or not the patient was under TGC. However, TGC did limit the incidence of kidney failure, reduce the total duration of hospital stay from a mean of 29 days to 24 days and lower health-care costs by a
mean of US$5,847. These effects were particularly notable in the subgroup of patients admitted to the intensive care unit (ICU) for reasons other than cardiac surgery (costs reduced by $13,120). To understand these results and how they might differ from those of the first randomized controlled trial on TGC in critically ill children^'' (henceforth referred to as the Belgian study), several aspects of the CHiP trial design should be considered. These include the chosen target ranges for blood glucose; the anticipated effect size and stafistical power; and the time window during which the primary outcome was assessed. Macrae and colleagues hypothesized that hyperglycaemia during critical illness in children causes harm. To test this hypothesis,
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4 5 6 7 Time since randomization (days)
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Figure 1 1 Different outcomes related to levels of TGC in the CHiP and Belgian trials. Blood glucose concentrations achieved in the CHiP trial^ compared with the Belgian study.^-^ Lines represent mean values and error bars are 95% confidence intervals. The dotted line represents the upper limit of normoglycaemia in the CHiP trial (>7.0 mmol/1). CHiP-CGC denotes the conventional treatment arm in CHiP; CHiP-TGC denotes the intervention arm in CHiP; BE-CGC denotes the conventional treatment arm in the Belgian study; BE-TGC denotes the intervention arm in the Belgian study. Abbreviations; BE, Belgian; CGC, conventional glycaemic control; CHiP, Control of Hyperglycaemia in Paediatric Intensive Care; TGC, tight glycaemic control.
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children in the control group should have hyperglycaemia and those in the intervention group should be treated to achieve normoglycaemia. Although these terms have been widely used,''' the definitions of hyperglycaemia and normoglycaemia vary substantially. In the CHiP trial, hyperglycaemia was defined as blood glucose levels >7.0 mmol/1, as the target range for TGC in the intervention arm was set at 4.0-7.0 mmol/1. This target range was assumed to reflect normoglycaemia in children. Macrae and coworkers also assumed that children in the control group would all have blood glucose concentrations >7.0 mmol/1. By comparison, the Belgian study based the definition of normoglycaemia on the normal fasting ranges for blood glucose; 2.8-4.4 mmol/1 for infants (1 year).^'' The Belgian study showed that targeting such lower ranges for blood levels of glucose reduced morbidity and mortality, and improved long-term neurocognitive development.^-' Both studies included similar proportions of infants and of patients undergoing cardiac surgery. The Belgian study included somewhat more severely ill patients than the CHiP trial (as indicated by the paediatric logistic organ dysfunction score being three points higher on admission and a higher baseline blood level of glucose). In the CHiP trial, about half of the children in the control group were already in the normoglycaemia range without insulin treatment (day 1 blood levels of glucose 6.7 mmol/1 and settling at -6.3 mmol/1 thereafter). The finding that only 66% of patients in the intervention group required insulin at any time further supported this assertion. In addition, the Belgian study had previously shown that when left untreated, critically ill children spontaneously settled at blood glucose levels of -6.4 mmol/1.- Hence, from the choice of the target levels in the intervention arm of the CHiP trial, and also in an earlier American study performed after cardiac surgery,'' it could have been anticipated that the results in the patients on TGC would hardly differ from those of the comparator group. Indeed, TGC in CHiP reduced the mean blood levels of glucose by just 0.4 mmol/1. As point-ofcare blood glucose meters can have a total analytical error of 10%,* the overall difference in blood glucose was smaller than the assay error, which could call into the question the clinical relevance of these findings. In the Belgian study, the difference between the two groups was 1.7 mmol/1, which might explain the stronger findings (Figure 1).
