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Table of Contents    
ORIGINAL ARTICLE
Year : 2016  |  Volume : 64  |  Issue : 2  |  Page : 259-264

Intracerebral hypoglycemia and its clinical relevance as a prognostic indicator in severe traumatic brain injury: A cerebral microdialysis study from India


Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication3-Mar-2016

Correspondence Address:
Deepak K Gupta
Department of Neurosurgery, All India Institute of Medical Sciences, Room No. 720, CN Centre, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.177617

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 » Abstract 

Context: Traumatic brain injury (TBI) remains a major cause of morbidity and mortality worldwide. Largely, the prognosis is dependent on the nonmodifiable factors such as severity of the initial injury, Glasgow coma scale score, pupillary response, age, and presence of additional physiological derangements such as hypoxia or hypotension. However, secondary insults continue to take place after the initial injury and resuscitation. The study hypothesis in the present research article was that hypoglycemia is an independent outcome prognosticator in severe traumatic brain injury. The study aimed to assess the role of glucose monitoring in the brain parenchyma as an independent outcome prognosticator and also to study its association with plasma glucose levels.
Aims: The aim of the study was to analyze the relationship of intracerebral glucose measured by intraparenchymal cerebral microdialysis (CMD), and also to study its relationship with blood glucose levels. We also evaluated the relationship of these values to the outcome of patients.
Settings and Design: Prospective nonrandomized study conducted at a tertiary care trauma center in India.
Subjects and Methods: Twenty-five patients with severe TBI, who underwent decompressive craniectomy, were prospectively monitored with CMD catheters. Twenty cases had unilateral catheters placed intraparenchymally (20 mm inside the brain parenchyma to accommodate 10 mm of the semipermeable catheter tip and another 10 mm of extra catheter length). Frontotemporal contusions were noted in 21 cases and an acute subdural hematoma (with/without associated contusions) were noted in 15 cases in the present series. Bilateral CMD catheters were placed during bifrontal decompressive craniectomies in five patients (two patients had peri-contusional catheters placement; these patients had bilateral frontal contusions); while, the remaining 3 patients had a contralateral catheter placement in the normal brain parenchyma [Table 1]. The position of the catheters was confirmed on postoperative computerized tomographic scan carried out in these subjects. However, bilateral catheter placement to compare the difference in cerebral biochemical values of glucose in the penumbric zone as well as the normal brain could not be done in all cases due to cost restraints. The relation between plasma glucose and CMD-measured interstitial brain glucose concentrations, as well as the temporal pattern of CMD glucose was studied for 3–5 days following a decompressive craniectomy using a CMD analyzer at the patient's bedside at 1 hourly intervals.
Statistical Analysis Used: All data were tabulated in Microsoft Excel 2011 and analyzed using SPSS version 21. To calculate the correlation between plasma and CMD glucose, Pearson's correlation was used with a two-tailed test of significance. Student's t-test was used to calculate the difference in means between the two groups. Significance was assumed at P ≤ 0.05.
Results: Fifteen patients (60%) had a good outcome in terms of the Glasgow Outcome Scale (GOS) at 3 months while the rest (10 patients) had a poor GOS at 3 months. There was a significant difference in the incidence of hyperglycemia (random blood sugar >10 mmol/L) between the two groups (P < 0.0001). The difference between the two groups while comparing episodes of hypoglycemia was also significant (P = 0.0026). The good outcome group had fewer episodes of brain hypoglycemia during the presence of systemic hypoglycemia (P = 0.0026). Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months.
Conclusions: After decompressive craniectomy in severe TBI, there was a poor correlation between the plasma and CMD glucose concentration. A higher degree of variation was seen in the correlations for individual patients. Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months. The good outcome group had fewer episodes of both hyperglycemia and hypoglycemia.


