Intensive versus nonintensive insulin therapy for hyperglycemia after traumatic brain injury: study protocol for a randomized controlled trial

Wen-xue Wang, Ai-min Li, Jian-wei Wang Xin Kang Guang-hui Fu Yu-liang Liu

1 Department of Neurosurgery, Oriental Hospital of Lianyungang, Lianyungang, Jiangsu Province, China

2 Department of Neurosurgery, the First People’s Hospital of Lianyungang, Lianyungang, Jiangsu Province, China

Background

Numerous studies have confirmed that hyperglycemia generally occurs after severe traumatic brain injury, and is an important factor of secondary brain injury (Graffagnino et al., 2010; Green et al., 2010; Kanji et al., 2010). Hyperglycemia is a physiological and metabolic disorder that occurs after traumatic brain injury. Traumatic brain injury can lead to hyperglycemia that further exacerbates secondary brain injury (Oddo et al., 2008; Sharma et al., 2009); therefore,effective treatment of hyperglycemia after traumatic brain injury has important clinical significance.

Hyperglycemia after severe traumatic brain injury is correlated with nerve stress, hypothalamic-pituitary system damage, pancreatic beta cell dysfunction, insulin resistance,and increased serum glucagon levels. Mechanisms underlying hyperglycemia-induced nerve injury may involve lactic acidosis, blood-brain barrier damage, local cerebral ischemia, hypoxia, and intracellular calcium overload. Early use of intensive insulin therapy can control the blood glucose level in the target range of 4.4–6.1 mM. This glucose level can directly protect against nerve ischemia injury after severe traumatic brain injury, promote neurologic function recovery, reduce disability and mortality, and improve patients’ prognosis (Tang et al., 2012). However,one study found that although intensive insulin therapy has a clear advantage in the reduction of short-term mortality and infections associated with severe traumatic brain injury combined with hyperglycemia, such therapy is more likely to induce hypoglycemia and have no preponderance in the long-term improvement of neurologic function (Hu et al.,2014). Consequently, we aim to compare and analyze the clinical efficacy of intensive versus nonintensive insulin therapy on blood glucose control, mortality, degree of brain injury, and functional prognosis in patients with hyperglycemia after severe traumatic brain injury through a randomized, double-blind, controlled, parallel clinical trial.

Methods/design

Study design

This study is a randomized, double-blind, controlled, parallel clinical trial and has been registered in ClinicalTrials.gov.It will be conducted at Oriental Hospital of Lianyungang,China. Eligible patients with hyperglycemia after severe traumatic brain injury will be randomly assigned to either the intensive insulin therapy group or the nonintensive insulin therapy group, each of which will have a specific blood glucose control protocol. Outcome assessment and statistical analysis will be performed in a blinded manner by professionals. A flow chart of the study design is shown in Figure 1.

Ethical review and informed consent

Because the patients with severe closed traumatic brain injury will be unconscious, informed consent will be signed by their legal representatives. When the patients regain consciousness and are able to understand the content of the trial, we will explain the benefits and risks of participating in the study to the patients and obtain their written informed consent. The study protocol follows the Declaration of Helsinki and was approved by the Ethics Committee of Oriental Hospital of Lianyungang, China.

Study participants

To be eligible for the trial, patients with hyperglycemia after severe traumatic brain injury admitted to the Department of Neurosurgery of Oriental Hospital of Lianyungang, China must fulfill the following criteria.

Inclusion criteria: (1) clinical diagnosis of severe closed traumatic brain injury, (2) CT confirmation of severe closed traumatic brain injury, (3) severe traumatic brain injury in accordance with the indications for craniotomy, (4) blood glucose levels of ＞ 7.0 mM measured twice by rapid examination within 2 hours after admission, (5) Glasgow coma score (Rowley and Fielding, 1991) of 3 to 8, (6) 18 to 80 years of age, and (7) no history of diabetes mellitus.Patients will be enrolled irrespective of sex.

Exclusion criteria: (1) ＜ 18 or ＞ 80 years of age, (2)Glasgow coma score of ＞ 8, (3) multiple-site damage,(4) hemodialysis dependence combined with diabetic nephropathy, (5) nervous system disease before traumatic brain injury, and (6) a history of diabetes before traumatic brain injury.

In addition, patients will be excluded if they are ineligible for the inclusion criteria and their case report form is nonstandard. Moreover, patients can withdraw from the trial if they fit the following criteria: (1) discontinuation of the trial is necessary from a medical point of view or (2) a request is received from the patient’s family to stop the trial.

