NIHR Signal Very strict blood sugar control in critically ill children provides no benefit

Published on 23 May 2017

Strict control of blood sugar levels for critically ill children in ICU with high blood sugar did not increase the number of days they spent outside of ICU in the first month.

The trial was stopped early as more infections and very low glucose levels were recorded in the strict control group.

This trial found that using insulin to control blood sugar to within 4.4 to 6.1 mmol/L, rather than 8.3 to 10mmol/L, in critically ill children made no difference to the number of days they spent in the intensive care unit.

This trial indicates that maintaining blood sugar control within tight boundaries in this group is of no benefit and may be harmful. It is time to review the target blood sugar levels for critically ill children with high blood sugar.

Very strict blood sugar control in critically ill children provides no benefit

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Why was this study needed?

In 2014 about 20,000 young people were admitted to children’s intensive care in England. Critically ill children can have raised blood sugar levels (hyperglycaemia) as a result of the stress that their bodies are under.

A study in critically ill children who had undergone heart surgery suggested that bringing blood sugar levels to within the normal range of 4 to 7 mmol/L leads to better short-term outcomes than using a higher threshold. Other studies in children, such as the SPECs trial following heart surgery and the NIHR-funded CHiP trial in general and cardiac intensive care, have not shown better outcomes with blood sugar targets in the normal range.

This trial aimed to compare different target blood sugar ranges in critically ill children. Specifically it looked at those receiving support for hypotension or invasive mechanical ventilation who had not undergone heart surgery.

What did this study do?

The Heart And Lung Failure - Pediatric INsulin Titration (HALF-PINT) study was a randomised controlled trial from 32 units in the US and Canada.  They recruited 713 critically ill children with hyperglycaemia (blood sugar levels more than 8.3 mmol/L) who had not undergone cardiac surgery. 

Children were randomly assigned to a blood sugar target within the lower normal range (4.4 to 6.1 mmol/L; 360 children) or to a higher target range (8.3 to 10.0 mmol/L; 353 children). Blood sugar levels were monitored continuously and managed by adjusting insulin infusions.

The main outcome was the proportion of days in the first 4 weeks spent outside intensive care (on the ward or out of hospital).

The study was stopped early, when 50% of participants had been recruited, because interim analyses suggested that the lower blood sugar target was unlikely to be beneficial and could be harmful.

What did it find?

  • Children with the lower blood sugar target range had about the same number of days out of ICU to day 28 compared with children with the higher target range (median number of days out of ICU [primary outcome]: 19.4 days for the lower target, interquartile range [IQR], 0 to 24.2 versus 19.4 days for the higher target, IQR 6.7 to 23.9).
  • Children in the lower target group had higher rates of healthcare-associated infections (12 patients [3.4%] versus 4 [1.1%] in the higher-target group). Specifically, there was a higher rate of catheter-associated bloodstream infections.
  • Children in the lower-target group were also more likely to experience dangerously low blood sugar levels below 2.2 mmol/L (18 patients [5.2%] versus 7 [2.0%] in the higher-target group).
  • There was no significant difference between the two groups in number of deaths at 28 days (47 [13.5%] in the lower-target group and 32 [9.2%] in the higher-target group) and 90 days (52 [14.9%] and 40 [11.5%]).

What does current guidance say on this issue?

Most units have their own guidelines such as Guidance from Great Ormond Street Hospital (2014) which recommends monitoring blood sugar levels every 4 hours in children in intensive care and suggests intervention if a child’s blood sugar level does not fall between 4 mmol/L and 7 mmol/L.

What are the implications?

There is sparse evidence for the optimum blood sugar range for critically ill children with hyperglycaemia. Intensive care paediatricians have varying opinions on the threshold for starting insulin management in critically ill children, and according to some sources few would be willing to target a blood glucose level of less than 6.1 mmol/L.

This well-conducted trial indicates that targeting a normal blood sugar level in critically ill hyperglycaemic children is of no benefit compared with a higher, more relaxed target, and may be harmful.  This fits with other recent evidence. Intensivists should consider a more permissive approach to blood sugar management in critically ill children.

Citation and Funding

Agus MS, Wypij D, Hirshberg EL, et al. Tight glycemic control in critically ill children. N Engl J Med. 2017;376(8):729-41.

This project was funded by the National Heart, Lung, and Blood Institute, US National Institutes of Health.

Bibliography

Gilbert C, Morgan K, Rathwell A, et al. Blood glucose monitoring. London: Great Ormond Street Hospital; 2014.

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.

Why was this study needed?

In 2014 about 20,000 young people were admitted to children’s intensive care in England. Critically ill children can have raised blood sugar levels (hyperglycaemia) as a result of the stress that their bodies are under.

A study in critically ill children who had undergone heart surgery suggested that bringing blood sugar levels to within the normal range of 4 to 7 mmol/L leads to better short-term outcomes than using a higher threshold. Other studies in children, such as the SPECs trial following heart surgery and the NIHR-funded CHiP trial in general and cardiac intensive care, have not shown better outcomes with blood sugar targets in the normal range.

This trial aimed to compare different target blood sugar ranges in critically ill children. Specifically it looked at those receiving support for hypotension or invasive mechanical ventilation who had not undergone heart surgery.

What did this study do?

The Heart And Lung Failure - Pediatric INsulin Titration (HALF-PINT) study was a randomised controlled trial from 32 units in the US and Canada.  They recruited 713 critically ill children with hyperglycaemia (blood sugar levels more than 8.3 mmol/L) who had not undergone cardiac surgery. 

