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Duncan Macrae 1,*, Richard Grieve 2, Elizabeth Allen 3, Zia Sadique 2, Helen Betts 1, Kevin Morris 4, Vithayathil John Pappachan 5, Roger Parslow 6, Robert C Tasker 7, Paul Baines 8, Michael Broadhead 9, Mark L Duthie 10, Peter-Marc Fortune 11, David Inwald 12, Paddy McMaster 13, Mark J Peters 9, Margrid Schindler 14, Carla Guerriero 2, Deborah Piercy 3, Zdenek Slavik 1, Claire Snowdon 3, Laura Van Dyck 3, Diana Elbourne 3

1 Royal Brompton Hospital, London, UK
2 Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK
3 Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, UK
4 Birmingham Children’s Hospital, Birmingham, UK
5 Southampton General Hospital, Southampton, UK
6 Faculty of Medicine and Health, University of Leeds, Leeds, UK
7 Boston Children’s Hospital, Boston, MA, USA
8 Alder Hey Hospital, Liverpool, UK
9 Great Ormond Street Hospital for Children, London, UK
10 Glenfield Hospital and Leicester Royal Infirmary, Leicester, UK
11 Royal Manchester Children’s Hospital, Manchester, UK
12 St Mary’s Hospital, London, UK
13 University Hospital of North Staffordshire, Stoke-on-Trent, UK
14 Bristol Royal Hospital for Children, Bristol, UK
* Corresponding author Email: d.macrae@rbht.nhs.uk

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Abstract

BACKGROUND

Early research in adults admitted to intensive care suggested that tight control of blood glucose during acute illness can be associated with reductions in mortality, length of hospital stay and complications such as infection and renal failure. Prior to our study, it was unclear whether or not children could also benefit from tight control of blood glucose during critical illness.

OBJECTIVES

This study aimed to determine if controlling blood glucose using insulin in paediatric intensive care units (PICUs) reduces mortality and morbidity and is cost-effective, whether or not admission follows cardiac surgery.

DESIGN

Randomised open two-arm parallel group superiority design with central randomisation with minimisation. Analysis was on an intention-to-treat basis. Following random allocation, care givers and outcome assessors were no longer blind to allocation.

SETTING

The setting was 13 English PICUs.

PARTICIPANTS

Patients who met the following criteria were eligible for inclusion: â ¥â 36 weeks corrected gestational age; â ¤â 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment >â 12 hours; arterial line; mechanical ventilation; and vasoactive drugs. Exclusion criteria were as follows: diabetes mellitus; inborn error of metabolism; treatment withdrawal considered; in the PICU >â 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care).

INTERVENTION

The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0â mmol/l.

CONVENTIONAL MANAGEMENT (CM)

This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0â mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0â mmol/l.

MAIN OUTCOME MEASURES

The primary outcome was the number of days alive and free from mechanical ventilation within 30 days of trial entry (VFD-30). The secondary outcomes comprised clinical and economic outcomes at 30 days and 12 months and lifetime cost-effectiveness, which included costs per quality-adjusted life-year.

RESULTS

CHiP recruited from May 2008 to September 2011. In total, 19,924 children were screened and 1369 eligible patients were randomised (TGC, 694; CM, 675), 60% of whom were in the cardiac surgery stratum. The randomised groups were comparable at trial entry. More children in the TGC than in the CM arm received insulin (66% vs. 16%). The mean VFD-30 was 23 [mean difference 0.36; 95% confidence interval (CI) -0.42 to 1.14]. The effect did not differ among prespecified subgroups. Hypoglycaemia occurred significantly more often in the TGC than in the CM arm (moderate, 12.5% vs. 3.1%; severe, 7.3% vs. 1.5%). Mean 30-day costs were similar between arms, but mean 12-month costs were lower in the TGC than in CM arm (incremental costs -£3620, 95% CI -£7743 to £502). For the non-cardiac surgery stratum, mean costs were lower in the TGC than in the CM arm (incremental cost -£9865, 95% CI -£18,558 to -£1172), but, in the cardiac surgery stratum, the costs were similar between the arms (incremental cost £133, 95% CI -£3568 to £3833). Lifetime incremental net benefits were positive overall (£3346, 95% CI -£11,203 to £17,894), but close to zero for the cardiac surgery stratum (-£919, 95% CI -£16,661 to £14,823). For the non-cardiac surgery stratum, the incremental net benefits were high (£11,322, 95% CI -£15,791 to £38,615). The probability that TGC is cost-effective is relatively high for the non-cardiac surgery stratum, but, for the cardiac surgery subgroup, the probability that TGC is cost-effective is around 0.5. Sensitivity analyses showed that the results were robust to a range of alternative assumptions.