Randomization

When a blood glucose level of ＞ 7.0 mM measured twice by rapid examination within 2 hours after admission is confirmed, patients with hyperglycemia after severe closed traumatic brain injury will be randomly divided into an intensive insulin therapy group and a nonintensive insulin therapy group. The intensive insulin therapy group will be divided into three subgroups based on the target blood glucose level. Computerized randomization will be completed by researchers who cannot directly contact the participants. Patients, outcome assessors, and statisticians will be blinded to information regarding grouping. If the eligible patients consent to the trial, sealed opaque envelopes with a randomly assigned serial number containing the accepted treatment programs will be opened. The patients will then undergo the corresponding treatment measures.If any error or disclosure with regard to randomization occurs, a new randomization sequence will be generated starting from the problematic serial number and applied to subsequent patients.

Interventions

Patients in both groups will be treated using the following uniform protocol.

(1) Craniotomy for traumatic brain injury will be performed to mainly decompress and remove hematomas.Standard trauma craniotomy and incision of the trachea will be performed. (2) During the operation, all patients will undergo ventricular puncture. Cerebrospinal fluid will

be obtained for biochemical analysis and cell culture. (3)All patients will be closely monitored in the intensive care unit of the Department of Neurosurgery. (4) Therapeutic protocols for severe traumatic brain injury will be used.(5) Glucocorticoids, which can cause disorders of glucose metabolism, will not be regularly applied in either group.(6) During intravenous injection, glucose and insulin will be mixed at a proportion of 5:1 to minimize the effects of exogenous glucose on the blood glucose level.

Table 1: Timeline for data collection, intervention, and outcome evaluation

Figure 1: Flow chart of study design.

The intensive insulin therapy group will be divided into three subgroups based on the following target blood glucose levels: 4.4–7.0 mM (strict control group), 7.1–10.0 mM (moderate control group), and 10.1–13.0 mM (slight control group). In these three subgroups, the blood glucose levels will be monitored and controlled according to the Yale Insulin Infusion Protocol (Goldberg et al., 2004), and insulin will be infused into the vein using a micropump at 0.1 U/kg per hour. When the blood glucose level is ＞ 20.0 mM, insulin will be infused intravenously at 10.0 U/h; when the blood glucose level is 17.1–20.0 mM, insulin will be infused at 8.0 U/h; when the blood glucose level is 14.1–17.0 mM, insulin will be infused at 6.0 U/h; and when the blood glucose level is 11.5–14.0 mM, insulin will be infused at 4.0 U/h. Within 12 and 24 hours, the blood glucose level will be maintained within the target range. During this period, the blood glucose level will be monitored once every 2 hours, and the insulin dose will be adjusted in time. If the blood glucose level is higher than the target value, the insulin dose will be gradually increased by 1–2 U/h. When blood glucose level reaches the target value, the insulin dose will be gradually decreased until insulin administration is terminated. According to the Yale Insulin Infusion Protocol,the amount of insulin (U) = [fasting blood glucose (mM) ×18 – 100] × 10 × body weight (kg) × 0.6/1,000/2. The insulin for injection (400 U per 10 mL) will be obtained from Wanbang Biochemical Pharmaceutical Co., Ltd., China (Lot Nos. 1307230, 1302225, and 1307210).

In the nonintensive insulin therapy group, rapid blood glucose level measurement will be performed once every 2 hours. When the blood glucose level is ≤ 13.0 mM, no intervention will be performed. When the blood glucose level is ＞ 13.0 mM, regular insulin will be subcutaneously injected. Insulin will be injected once every 8 hours in a fasting state; during venous or enteral nutrition infusion,insulin will be infused 30 minutes before nutrition infusion. When the blood glucose level is ≤ 13.0 mM, insulin infusion will be terminated.

Blood glucose measurement

Capillary blood samples will be obtained from the tip of the ring finger to measure the blood glucose level. The blood samples will be collected from the same finger to ensure accurate measurement. However, when the blood glucose level of a patient undergoing transfusion is measured, the blood sample should be collected from the fingertip of the limb without transfusion to ensure measurement accuracy.

Outcome measures

Primary outcomes

The target blood glucose level will be monitored as the primary outcome measure. Within 1 week of hospitalization,the rapid blood glucose level will be recorded once every 2 hours in each group. The glycosylated serum protein level will be measured once a week for 4 consecutive weeks. This index reflects the mean blood glucose level of the previous 2 to 3 weeks.

Secondary outcomes

To assess mortality, we will calculate the percentage of patients who die during hospitalization, at 1 and 2 weeks after surgery, and at 3 months after injury.