www.nature.com/nrendo
NEWS & VIEWS With the chosen design of the CHiP study, only slightly more than half of the patients in both groups actually received a different study intervention. The population at risk was thus diluted in a population not at risk. Therefore, the expected size of the treatment effect (a 2-day reduction in the number of days spent on a ventilator within thefirst30 days) was overestimated. Of note, most children were on the ventilator for only a day or two. In addition, the Belgian study had previously shown that the main benefit of TGC was reducing the number of patients needing long-term intensive care, rather than reducing the number of days they needed mechanical ventilation. The net result of these design issues is that the statistical power of the CHiP trial was far too low to detect the chosen primary treatment effect. In other words, the odds were very high of not picking up the primary treatment effect of TGC. By contrast, patients who were really at risk did show the other outcome effects. More data from the CHiP study support this concern. The use of TGC is essentially a strategy to minimize complications of critical illness in the long term.^"''' Therefore, patients who are exposed to potentially hazardous effects of hyperglycaemia for an extended period of time (at least several days for patients in ICU, that is, the longstayers), might benefit most. The long-stay ICU population are also well-known to use a disproportionate fraction of the ICU capacity and health-care resources.'" Hence, with the target ranges of blood glucose set high compared with the paediatric reference for healthy fasting values, only the most severely ill patients, with the highest risk of a long stay, received treatment and could possibly benefit. The CHiP study showed that the duration of hospital stay was significantly reduced by 5 days, which occurred late in the treatment regimen. Indeed, the Kaplan-Meier curves of hospital stay show that the difference occurred in 'the tail'. With the observation window cut short at 30 days for days on the ventilator, again the odds of missing any effect in the primary end point analysis were predictably high. In the CHiP trial, the difference in hospital length of stay in the total population was explained exclusively by 5 days shorter stay between
NATURE REVIEWS ENDOCRINOLOGY
day 30 and 12 months after inclusion. In the group of patients who did not undergo cardiac surgery (which is the group more at risk of longer stays), this difference was even larger; their hospital stay was 13 days shorter than other patients. The finding that TGC had more benefit among longstayers was also elegantly picked up in the health economy analysis that showed a significant reduction in costs in the total population ($5,847). A longer time horizon of 12 months was chosen for this analysis and health-care expenditures are cumulative, which gives more weight to the longstay patients.'" At 30 days, the health-care costs were still indistinguishable in the two study groups. Certainly for preventive strategies, such as TGC, the length of follow-up of clinical trials should cover the duration of hospital stay of patients who are likely to be long-stayers, which exceeds the 30 days afier randomization used in the CHiP trial. In addition, investigators should realize that the population of long-term critically ill patients is small but relevant, as reflected in a skewed distribution of the ICU length of stay, with a long tail on the right of the distribution curve. To enable readers to grasp this information, median and interquartile ranges should be reported. Means and standard errors (as reported in the CHiP trial) do not provide information about the distribution of the end point in the population, but are rather an indicator of the accuracy of the point estimation of the mean. Several issues need to be addressed in future studies. For example, consensus definitions of hyperglycaemia and normoglycaemia, specifically for the paediatric population, should be based on observational studies in healthy and critically ill chfldren. Furthermore, multicentre clinical studies should be performed that target 'true' normoglycaemia, which is then compared with a strategy of avoiding any insulin administration in a large population of patients at risk of pronounced and sustained hyperglycaemia. Finally, clinical studies need to have a longer duration than the CHiP trial of at least the hospital stay, and up to 90 days, to accommodate the clinically relevant long-term ICU-stay population. In conclusion, lowering blood glucose concentrations in critically ill children at
risk of pronounced and sustained hyperglycaemia seems to generate a dosedependent benefit on outcomes. Even a quite conservative target range shortened the duration of hospital stay and reduced health-care costs in the CHiP trial. Future studies should include a larger sample size or only select patients with hyperglycaemia and extend the foflow-up for the primary end point analysis far beyond thefirst30 days. Laboratory and Clinical Department of Intensive Care Medicine, Division Cellular and Molecular Medicine, Catholic University of Leuven (KU Leuven), Herestraat 49, B-3000 Leuven, Belgium (G.V.d.B., D.M.). Correspondence to: G.V.d.B. [email protected] Acknowiedgertients
G.V.d.B. wouid iike to acknowledge the support of structurai research funding from the Methusaiem programme of the Flemish Government in Beigium (ME08/07) and an ERC Advanced Grant from the European Union FP7 (AdvG-2012-321670). D.M. wouid like to acknowiedge the support of a Senior Ciinicai investigator Feiiowship from the FWO Research Foundation, Fianders, Beigium. Competing interests
The authors deciare no competing interests. 1.
