Relationships of Hyperglycemia and Neurological Outcome in Patients with Head Injury, and Insulin Therapy
Jahan Porhomayon, MD. FCCP
Assistant Professor , Dept. of Anesthesiology, Critical Care Medicine
State University of New York at Buffalo, Buffalo, New York
Nader D. Nader M.D., PH.D. FCCP
Professor, Dept. of Anesthesiology, Surgery, Pathology
State University of New York at Buffalo, Buffalo, New York
Firooz Salehpour, M.D.
Associate Professor, Dept. of Neurosurgery, Tabriz University in Medical Sciences
Ali Meshkini ,M.D.
Assistant Professor, Dept. of Neurosurgery, Tabriz University in Medical Sciences
Amir Bahrami M.D.
Assistant Professor, Dept. of Medicine, Tabriz University in Medical Sciences
Hamzeh Hoseinzadeh M.D.
Assistant Professor, Dept. of Anesthesiology, Tabriz University in Medical Sciences
Background: Neurological outcome following closed head injury is generally assessed by clinical scoring systems such as Glasgow Coma Scale (GCS) and presence or absence of cerebral edema and intracranial hematoma in imaging studies. Metabolic markers, such as blood glucose levels, have recently been used as prognostic factors of head injury in trauma patients. The primary objective of this study is to determine the relationship between serum glucose level and its prognostic value in predicting neurological outcomes in trauma patients suffering from a moderate or severe head injury.
Methods: The study protocol was approved by Institutional Review Board on human subjects enrollment of University of Tabriz affiliated hospitals. Informed consent was obtained from the patient’s surrogate or healthcare proxy. A prospective study of 96 consecutive patients with moderate and/or severe head injury admitted to the Neurointensive Care Unit were enrolled. Baseline and daily Glasgow Coma Score (GCS) values were recorded along with blood glucose concentrations every 6 hours. A subset of patients were treated with an insulin infusion to maintain blood glucose levels ≤ 120 mg/dL. Patient outcome was scored according to Glascow Outcome Score (GOS) at the end of their admission. GOS results were normalized to the patients baseline GCS and correlated to serum glucose level and administration of insulin.
Results: Seventy-nine male (82%) and 17 female patients (18%) were enrolled. The mean age was 33.2 ± 4.2 (Range: 18-84 years). Motor vehicle accidents were the most common cause of head trauma. Fifty-five patients (59%) had an admission GCS≤8 while 39 patients (41%) had a GCS ≥9. There was an inverse relation between GCS and GOS (p<0.01). Similarly, admission levels of blood glucose were inversely correlated to GCS (p<0.05). Although glucose concentrations were higher in patients with poor outcomes (p<0.001), insulin treatment did not improve the neurological outcome in patients with blood glucose concentrations of less than 150 mg/dL.
Conclusion: Hyperglycemia is commonly seen in patients suffering severe traumatic brain injury. Increased levels of blood glucose are associated with a poor neurological outcome. We were unable to improve the neurological outcome through an aggressive glucose control by insulin. A larger group of patients needs to be studied to elicit any potential benefit of tight glucose control in victims of cerebral trauma.
Neurological outcomes are poor when patients present to the hospital with low Glasgow Coma Scale (GCS) scores following traumatic brain injury. These patients often suffer from multiple trauma (1), and manifest with intractable hypoxia, hypotension and disseminated intravascular coagulation. Neurologic findings in these patients include abnormal pupil responses, brain edema, brain stem reflexes and early development of posttraumatic seizures (2). Trauma is associated with an acute stress response and increased sympathetic activity through hypothalamus-pituitary-adrenal axis (3). The end result of this hormonal response includes increased circulating levels of catecholamines and cortisol leading to altered metabolism of glucose (4). This increase in circulating catecholamines causes a rise in blood glucose concentration in addition to a hyperdynamic cardiovascular response (5). Hyperglycemia is commonly manifested in trauma victims as a part of systemic hypermetabolic response (2, 6). Increased plasma concentrations of glucose, regardless of the underlying etiology, have detrimental effects on multiple varieties of human cells including neurons (7, 8). Therefore, hyperglycemia may adversely affect neurological outcome following cerebral trauma (5, 9, 10). An elevation of blood glucose concentrations and serum lactate levels often corresponds to an increase in glucose in the cerebrospinal fluid (CSF) (11, 12) in patients with severe head injuries.