To evaluate the activities of daily living, the Modified Rankin Scale score and Glasgow outcome score will be calculated 2 weeks after hospital admission. The Barthel index, Glasgow outcome score, and Modified Rankin Scale score will then be calculated 3 months after injury. Finally,the Barthel index and Glasgow outcome score will be calculated 6 months after injury.

Other outcomes

To evaluate the severity of each patient’s condition, the Glasgow coma score will be calculated and a recording sheet will be used to evaluate each patient’s condition at hospital admission. The Acute Physiology and Chronic Health Evaluation II will be administered each subsequent day in the intensive care unit.

To monitor morphological changes in the brain, CT scans will be performed at admission, preoperatively, 1 to 3 days,7 and 14 days postoperatively.

Finally, to monitor changes in the cerebrospinal fluid,cerebrospinal fluid will be obtained for biochemical analysis and cell culture. Cerebrospinal fluid will be collected during surgery and 1 week after surgery by lumbar puncture.

All endpoints are listed in Table 1.

Safety assessment

All serious adverse events will be reported to the ethics committee, including the occurrence time, drug-related index, and association with drug use. The development of serious adverse events will be followed up and recorded.Patients who withdraw from the trial because of an adverse event will be followed until completely removed. Researchers must determine whether adverse events are related to the drug used in this trial and provide the basis to support this judgment.

Data collection, management, and statistical analysis

All acquired case data will be collected by auditors who are responsible for ensuring the accuracy of data entry and records. Completed medical observation sheets will be reviewed and recovered by the auditors. If confirmed, the data from the medical report form will be input into the database. The researchers will ensure that the data are preserved completely, and a fixed location that can be latched to store the data for future review will be utilized. According to Chinese Good Clinical Practice, the study protocol will be kept for at least 5 years.

All statistical data will be calculated by professional statisticians using SAS 9.0 software. Count data will be expressed as a percentage, and measurement data will be expressed as the mean ± SD. Count data will be compared using the chi-square test. Analysis of variance and the Student-Newman-Keuls test will be used for intergroup comparison of measurement data. A P value of ＜ 0.05 will be considered statistically significant.

DISCUSSION

Acute traumatic brain injury is characterized by sudden occurrence, rapid development, complexity, high disability and mortality rates, and hyperglycemia. Therefore,we will compare the short-term effects (Acute Physiology and Chronic Health Evaluation II) and long-term effects(Glasgow outcome scale, Barthel index) of early use of insulin to analyze the clinical efficacy of early use of insulin therapy in patients with acute traumatic brain injury.

Dynamic monitoring of blood glucose levels contributes to the reasonable control of blood glucose levels. Accurate blood glucose monitoring is the premise for prevention of hyperglycemia and concurrent metabolic disorders (Zhang et al., 2010). In patients with severe traumatic brain injury,elevated blood glucose levels are closely associated with the prognosis. Therefore, we should strictly monitor changes in blood glucose levels and employ intensive insulin therapy as early as possible. Continuous infusion of insulin is safer,faster, and easier to control than is traditional subcutaneous injection. Some scholars believe that insulin can pass through the blood-brain barrier and that continuous therapy is critical for maintaining the insulin concentration in both the brain and body. Therefore, intravenous injection using a micropump will be adopted in this study to achieve more sustained action and more adequate blood insulin concentrations than can be achieved with traditional subcutaneous insulin injection.

Intensive insulin therapy can control the blood glucose levels of patients with severe traumatic brain injury within the range of 4.44–6.11 mM, significantly reducing mortality and complication-related morbidity (Li et al., 2007). In this study, intensive insulin therapy will be used to control the target blood glucose level within a range of 4.4–7.0 mM.Additionally, control groups of 7.1–10.0 mM and 10.1–13.0 mM will be set to understand the mortality and functional prognosis of these patients with hyperglycemia after severe traumatic brain injury.

In conclusion, the results of this randomized, controlled,double-blind clinical trial will provide reference data for the rational use of insulin for treatment of severe traumatic brain injury combined with hyperglycemia. These data will help clinicians to lower patients’ blood glucose levels and mortality rates and improve patients’ functional outcomes.

Trial status

Recruitment of participants is ongoing.

Conflicts of interest

None declared.

Author contributions

WXW conceived and designed the study, wrote the protocol, provided critiques and revised the paper for important intellectual content. AML, JWW, XK, GHF, YLL were responsible for the design of the study. All authors read and approved the final paper.

Plagiarism check

This paper was screened twice using CrossCheck to verify originality before publication.

Peer review

This paper was double-blinded and stringently reivewed by international expert reviewers.

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