Keywords: Decompressive craniectomy; glucose; microdialysis; traumatic brain injury


How to cite this article:
Gupta DK, Singla R, Kale SS, Sharma BS. Intracerebral hypoglycemia and its clinical relevance as a prognostic indicator in severe traumatic brain injury: A cerebral microdialysis study from India. Neurol India 2016;64:259-64

How to cite this URL:
Gupta DK, Singla R, Kale SS, Sharma BS. Intracerebral hypoglycemia and its clinical relevance as a prognostic indicator in severe traumatic brain injury: A cerebral microdialysis study from India. Neurol India [serial online] 2016 [cited 2020 Dec 4];64:259-64. Available from: https://www.neurologyindia.com/text.asp?2016/64/2/259/177617



 » Introduction Top


Traumatic brain injury (TBI) remains a major cause of worldwide morbidity and mortality. The prognosis is largely dependent on the nonmodifiable factors such as the severity of the initial injury, the Glasgow coma score, the pupillary response, the age of the patient, and the presence of additional physiological derangements such as hypoxia or hypotension.[1],[2] However, secondary insults continue to take place after the initial injury and resuscitation.[3] With the advent of microdialysis (MD), the monitoring of the penumbric zone and of biochemical changes taking place inside brain tissue has become possible for the neurosurgeon. This has palyed the important role of transporting research in this arena from bench-side to bedside. The present study aimed to assess the role of glucose monitoring in the brain parenchyma and its association with plasma glucose for outcome prediction in patients suffering from severe traumatic brain injury.


 » Subjects and Methods Top


The study included all patients of severe TBI (Glasgow Coma Scale [GCS] score ≤8) with a surgically treatable lesion. The patients included were >18 years in age. As part of the routine protocol, the patients underwent a noncontrast computed tomography (NCCT) of the head at admission along with an assessment of other systemic injuries. Patients who were pregnant, those with GCS score of 3 with fixed dilated pupils, or those who were hemodynamically unstable were not enrolled in this prospective, nonrandomized study. Informed consent and Institute review board permission was obtained prior to the inclusion of the patients in this study.

Patient management

All severe traumatic brain injured patients with a surgically treatable lesion and/or raised intracranial pressure (ICP)/refractory intracranial hypertension (subdural hematoma, contusion, diffuse cerebral edema with refractory intracranial hypertension, that is, ICP >20 mm Hg for over 30 min) were subjected to decompressive craniectomy with augmentation duroplasty. Postoperatively, they were managed in the neuro-intensive care unit. At the time of dural closure, a single MD catheter, CMA-70 (a 20 kDa catheter), was inserted in the peri-contusional brain parenchyma at a depth of 20 mm and connected to the cerebral MD (CMD) pump which was preloaded with central nervous system (CNS) perfusion fluid. Few patients had catheters placed bilaterally. All patients were managed as per the standard treatment guidelines given by the Brain Trauma Foundation (BTF 2007). All patients also underwent a concurrent ICP monitoring using an intraparenchymal ICP catheter based monitoring. The patients also had invasive arterial pressure monitoring. Postoperative NCCT head was routinely done to confirm the position of the catheter(s) in the penumbric/intraparenchymal zone.

Cerebral microdialysis

MD catheter probes (molecular weight cut-off of 20 kDa, 10-mm membrane, CMA-70, CMA MD) were placed in the peri-lesional tissue at the time of dural closure. The probes were perfused with CNS perfusion fluid at 0.3 µl/min (P000151, CMA MD) and samples collected for intracerebral glucose every hour. Concentrations of glucose, lactate, pyruvate, glutamate, and glycerol in the microdialysate were analyzed using the CMA-ISCUS flex MD analyzer [Figure 1].
Figure 1: Anticlockwise from top: Microdialysis analyzer showing graphs for various parameters. Insertion of microdialysis catheter during decompressive craniectomy. Connecting the perfusion pump to the microdialysis catheter. Collection of sample in the Intensive Care Unit

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The MD catheter was kept in place for a minimum of 3 days and up to a maximum of 5 days. Hourly data points were recorded for each individual. A data point was defined as the MD values acquired after each hour in addition to the neurophysiological parameters from the multimodal brain monitoring including the ICP, cerebral perfusion pressure (CPP), and mean arterial pressure.