Macrae, D. et al. A randomized trial of hyperglycaemic control in paediatric intensive care. N. Engi.J. Med. 370.107-118 (2014). 2. Viasseiaers, D. eta/, intensive insuiin therapy in paediatric intensive care unit patients: a prospective randomized controiied study. Lancet 373. 547-556 (2009). 3. Mesotten, D. et ai. Neurocognitive development of chiidren 4 years after criticai iiiness and treatment with tight glucose control. A randomized controiied triai. JAMA 308,1641-1650 (2012). 4. Van den Berghe, G. et al. intensive insuiih therapy in criticaiiy iii patients. N. Engi.J. Med. 345,1359-1367 (2001). 5. Van den Berghe, G. etal. intensive insuiin therapy of medical intensive care patients. N. Engi.J. Med. 354,449-461 (2006). 6. Agus, M. S. etal. Tight giycaemic controi versus standard care after paediatric cardiac surgery. N. Engi.J. Med. 367,1208-1219 (2012). 7. Finfer, S. et ai. intensive versus conventionai glucose control in criticaiiy ili patients. N. Engi. J. /Med. 360,1283-1297 (2009). 8. Sacks, D. B. et ai. Point-of-Care Biood Glucose Testing in Acute and Chronic Care Faciiities: Approved Guideiine, 3'" edn (Ciinicai Laboratory Standards institute, 2013). 9. Van den Berghe, G. How does biood giucose control with ihsuiin save iives in intensive care? J. Clin. Invest. 114,1187-1195 (2004). 10. Vahderheyden, S. etal. Eariy versus iate parenterai nutrition in ICU patients: cost anaiysis of the EPaNiC triai. Crit. Care 16, R96 (2012).
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Copyright of Nature Reviews Endocrinology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Tight glycaemic control in criticaiiy iii chiidren Greet Van den Berghe and Dieter iVIesotten
A new triai has shown that targeting a biood giucose ievei of 4.0-7.0 mmoi/i in criticaiiy iii chiidren has some benefits, inciuding a reduced incidence of kidney faiiure, shortened duration of hospital stay and lowered health-care costs. iHowever, the chosen short-term primary end point was unaffected, which iimits the appiicabiiity of the findings. Van den Berghe, G. & Mesotten, D. Nat. Rev. Endocrinol. 10,196-197 (2014); published online 18 February 2014; doi:10.1038/nrendo.2014.16
The Control of Hyperglycaemia in Paediatric Intensive Care (CHiP) trial had the ambitious goal to assess in multiple centres whether 'tight glycaemic control' (TGC) with insulin titrated to a blood glucose target of 4.0-7.0 mmol/1 reduces morbidity and mortality of critically ill children in a costeffective manner compared with tolerating blood glucose levels up to 12.0 mmol/1.' The primary end point was the number of days alive and free from ventilator support assessed within 30 days of randomization. This primary end point was unaffected by whether or not the patient was under TGC. However, TGC did limit the incidence of kidney failure, reduce the total duration of hospital stay from a mean of 29 days to 24 days and lower health-care costs by a
mean of US$5,847. These effects were particularly notable in the subgroup of patients admitted to the intensive care unit (ICU) for reasons other than cardiac surgery (costs reduced by $13,120). To understand these results and how they might differ from those of the first randomized controlled trial on TGC in critically ill children^'' (henceforth referred to as the Belgian study), several aspects of the CHiP trial design should be considered. These include the chosen target ranges for blood glucose; the anticipated effect size and stafistical power; and the time window during which the primary outcome was assessed. Macrae and colleagues hypothesized that hyperglycaemia during critical illness in children causes harm. To test this hypothesis,
10-1
7-
654-
3
4 5 6 7 Time since randomization (days)
10
Figure 1 1 Different outcomes related to levels of TGC in the CHiP and Belgian trials. Blood glucose concentrations achieved in the CHiP trial^ compared with the Belgian study.^-^ Lines represent mean values and error bars are 95% confidence intervals. The dotted line represents the upper limit of normoglycaemia in the CHiP trial (>7.0 mmol/1). CHiP-CGC denotes the conventional treatment arm in CHiP; CHiP-TGC denotes the intervention arm in CHiP; BE-CGC denotes the conventional treatment arm in the Belgian study; BE-TGC denotes the intervention arm in the Belgian study. Abbreviations; BE, Belgian; CGC, conventional glycaemic control; CHiP, Control of Hyperglycaemia in Paediatric Intensive Care; TGC, tight glycaemic control.
