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Intensive Insulin Therapy After Severe Traumatic Brain Injury: A Randomized Clinical Trial

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Abstract

Introduction

To investigate the risks and possible benefits of routine versus intensive insulin therapy, assessed by the frequency of hypoglycemic events defined as a glucose concentration less than 80 mg/dl (<4.44 mmol/l) in patients admitted to the intensive care unit (ICU) after severe traumatic brain injury (TBI).

Methods and Results

Ninety-seven patients admitted after severe TBI, were enrolled and randomly assigned to two groups of target glycemia. Insulin was infused at conventional rates when blood glucose levels exceeded 220 mg/dl (12.22 mmol/l) or at intensive rates, to maintain glycemia at 80–120 mg/dl (4.44–6.66 mmol/l). The following primary and outcome variables were measured during follow-up: hypoglycemic episodes, duration of ICU stay, infection rate, and 6-month mortality and neurologic outcome measured using the Glasgow Outcome Scale (GOS). Episodes of hypoglycemia (defined as blood glucose <80 mg/dl or 4.44 mmol/l) were significantly higher in patients receiving intensive insulin therapy: median (min–max) conventional insulin therapy 7 (range 0–11) vs. intensive insulin therapy 15 (range 6–33); P<0.0001. Duration of ICU stay was shorter in patients receiving intensive insulin therapy (7.3 vs. 10.0 days; P < 0.05); while infection rates during ICU stay (25.0% vs. 38.8%, P = 0.15), and GOS scores and mortality at 6 months were similar in the two groups.

Conclusions

Intensive insulin therapy significantly increases the risk of hypoglycemic episodes. Even though patients receiving intensive insulin therapy have shorter ICU stays and infection rates similar to those receiving conventional insulin therapy, both groups have similar follow-up mortality and neurologic outcome. Hence if intensive insulin therapy is to be used, great effort must be taken to avoid hypoglycemia.

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Acknowledgments

We are indebted to all the intensive care staff for their active cooperation and excellent compliance with the study protocol. We also thank Drs Fabio Araimo, Floriana Baisi, Giovanna Branca, Donato Colagiovanni, Nicola DeBlasis, Carmela Imperiale, Giuseppina Magni, Filomena Musolino, Marina Pennacchia, Letizia Pennacchiotti, Francesca Rinaldi, Paolo Tordiglione for patient care; Dr Carolina Maurizio for collecting data; Dr Alessandro Laviano for advice on patients’ nutrition; and Drs Laura Scorsolini and Mario Venditti for their continuous assistance in the clinical and laboratory diagnosis of infections.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Critical Care and Pain Medicine, “La Sapienza” University of Rome, Viale Somalia 81, Rome, 00199, Italy

    Federico Bilotta, Remo Caramia, Andrea Doronzio, Vincenzo Cuzzone & Giovanni Rosa

  2. The Johns Hopkins University Applied Physics Laboratory, Biomedicine Business Area, Laurel, MD, USA

    Ibolja Cernak

  3. GIMEMA Data Center, Rome, Italy

    Francesca Paola Paoloni

  4. Department of Neurosurgery, “La Sapienza” University of Rome, Rome, Italy

    Antonio Santoro

Authors
  1. Federico Bilotta
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  2. Remo Caramia
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  3. Ibolja Cernak
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  4. Francesca Paola Paoloni
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  5. Andrea Doronzio
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  6. Vincenzo Cuzzone
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  7. Antonio Santoro
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  8. Giovanni Rosa
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Corresponding author

Correspondence to Federico Bilotta.

Additional information

This work was done in the Department of Neuroanaesthesia, University of Rome “La Sapienza”, Rome, Italy, and was in part presented at the Euroanaesthesia 2006 meeting Madrid, Spain.

Appendices

Appendix 1: ICU Protocol for Insulin Infusion

Glucose value (mg/dl)

Insulin dose

Intensive insulin therapy

For first blood glucose measurement

    121–130

½ unit/h

    131–140

1 unit/h

    141–160

2 units/h

    161–181

Give 2 units IV bolus and 2.5 units/h

    181–200

Give 2 units IV bolus and 3 units/h

    201–220

Give 2 units IV bolus and 3.5 units/h

    >220

Give 2 units IV bolus and 4 units/h

For successive blood glucose measurements

    80–120

Continue current infusion rate

    121–141

Increase insulin infusion by 0.5 unit/h

    141–160

Increase insulin infusion by 1 unit/h

    161–180

Increase insulin infusion by 1.5 unit/h

    181–200

Increase insulin infusion by 2 units/h

    201–220

Increase insulin infusion by 2.5 units/h

    >220

Increase insulin infusion by 3 units/h

Conventional insulin therapy

For first blood glucose measurement

    220–240

Give 2 units IV bolus and 2 units/h

    241–260

Give 2 units IV bolus and 3.5 units/h

    261–280

Give 2 units IV bolus and 4 units/h

    >280

Give 4 units IV bolus and 4 units/h

For successive blood glucose measurements

    <220

Continue current infusion rate

    220–240

Increase insulin infusion by 1 unit/h

    241–260

Increase insulin infusion by 2 units/h

    261–280

Increase insulin infusion by 3 units/h

    >280

Increase insulin infusion by 4–5 units/h

Appendix Legend

All patients with blood glucose levels <4.44 mmol/l (<80 mg/dl) received glucose in a bolus (0.1 g/kg at a concentration of 33%) with the insulin infusion stopped. The glucose concentration was then measured within 30 min.

All patients receiving continuous insulin must receive a continuous surge of enteral or parenteral nutrition.

The insulin infusion is discontinued if the patient has to leave the ICU for a diagnostic test as well as upon discharge from the ICU.

Appendix 2: Glasgow Outcome Score

Score

Rating

Definition

5

Good recovery

Resumption of normal life despite minor deficits

4

Moderate disability

Disabled but independent. Can work in sheltered setting

3

Severe disability

Conscious but disabled. Dependent for daily support

2

Persistent vegetative

Minimal responsiveness

1

Death

Non-survival

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Bilotta, F., Caramia, R., Cernak, I. et al. Intensive Insulin Therapy After Severe Traumatic Brain Injury: A Randomized Clinical Trial. Neurocrit Care 9, 159–166 (2008). https://doi.org/10.1007/s12028-008-9084-9

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