Plasma glucose

Simultaneous analysis of plasma glucose was done on an hourly basis through an arterial line and analyzed using an arterial blood gas (ABG) analyzer. Plasma glucose levels were maintained between 70 and 140 mg% as per our neuro-intensive care protocol and hyperglycemia (serum glucose >200 mg%), if any, was managed by the insulin sliding scale. As this was a preliminary, noninterventional, observational study to study the correlation between cerebral glucose and serum glucose in severe TBI patients, no attempt was made to correct the glucose levels on the basis of CMD glucose levels in any case.

Standard values

The normal extracellular glucose concentration in the human brain has not been well established. Normative data are dependent on several technical factors, including the perfusion rate. Careful assessment of the perfusion rate is required when comparing various studies. With the reduction in the perfusion rate to 0.3 uL/min, the in vivo recovery increases. In keeping with the international standards,[4] the standard CMD based biochemical values for reference were kept as: Glucose ≥2 mmol/L (≥36 mg%); lactate <2 mmol/L; pyruvate 0.12 mmol/L; glycerol 20–50 micromol/L; glutamate 10 micromol/L; and, lactate/pyruvate ratio 15–20.

Statistics

All data were tabulated in MS Excel 2011 and analyzed using IBM SPSS version 21 (IBM, USA). To calculate the correlation between plasma and MD glucose, the Pearson's correlation coefficient was used with a one-tailed test of significance. Student's t-test was used to calculate the difference in means between two groups. Significance was assumed at P ≤ 0.05.

Ethical clearance

The institutional ethical board permission was obtained for the study. All patients underwent decompressive craniectomy as per the standard management protocol. Informed and written consent for MD catheter insertion and monitoring was taken from a relative at the time of surgery[Table 1].
Table 1: Cerebral glucose and serum glucose in patients with bilateral CMD catheters

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 » Results Top


The mean age of the patients enrolled in the study was 31.76 (standard deviation [SD]: 10.71) years (range: 18–64 years). There were 21 males and four females in this group. The mean GCS before intervention was 5.36 (range: 4–8). The mean plasma glucose at the start of MD was 7.67 mmol/l with a SD of 1.55 (range: 5.23–8.44). The mean MD glucose at the start of the MD was 1.77 mmol/l with a SD of 1.59 (range: 0.1–7.7) [Table 2].
Table 2: Epidemiological data

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A total of 2116 corresponding arterial blood and brain MD readings were obtained. In our study, the mean random blood sugar (RBS) for the whole cohort was 7.39 mmol/l. In the good outcome group, 1303 values were obtained with a mean RBS of 7.264 mmol/l and a mean MD glucose of 1.841 mmol/l. In the bad outcome group, the mean RBS was 7.61 mmol/L with a mean MD glucose of 1.95 mmol/L. However, there was no significant difference in the mean RBS (P = 0.166) and mean cerebral glucose (P = 0.221) values amongst the good or bad outcome groups [Table 3].
Table 3: Values of MD glucose and RBS in the two groups

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There was a poor correlation between the plasma and cerebral glucose for the entire cohort (Pearson's correlation 0.01 with P = 0.642). No correlation was seen in the pooled glucose values in either the good Glasgow Outcome Scale (GOS) or the bad GOS groups. This suggests that brain MD glucose values are not reflective of changes in the systemic glucose values. Taking matched blood and MD glucose values individually for each patient, only 7 of the 25 patients (28%) had a significant correlation between plasma and cerebral glucose. Out of these, four patients belonged to the good outcome group, two to the bad outcome group, and one had the catheter placement in an uninjured lobe in the bad outcome group.

There was no significant difference in the mean RBS (P = 0.166) and the mean cerebral glucose (P = 0.221) values amongst good or bad outcome groups.