Systemic and CSF concentrations of glucose and other products of carbohydrate metabolism have been used as prognostic markers of recovery and neurological outcome following head injury (1, 13, 14). The predictive value of hyperglycemia as a prognostic indicator of poor outcome is increased if there is concurrent elevation in inflammatory markers (15). Although there is plenty of evidence for detrimental role of high glucose concentration in the presence of an underlying traumatic or ischemic neuronal injury, only a few studies have examined the role of tight glucose control in improving the neurological outcome following head injury(16). The main objective of this study is to investigate whether a close monitoring of glucose and adopting an aggressive therapeutic regimen to reduce serum glucose improves the neurological outcome in head injury patients. We hypothesize that if serum glucose levels are maintained below 120 mg/dL throughout the Neurointensive Care Unit (NICU) stay, there will be less residual neurologic damage following cerebral trauma.
Patient Enrollment: Ethics and conduct of the study was reviewed and approved by Institutional Committee on Ethics and Human Subject Research at the University of Tabriz in Medical Sciences. Informed consent was obtained from the surrogate and/or the health care proxy of 96 patients admitted to the Neurosurgery Department with severe head injuries from 2007 through 2008. Demographic information including age, gender and the nature of trauma were recorded. Patients remained NPO during their first 48-hours of admission to NICU. Daily fluid loss was replaced by intravenous infusion of Dextrose 5% in Water + normal saline (1/3:2/3 v.v). Enteral feeding was resumed after 48 hours of admission either orally or via tube feeding. An independent physician examined patients daily. GCS scores were assigned at the time of admission (GCS0) and the following day (GCSD1).
Blood Glucose Measurement and Insulin Therapy: A complete set of blood chemistry was obtained upon admission, which included a serum blood glucose measurement. Blood glucose levels are monitored every 6 hours by finger stick at the bedside by a registered nurse using Accucheck®. These devices received daily quality control and calibrated with two (“High” and “Low”) standard solutions. Blood glucose concentrations were recorded and also used as a guide to adjust insulin infusion. An insulin (Humulin R) infusion was initiated in patients who had initial glucose levels > 150mg/dl. The initial infusion rate was set at 1 unit/hour for every 30 mg/dL of blood glucose of above 120 mg/dL. The insulin infusion was titrated for serum glucose levels; 1) “Tight Control” Group with blood glucoses 90-120 mg/dL, 2) Normoglycemic Group (blood glucose 121-150 mg/dL), 3) Liberal Group (blood glucose between 151-180 mg/dL) and 4) Hyperglycemic Group (blood glucose greater than 181 mg/dL). The insulin infusion was stopped temporarily if the patients became hypoglycemic. Hypoglycemia was treated with dextrose solution in symptomatic patients with blood glucose less than 50 mg/dl.(36).
Outcome measures: All patients had clinical follow-up of 3 months (unless they died before this period had elapsed). Clinical outcomes were assessed according to the Glasgow Outcome Scale (GOS) as follows: 1 mild or no disability; 2, moderate disability; 3, severe disability; 4, vegetative state and 5 death. This outcome assessment was not independent but was performed by the investigators during routine clinical reviews and/or telephone survey. Formal neuropsychological assessment was not routinely performed. GOS scores were assessed at the time discharge from the hospital and 6 months thereafter during their clinic appointment notes. For statistical comparison, during the follow up visit patients with a GOS score of 1 or 2 were classified as having a favorable outcome (F), and those with a GOS score of 3 to 5 as having an unfavorable outcome (U).
Statistical Analysis: The groups were compared using analysis of variance for group-wise comparisons of three or more groups. Student’s t test was performed for pair-wise related variable comparisons. Tukey’s honest significant difference multiple comparison (post hoc) tests were performed for significant omnibus F tests. The predictive value of hyperglycemia was assessed using a stepwise logistic regression and Receiver Operating Characteristic (ROC) curve. The level of significance was set at p < 0.05 for all comparisons unless a lower level was substituted for statistical stringency (this will be noted in the text).