Children were randomly assigned to a blood sugar target within the lower normal range (4.4 to 6.1 mmol/L; 360 children) or to a higher target range (8.3 to 10.0 mmol/L; 353 children). Blood sugar levels were monitored continuously and managed by adjusting insulin infusions.

The main outcome was the proportion of days in the first 4 weeks spent outside intensive care (on the ward or out of hospital).

The study was stopped early, when 50% of participants had been recruited, because interim analyses suggested that the lower blood sugar target was unlikely to be beneficial and could be harmful.

What did it find?

  • Children with the lower blood sugar target range had about the same number of days out of ICU to day 28 compared with children with the higher target range (median number of days out of ICU [primary outcome]: 19.4 days for the lower target, interquartile range [IQR], 0 to 24.2 versus 19.4 days for the higher target, IQR 6.7 to 23.9).
  • Children in the lower target group had higher rates of healthcare-associated infections (12 patients [3.4%] versus 4 [1.1%] in the higher-target group). Specifically, there was a higher rate of catheter-associated bloodstream infections.
  • Children in the lower-target group were also more likely to experience dangerously low blood sugar levels below 2.2 mmol/L (18 patients [5.2%] versus 7 [2.0%] in the higher-target group).
  • There was no significant difference between the two groups in number of deaths at 28 days (47 [13.5%] in the lower-target group and 32 [9.2%] in the higher-target group) and 90 days (52 [14.9%] and 40 [11.5%]).

What does current guidance say on this issue?

Most units have their own guidelines such as Guidance from Great Ormond Street Hospital (2014) which recommends monitoring blood sugar levels every 4 hours in children in intensive care and suggests intervention if a child’s blood sugar level does not fall between 4 mmol/L and 7 mmol/L.

What are the implications?

There is sparse evidence for the optimum blood sugar range for critically ill children with hyperglycaemia. Intensive care paediatricians have varying opinions on the threshold for starting insulin management in critically ill children, and according to some sources few would be willing to target a blood glucose level of less than 6.1 mmol/L.

This well-conducted trial indicates that targeting a normal blood sugar level in critically ill hyperglycaemic children is of no benefit compared with a higher, more relaxed target, and may be harmful.  This fits with other recent evidence. Intensivists should consider a more permissive approach to blood sugar management in critically ill children.

Citation and Funding

Agus MS, Wypij D, Hirshberg EL, et al. Tight glycemic control in critically ill children. N Engl J Med. 2017;376(8):729-41.

This project was funded by the National Heart, Lung, and Blood Institute, US National Institutes of Health.

Bibliography

Gilbert C, Morgan K, Rathwell A, et al. Blood glucose monitoring. London: Great Ormond Street Hospital; 2014.

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.

Tight Glycemic Control in Critically Ill Children

Published on 25 January 2017

Agus, M. S.,Wypij, D.,Hirshberg, E. L.,Srinivasan, V.,Faustino, E. V.,Luckett, P. M.,Alexander, J. L.,Asaro, L. A.,Curley, M. A.,Steil, G. M.,Nadkarni, V. M.

N Engl J Med , 2017

Background In multicenter studies, tight glycemic control targeting a normal blood glucose level has not been shown to improve outcomes in critically ill adults or children after cardiac surgery. Studies involving critically ill children who have not undergone cardiac surgery are lacking. Methods In a 35-center trial, we randomly assigned critically ill children with confirmed hyperglycemia (excluding patients who had undergone cardiac surgery) to one of two ranges of glycemic control: 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter; lower-target group) or 150 to 180 mg per deciliter (8.3 to 10.0 mmol per liter; higher-target group). Clinicians were guided by continuous glucose monitoring and explicit methods for insulin adjustment. The primary outcome was the number of intensive care unit (ICU)-free days to day 28. Results The trial was stopped early, on the recommendation of the data and safety monitoring board, owing to a low likelihood of benefit and evidence of the possibility of harm. Of 713 patients, 360 were randomly assigned to the lower-target group and 353 to the higher-target group. In the intention-to-treat analysis, the median number of ICU-free days did not differ significantly between the lower-target group and the higher-target group (19.4 days [interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P=0.58). In per-protocol analyses, the median time-weighted average glucose level was significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1 mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter [IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P<0.001). Patients in the lower-target group also had higher rates of health care-associated infections than those in the higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P=0.04), as well as higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant differences were observed in mortality, severity of organ dysfunction, or the number of ventilator-free days. Conclusions Critically ill children with hyperglycemia did not benefit from tight glycemic control targeted to a blood glucose level of 80 to 110 mg per deciliter, as compared with a level of 150 to 180 mg per deciliter. (Funded by the National Heart, Lung, and Blood Institute and others; HALF-PINT ClinicalTrials.gov number, NCT01565941 .).

Expert commentary

This paper provides high quality evidence that attempting to maintain blood glucose concentrations between 4.4 and 6.1 mmol/L, as opposed to 8.3 to 10 mmol/L, has no advantage for children receiving intensive care. It provides some evidence of harm associated with the lower target range, and calls into question the contention that high blood glucose concentrations are in themselves harmful, rather than merely being a marker for greater disease severity. Intensive care services where more stringent control of blood glucose has become standard practice should consider moving to a more permissive approach in relation to blood glucose control.

Dr Martin Ward Platt, Editor in Chief, Archives of Disease in Childhood; Consultant Paediatrician (Neonatal Medicine) & Honorary Clinical Reader in Neonatal & Paediatric Medicine, Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle upon Tyne