Hyperglycemia

There was a significant difference in the incidence of hyperglycemia (RBS >10 mmol/L) between the two groups (P < 0.0001). However, the MD glucose values during the episodes of hyperglycemia did not show a significant difference between the two groups (P = 0.859).

Hypoglycemia

There was a significant difference in the incidence of hypoglycemia (RBS <5 mmol/L) between the two groups (P = 0.0026). However, the MD glucose values during the episodes of hypoglycemia did not show a significant difference between the two groups (P = 0.455).

The plasma glucose values were divided into 6 clusters to assess the role of plasma glucose on cerebral glucose [Table 4] and [Figure 2].
Table 4: Distribution of the MD glucose values with blood sugar values

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Figure 2: Box-whisker plot showing the distribution of microdialysis glucose with random blood sugar. Microdialysis glucose values do not seem to follow a particular trend with blood sugar values

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Patients were also assessed with respect to the incidence of hypoglycemia and the low levels of MD glucose. A large proportion of MD glucose values below 2 mM were observed in both the groups, whereas low blood sugar values were seen in a higher proportion in the poor GOS patients. The difference between the two groups while comparing episodes of MD hypoglycemia during the hypoglycemic episodes (RBS <5 mmol/L) was significant (P = 0.0026). Authors opine that this reflects an increased susceptibility of brain tissue to hypoglycemia in the poorer outcome group [Table 5].
Table 5: Incidence of hypoglycemia in the two groups

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Outcome analysis

Fifteen of the 25 patients enrolled in the study had a good GOS (4, 5) at 3 months. The good outcome group had fewer episodes of brain hypoglycemia during systemic hypoglycemia (P = 0.0026). Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months. While comparing the daily mean values in both the groups, it was seen that MD glucose values showed a rising trend in the good outcome group. Similarly, the good outcome group also showed rising MD glucose to blood glucose ratios. Authors hypothesize that this indicates a recovering metabolic state in the brain tissue. Rising MD glucose levels or recovering the value of brain glycemic control can be taken as a real time, early bedside sign of a good neurological outcome [Figure 3].
Figure 3: Rising trend of microdialysis glucose observed in the good outcome group as compared to the poor outcome group. Similarly, the good outcome group also showed rising microdialysis glucose to blood glucose ratios

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Of the 15 cases with a good outcome (GOS 4 and 5), 4 cases showed a positive correlation (Pearson's correlation coefficient analysis) between the CPP and MD glucose values while 2 patients showed a negative correlation. Of the 10 cases with a poor outcome (GOS 1–3), only one case had a positive correlation between the CPP and MD glucose values.


 » Discussion Top


It is well known that hyperglycemia and hypoglycemia need to be avoided to prevent increase in the underlying brain damage.[5],[6],[7] Hyperglycemia exacerbates tissue acidosis and oxidative stress aggravating underlying brain damage which, in turn, promote the development of multiorgan failure.[5],[6] Hypoglycemia impairs energy supply causing metabolic perturbations and inducing spreading cortical depolarization.[7] The NICE-SUGAR trial showed a significant increase in the mortality in patients subjected to the tight blood glucose range of 4.5–6.0 mmol/l compared with the conventional glucose control group with a blood glucose target of 10 mmol/l or less.[8] In our study, patients of both the groups had their blood glucose maintained at an average of 7.39 mmol/l. Neutralizing dose of insulin was giving in the case of high blood sugar values. However, both hypoglycemic and hyperglycemic episodes were more common in the poor outcome group.

It was earlier thought that cerebral extracellular glucose concentration levels would change in parallel to the blood glucose values.[9] This may, however, be an over simplification. Vespa et al., have shown that following head injury, there may be an increased utilization of cerebral glucose leading to lower MD glucose values.[10] Schlenk et al., also found a poor correlation between the blood and extracellular blood glucose in a patient with subarachnoid hemorrhage.[11] This may also be the case with TBI patients. Abate et al., attributed the poor control of MD glucose (based on blood glucose values) to the metabolic heterogeneity that may be expected in TBI patients.[12] In our study too, a poor correlation was noted between the MD glucose and blood glucose values.