CONCLUSIONS

CHiP found no differences in the clinical or cost-effectiveness of TGC compared with CM overall, or for prespecified subgroups. A higher proportion of the TGC arm had hypoglycaemia. This study did not provide any evidence to suggest that PICUs should stop providing CM for children admitted to PICUs following cardiac surgery. For the subgroup not admitted for cardiac surgery, TGC reduced average costs at 12 months and is likely to be cost-effective. Further research is required to refine the TGC protocol to minimise the risk of hypoglycaemic episodes and assess the long-term health benefits of TGC.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN61735247.

FUNDING

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 26. See the NIHR Journals Library website for further project information.

Abstract

BACKGROUND

Early research in adults admitted to intensive care suggested that tight control of blood glucose during acute illness can be associated with reductions in mortality, length of hospital stay and complications such as infection and renal failure. Prior to our study, it was unclear whether or not children could also benefit from tight control of blood glucose during critical illness.

OBJECTIVES

This study aimed to determine if controlling blood glucose using insulin in paediatric intensive care units (PICUs) reduces mortality and morbidity and is cost-effective, whether or not admission follows cardiac surgery.

DESIGN

Randomised open two-arm parallel group superiority design with central randomisation with minimisation. Analysis was on an intention-to-treat basis. Following random allocation, care givers and outcome assessors were no longer blind to allocation.

SETTING

The setting was 13 English PICUs.

PARTICIPANTS

Patients who met the following criteria were eligible for inclusion: â ¥â 36 weeks corrected gestational age; â ¤â 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment >â 12 hours; arterial line; mechanical ventilation; and vasoactive drugs. Exclusion criteria were as follows: diabetes mellitus; inborn error of metabolism; treatment withdrawal considered; in the PICU >â 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care).

INTERVENTION

The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0â mmol/l.

CONVENTIONAL MANAGEMENT (CM)

This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0â mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0â mmol/l.

MAIN OUTCOME MEASURES

The primary outcome was the number of days alive and free from mechanical ventilation within 30 days of trial entry (VFD-30). The secondary outcomes comprised clinical and economic outcomes at 30 days and 12 months and lifetime cost-effectiveness, which included costs per quality-adjusted life-year.

RESULTS

CHiP recruited from May 2008 to September 2011. In total, 19,924 children were screened and 1369 eligible patients were randomised (TGC, 694; CM, 675), 60% of whom were in the cardiac surgery stratum. The randomised groups were comparable at trial entry. More children in the TGC than in the CM arm received insulin (66% vs. 16%). The mean VFD-30 was 23 [mean difference 0.36; 95% confidence interval (CI) -0.42 to 1.14]. The effect did not differ among prespecified subgroups. Hypoglycaemia occurred significantly more often in the TGC than in the CM arm (moderate, 12.5% vs. 3.1%; severe, 7.3% vs. 1.5%). Mean 30-day costs were similar between arms, but mean 12-month costs were lower in the TGC than in CM arm (incremental costs -£3620, 95% CI -£7743 to £502). For the non-cardiac surgery stratum, mean costs were lower in the TGC than in the CM arm (incremental cost -£9865, 95% CI -£18,558 to -£1172), but, in the cardiac surgery stratum, the costs were similar between the arms (incremental cost £133, 95% CI -£3568 to £3833). Lifetime incremental net benefits were positive overall (£3346, 95% CI -£11,203 to £17,894), but close to zero for the cardiac surgery stratum (-£919, 95% CI -£16,661 to £14,823). For the non-cardiac surgery stratum, the incremental net benefits were high (£11,322, 95% CI -£15,791 to £38,615). The probability that TGC is cost-effective is relatively high for the non-cardiac surgery stratum, but, for the cardiac surgery subgroup, the probability that TGC is cost-effective is around 0.5. Sensitivity analyses showed that the results were robust to a range of alternative assumptions.

CONCLUSIONS

CHiP found no differences in the clinical or cost-effectiveness of TGC compared with CM overall, or for prespecified subgroups. A higher proportion of the TGC arm had hypoglycaemia. This study did not provide any evidence to suggest that PICUs should stop providing CM for children admitted to PICUs following cardiac surgery. For the subgroup not admitted for cardiac surgery, TGC reduced average costs at 12 months and is likely to be cost-effective. Further research is required to refine the TGC protocol to minimise the risk of hypoglycaemic episodes and assess the long-term health benefits of TGC.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN61735247.

FUNDING

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 26. See the NIHR Journals Library website for further project information.

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