Ninety-six patients were enrolled with 82.3% of the patients being male and 17.7% female (M:F ratio of 5 to 1). The mean age of the patients were 33.2 ± 4.2 years old ranging from 18 to 84 years. The most common cause of trauma was motor vehicle accidents (72.9%) followed by fall (17.7%). All other causes comprised only 9.4% of the etiology. GCS scores on admission to the NICU were 8 ± 3. Fifty-nine percent of patients had severe head injury (GCS< 8), while the remaining 41% suffered from mild/moderate head injury (GCS>9). The mean GOS of the patients was 3.11 ± 0.32. Death, vegetative state or severe neurologic incapacitation occurred in 62.5% of the patients. Favorable outcome (F) was observed in 37.5% of the patients upon discharge from the hospital. Twenty-four percent of patients experienced severe neurological incapacitation and were included in the “Unfavorable Outcome” (U). Regression analysis of the outcome data revealed no significant relation based on age, gender and the cause of head injury (See Table 1).
Admission GCS score was an independent variable that determined the final GOS score and neurological outcome. There was an inverse correlation between GCS scores on admission and GOS score at the time of discharge (R2=0.45, p<0.01). The changes in GCS score from the time of admission and the next day was more correlated to the final GOS score at the time of discharge (R2=0.63, p<0.01). The patients with a favorable outcome during their 6 months follow up visit demonstrated a higher improvement in their GCS score on the first day of injury (Figure 1).
The mean glucose levels plus or minus standard deviations of the patients upon their admission to the NICU were 175.1 mg/dl ± 5.8 mg/dL. Overall, mean glucose levels for all patients during their admissions to NICU was 154.6 mg/dl ± 5.8 mg/dL. There was an inverse correlation between GCS scores and the serum glucose concentration measured on admission. (R2=0.18, p<0.05) Six patients were classified into the “Tight controlled” Group I (mean BG of 104.1 mg/dl ± 0.6 mg/dL), 23 patients into the “Normoglycemic” Group II (mean BG of 139.8 mg/dl ± 0.3 mg/dL), 33 patients in the “Liberal” Group III (mean BG of 163.7 mg/dl ± 0.3 mg/dl ) and 38 patients were in the “Hyperglycemic” Group IV (mean BG of 211.0 mg/dl ± 0.25 mg/dL).
Blood glucose concentration measured at the time of admission was unable to predict the neurological outcome of the surviving patients in 6 months χ2=0.096 (Figure 2a). ROC curve for the admission levels of blood glucose revealed a very low sensitivity 20% for 90% specificity (Figure 2b). The area under the curve for this parameter in predicting the neurological outcome was 0.54. However, mean blood glucose concentrations within the first 48 hours of ICU stay was a better predictor of the neurological outcome in these patients (χ2=7.24, p<0.01) (Figure 3a). ROC curve for mean blood glucose concentration still revealed a low sensitivity (30%) for a specificity of 90% in predicting the neurological outcome in these patients. (Figure 3b)
The ROC analysis shows that the predictive power of both mean glucose concentrations and admission glucose is very poor.
Mean blood glucose concentrations in patients with a favorable outcome and patient recovered with severe neurological disability (158.1 mg/dl ± 5.8 vs.156.9 mg/dl ± 7.2 mg/dL). However, patients with unfavorable neurological outcome had higher mean blood glucose levels
(192.5 mg/dl ± 5.7 mg/dL) when compared to the other patients with a better outcome (Figure 4). Although there was no difference in the age of the patients based on the extent of the hyperglycemic response, there was strong trend associated with the severity of the hyperglycemic response in older patients R2=0.63 (Figure 5).
From the total of 70 patients who had an admission blood glucose concentrations >150 mg/dL, 35 patients were to receive insulin infusion and other 35 were observed by frequent blood glucose measurements. The patients were not rfandomized. Mean blood glucose concentrations were 172.5 mg/dl ± 5.8 mg/dL in the insulin-treated patients and 189.4 mg/dl ± 5.5 mg/dl in the observation group (p<0.05). Glucose measurements were normally distributed. While there was no overall difference in GOS of the insulin-treated and observed patients, insulin treatment was associated with more favorable outcome in patients with admission blood glucose levels >150 mg/dL, p<0.01 (Figure 4). In the treated group, mean glucose concentrations were 133.8 ± 12.2 mg/dL which was significantly lower than the glucose concentrations in patients with unfavorable outcome (189.1 mg/dl ± 21.3 mg/dL, p<0.05). A similar observation was made in non-treated groups.