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children in the control group should have hyperglycaemia and those in the intervention group should be treated to achieve normoglycaemia. Although these terms have been widely used,''' the definitions of hyperglycaemia and normoglycaemia vary substantially. In the CHiP trial, hyperglycaemia was defined as blood glucose levels >7.0 mmol/1, as the target range for TGC in the intervention arm was set at 4.0-7.0 mmol/1. This target range was assumed to reflect normoglycaemia in children. Macrae and coworkers also assumed that children in the control group would all have blood glucose concentrations >7.0 mmol/1. By comparison, the Belgian study based the definition of normoglycaemia on the normal fasting ranges for blood glucose; 2.8-4.4 mmol/1 for infants (1 year).^'' The Belgian study showed that targeting such lower ranges for blood levels of glucose reduced morbidity and mortality, and improved long-term neurocognitive development.^-' Both studies included similar proportions of infants and of patients undergoing cardiac surgery. The Belgian study included somewhat more severely ill patients than the CHiP trial (as indicated by the paediatric logistic organ dysfunction score being three points higher on admission and a higher baseline blood level of glucose). In the CHiP trial, about half of the children in the control group were already in the normoglycaemia range without insulin treatment (day 1 blood levels of glucose 6.7 mmol/1 and settling at -6.3 mmol/1 thereafter). The finding that only 66% of patients in the intervention group required insulin at any time further supported this assertion. In addition, the Belgian study had previously shown that when left untreated, critically ill children spontaneously settled at blood glucose levels of -6.4 mmol/1.- Hence, from the choice of the target levels in the intervention arm of the CHiP trial, and also in an earlier American study performed after cardiac surgery,'' it could have been anticipated that the results in the patients on TGC would hardly differ from those of the comparator group. Indeed, TGC in CHiP reduced the mean blood levels of glucose by just 0.4 mmol/1. As point-ofcare blood glucose meters can have a total analytical error of 10%,* the overall difference in blood glucose was smaller than the assay error, which could call into the question the clinical relevance of these findings. In the Belgian study, the difference between the two groups was 1.7 mmol/1, which might explain the stronger findings (Figure 1).
www.nature.com/nrendo
NEWS & VIEWS With the chosen design of the CHiP study, only slightly more than half of the patients in both groups actually received a different study intervention. The population at risk was thus diluted in a population not at risk. Therefore, the expected size of the treatment effect (a 2-day reduction in the number of days spent on a ventilator within thefirst30 days) was overestimated. Of note, most children were on the ventilator for only a day or two. In addition, the Belgian study had previously shown that the main benefit of TGC was reducing the number of patients needing long-term intensive care, rather than reducing the number of days they needed mechanical ventilation. The net result of these design issues is that the statistical power of the CHiP trial was far too low to detect the chosen primary treatment effect. In other words, the odds were very high of not picking up the primary treatment effect of TGC. By contrast, patients who were really at risk did show the other outcome effects. More data from the CHiP study support this concern. The use of TGC is essentially a strategy to minimize complications of critical illness in the long term.^"''' Therefore, patients who are exposed to potentially hazardous effects of hyperglycaemia for an extended period of time (at least several days for patients in ICU, that is, the longstayers), might benefit most. The long-stay ICU population are also well-known to use a disproportionate fraction of the ICU capacity and health-care resources.'" Hence, with the target ranges of blood glucose set high compared with the paediatric reference for healthy fasting values, only the most severely ill patients, with the highest risk of a long stay, received treatment and could possibly benefit. The CHiP study showed that the duration of hospital stay was significantly reduced by 5 days, which occurred late in the treatment regimen. Indeed, the Kaplan-Meier curves of hospital stay show that the difference occurred in 'the tail'. With the observation window cut short at 30 days for days on the ventilator, again the odds of missing any effect in the primary end point analysis were predictably high. In the CHiP trial, the difference in hospital length of stay in the total population was explained exclusively by 5 days shorter stay between
NATURE REVIEWS ENDOCRINOLOGY
