A clinical and economic evaluation of Control of Hyperglycaemia in Paediatric intensive care (CHiP): a randomised controlled trial.
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.


OBJECTIVE
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.


METHODS
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.


METHODS
The setting was 13 English PICUs.


METHODS
Patients who met the following criteria were eligible for inclusion: ≥ 36 weeks corrected gestational age; ≤ 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment > 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 > 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care).


METHODS
The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0 mmol/l.
This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0 mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0 mmol/l.


METHODS
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.


BACKGROUND
Current Controlled Trials ISRCTN61735247.


BACKGROUND
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.
Royal Brompton Hospital, London, UK.
Duncan
D
Macrae
Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK.
Richard
R
Grieve
Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, UK.
Elizabeth
E
Allen
Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK.
Zia
Z
Sadique
Royal Brompton Hospital, London, UK.
Helen
H
Betts
Birmingham Children's Hospital, Birmingham, UK.
Kevin
K
Morris
Southampton General Hospital, Southampton, UK.
Vithayathil John
VJ
Pappachan
Faculty of Medicine and Health, University of Leeds, Leeds, UK.
Roger
R
Parslow
Boston Children's Hospital, Boston, MA, USA.
Robert C
RC
Tasker
Alder Hey Hospital, Liverpool, UK.
Paul
P
Baines
Great Ormond Street Hospital for Children, London, UK.
Michael
M
Broadhead
Glenfield Hospital and Leicester Royal Infirmary, Leicester, UK.
Mark L
ML
Duthie
Royal Manchester Children's Hospital, Manchester, UK.
Peter-Marc
PM
Fortune
St Mary's Hospital, London, UK.
David
D
Inwald
University Hospital of North Staffordshire, Stoke-on-Trent, UK.
Paddy
P
McMaster
Great Ormond Street Hospital for Children, London, UK.
Mark J
MJ
Peters
Bristol Royal Hospital for Children, Bristol, UK.
Margrid
M
Schindler
Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK.
Carla
C
Guerriero
Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, UK.
Deborah
D
Piercy
Royal Brompton Hospital, London, UK.
Zdenek
Z
Slavik
Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, UK.
Claire
C
Snowdon
Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, UK.
Laura
L
Van Dyck
Medical Statistics Department, London School of Hygiene and Tropical Medicine, London, UK.
Diana
D
Elbourne
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003362:Cost-Benefit Analysis; D004739:England; D005260:Female; D017048:Health Care Costs / Q000706:statistics & numerical data; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000191:economics; D007004:Hypoglycemic Agents / Q000191:economics* / Q000627:therapeutic use; D007223:Infant; D007328:Insulin / Q000191:economics* / Q000627:therapeutic use; D015278:Intensive Care Units, Pediatric / Q000191:economics*; D008297:Male; D017063:Outcome Assessment, Health Care; D011795:Surveys and Questionnaires
D007004:Hypoglycemic Agents; D007328:Insulin