Vespa et al.,[10] also showed that MD glucose values were better predictors of outcome at 6 months as compared to blood glucose values. However, our study showed no statistical difference in MD values amongst the two groups at 3 months post-injury.


 » Conclusions Top


After decompressive craniectomy in severe TBI, there was a poor correlation between the plasma and MD glucose concentration. A high degree of variation was seen in the correlations for individual patients. Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months. The good outcome group had fewer episodes of both hyperglycemia and hypoglycemia.

Acknowledgment

The authors wish to thank staff nurse Ms. Jyoti Sohal (RN) at our institute for handling the CMD machine in the neurosurgery intensive care unit of our hospital.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Murray GD, Butcher I, McHugh GS, Lu J, Mushkudiani NA, Maas AI, et al. Multivariable prognostic analysis in traumatic brain injury: Results from the IMPACT study. J Neurotrauma 2007;24:329-37.  Back to cited text no. 1
    
2.
MRC CRASH Trial Collaborators, Perel P, Arango M, Clayton T, Edwards P, Komolafe E, et al. Predicting outcome after traumatic brain injury: Practical prognostic models based on large cohort of international patients. BMJ 2008;336:425-9.  Back to cited text no. 2
    
3.
McHugh GS, Engel DC, Butcher I, Steyerberg EW, Lu J, Mushkudiani N, et al. Prognostic value of secondary insults in traumatic brain injury: Results from the IMPACT study. J Neurotrauma 2007;24:287-93.  Back to cited text no. 3
    
4.
Reinstrup P, Ståhl N, Mellergård P, Uski T, Ungerstedt U, Nordström CH. Intracerebral microdialysis in clinical practice: Baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery 2000;47:701-9.  Back to cited text no. 4
    
5.
Zygun DA, Steiner LA, Johnston AJ, Hutchinson PJ, Al-Rawi PG, Chatfield D, et al. Hyperglycemia and brain tissue pH after traumatic brain injury. Neurosurgery 2004;55:877-81.  Back to cited text no. 5
    
6.
Diaz-Parejo P, Ståhl N, Xu W, Reinstrup P, Ungerstedt U, Nordström CH. Cerebral energy metabolism during transient hyperglycemia in patients with severe brain trauma. Intensive Care Med 2003;29:544-50.  Back to cited text no. 6
    
7.
Strong AJ, Hartings JA, Dreier JP. Cortical spreading depression: An adverse but treatable factor in intensive care? Curr Opin Crit Care 2007;13:126-33.  Back to cited text no. 7
    
8.
NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-97.  Back to cited text no. 8
[PUBMED]    
9.
Choi IY, Lee SP, Kim SG, Gruetter R.In vivo measurements of brain glucose transport using the reversible Michaelis-Menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia. J Cereb Blood Flow Metab 2001;21:653-63.  Back to cited text no. 9
    
10.
Vespa PM, McArthur D, O'Phelan K, Glenn T, Etchepare M, Kelly D, et al. Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: A microdialysis study. J Cereb Blood Flow Metab 2003;23:865-77.  Back to cited text no. 10
    
11.
Schlenk F, Nagel A, Graetz D, Sarrafzadeh AS. Hyperglycemia and cerebral glucose in aneurysmal subarachnoid hemorrhage. Intensive Care Med 2008;34:1200-7.  Back to cited text no. 11
    
12.
Abate MG, Trivedi M, Fryer TD, Smielewski P, Chatfield DA, Williams GB, et al. Early derangements in oxygen and glucose metabolism following head injury: The ischemic penumbra and pathophysiological heterogeneity. Neurocrit Care 2008;9:319-25.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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