Our findings have shown that there is a hyperglycemic response in non-diabetic victims of head trauma that correlates to the severity of the head injury. Patients with over-exuberant hyperglycemic response tend to do poorly and have unfavorable outcome. Majority of these patients develop severe neurological disabilities if they survive the initial insult of the trauma. Our results also validate GCS scoring system in predicting the neurological outcome during a short- as well as a long-term recovery. In addition to a static scoring system based on GCS, as originally described, a frequent evaluation and monitoring the progress in the neurological state can be obtained using this system. A frequent assessment of the patients using this tool increases the predictive value of GCS system in the patient neurological outcome.
Glasgow Coma Scale (eye, verbal, motor responses) has been widely used by clinicians as a prognostic tool since its development in 1974. The scoring process is generally performed at the time of admission as an indicator of severity-of-illness and its criteria is incorporated in other clinical predictors of prognosis such as Revised Trauma Score, Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, and TRISS used to predict and compare patient outcomes. The relationship between GCS score and mortality is not linear and should not be used to continuous categorical scales (17). Longitudinal assessment of the patient’s neurological function using GCS scoring system has been previously described. Udekwu et al. proposed a mathematical formula using pre- post-resuscitation GCS scores to increase the predictive value of GCS in determining the final outcome(18). Our data indicate that the extent of changes in GCS score from the initial time to the next day demonstrates a stronger correlation with both short-term and long-term outcome of head injury victims. These data are validated using another outcome assessment tool (Glasgow Outcome Scale).
Our findings indicate that there is a relation between early-admission hyperglycemia and neurological outcome following head injury. A similar finding has been reported by others (19). Glucose metabolism is severely altered following a major trauma. Activation of sympathetic activity and release of catecholamines deter the uptake and the utilization of glucose by a wide variety of cells which results in a clinical condition similar to insulin resistance(20). The extent of the catecholamine surge in the body is directly related to the severity of the insult and may adversely affect the clinical outcome of trauma patients (21). Furthermore, the secretion of insulin from the pancreatic islet cells is also markedly depressed. Inhibition of insulin secretion is believed to be mediated through elevated levels of glucagon and/or circulating catecholamines (22). Although a cause-effect relationship has not been established under these clinical situations, it is proposed that the level of hyperglycemia elicits a stress response as a reflection of the extent of the injury. A systemic stress response is generally associated with severe traumatic brain injury (23).
The role of hyperglycemia in the clinical outcome of the patients following brain injury is less clear. Our results indicated an association between higher concentration blood glucose and poor clinical outcome in head injury victims. Although there is evidence for the adverse effects of glucose on the nervous system recovering from focal ischemia and the observation made in this study, we can not exclude hyperglycemia as an epiphenomenon secondary to the extent of the trauma. Focal ischemic changes of the brain tissue are often seen following head injury. Upon reperfusion of these ischemic foci, the neuronal tissue is exposed to excessive amount of reactive oxygen species and inflammatory mediators that results in ischemia-reperfusion injury (24, 25)}. Experimental models of cerebral ischemia-reperfusion have shown an escalation of neurological deficits in the presence of hyperglycemia (26-28). It is believed that the oversupply of glucose under ischemic conditions allows the anaerobic metabolism to continue along with the accumulation of lactate and hydrogen ions (29). Intracellular acidosis, in turn, initiates neuronal influx of calcium, release of lipid peroxide species and ultimate destruction of neurons (30).
Exogenous insulin has been successfully used to improve mortality and ICU length of stay in critically-ill patients(32). In addition to direct vasodilatation, insulin has anti-inflammatory effects that down regulates the extent of local inflammatory cytokine production (33-35). Both of these effects have potentially a beneficial effect on the extent of neuronal damage following head injury. Our results have shown a modest decrease in mortality and improvement in GOS score in patients treated with insulin. Since we were unable to see any beneficial effect for insulin treatment in patients with normal glucose concentration throughout their ICU stay, we believe that the effects of insulin on the neuronal tissue are mediated through its effects on glucose. Demonstration of the beneficial effects of insulin in normoglycemic patients will require a larger sample size due to a smaller effect size.
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First Published November 2009