day 30 and 12 months after inclusion. In the group of patients who did not undergo cardiac surgery (which is the group more at risk of longer stays), this difference was even larger; their hospital stay was 13 days shorter than other patients. The finding that TGC had more benefit among longstayers was also elegantly picked up in the health economy analysis that showed a significant reduction in costs in the total population ($5,847). A longer time horizon of 12 months was chosen for this analysis and health-care expenditures are cumulative, which gives more weight to the longstay patients.'" At 30 days, the health-care costs were still indistinguishable in the two study groups. Certainly for preventive strategies, such as TGC, the length of follow-up of clinical trials should cover the duration of hospital stay of patients who are likely to be long-stayers, which exceeds the 30 days afier randomization used in the CHiP trial. In addition, investigators should realize that the population of long-term critically ill patients is small but relevant, as reflected in a skewed distribution of the ICU length of stay, with a long tail on the right of the distribution curve. To enable readers to grasp this information, median and interquartile ranges should be reported. Means and standard errors (as reported in the CHiP trial) do not provide information about the distribution of the end point in the population, but are rather an indicator of the accuracy of the point estimation of the mean. Several issues need to be addressed in future studies. For example, consensus definitions of hyperglycaemia and normoglycaemia, specifically for the paediatric population, should be based on observational studies in healthy and critically ill chfldren. Furthermore, multicentre clinical studies should be performed that target 'true' normoglycaemia, which is then compared with a strategy of avoiding any insulin administration in a large population of patients at risk of pronounced and sustained hyperglycaemia. Finally, clinical studies need to have a longer duration than the CHiP trial of at least the hospital stay, and up to 90 days, to accommodate the clinically relevant long-term ICU-stay population. In conclusion, lowering blood glucose concentrations in critically ill children at
risk of pronounced and sustained hyperglycaemia seems to generate a dosedependent benefit on outcomes. Even a quite conservative target range shortened the duration of hospital stay and reduced health-care costs in the CHiP trial. Future studies should include a larger sample size or only select patients with hyperglycaemia and extend the foflow-up for the primary end point analysis far beyond thefirst30 days. Laboratory and Clinical Department of Intensive Care Medicine, Division Cellular and Molecular Medicine, Catholic University of Leuven (KU Leuven), Herestraat 49, B-3000 Leuven, Belgium (G.V.d.B., D.M.). Correspondence to: G.V.d.B. [email protected] Acknowiedgertients
G.V.d.B. wouid iike to acknowledge the support of structurai research funding from the Methusaiem programme of the Flemish Government in Beigium (ME08/07) and an ERC Advanced Grant from the European Union FP7 (AdvG-2012-321670). D.M. wouid like to acknowiedge the support of a Senior Ciinicai investigator Feiiowship from the FWO Research Foundation, Fianders, Beigium. Competing interests
The authors deciare no competing interests. 1.
Macrae, D. et al. A randomized trial of hyperglycaemic control in paediatric intensive care. N. Engi.J. Med. 370.107-118 (2014). 2. Viasseiaers, D. eta/, intensive insuiin therapy in paediatric intensive care unit patients: a prospective randomized controiied study. Lancet 373. 547-556 (2009). 3. Mesotten, D. et ai. Neurocognitive development of chiidren 4 years after criticai iiiness and treatment with tight glucose control. A randomized controiied triai. JAMA 308,1641-1650 (2012). 4. Van den Berghe, G. et al. intensive insuiih therapy in criticaiiy iii patients. N. Engi.J. Med. 345,1359-1367 (2001). 5. Van den Berghe, G. etal. intensive insuiin therapy of medical intensive care patients. N. Engi.J. Med. 354,449-461 (2006). 6. Agus, M. S. etal. Tight giycaemic controi versus standard care after paediatric cardiac surgery. N. Engi.J. Med. 367,1208-1219 (2012). 7. Finfer, S. et ai. intensive versus conventionai glucose control in criticaiiy ili patients. N. Engi. J. /Med. 360,1283-1297 (2009). 8. Sacks, D. B. et ai. Point-of-Care Biood Glucose Testing in Acute and Chronic Care Faciiities: Approved Guideiine, 3'" edn (Ciinicai Laboratory Standards institute, 2013). 9. Van den Berghe, G. How does biood giucose control with ihsuiin save iives in intensive care? J. Clin. Invest. 114,1187-1195 (2004). 10. Vahderheyden, S. etal. Eariy versus iate parenterai nutrition in ICU patients: cost anaiysis of the EPaNiC triai. Crit. Care 16, R96 (2012).
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Copyright of Nature Reviews Endocrinology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
