Independent prognostic predictors of Glasgow Outcome Scale in

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					Prognostic predictors of outcome in an operative series in traumatic brain injury

patients




Running title: Prognostic predictors in traumatic brain injury




Jinn-Rung, Kuo1, 2, 4, Che-Chuan, Wang 1, Chung-Ching, Chio1, Kao-Chang, Lin 3, 4

1
    Institute of Clinical Medicine, School of Medicine, National Cheng-Kung University, Tainan,

    Taiwan;

2
 Departments of Neurosurgery Chi-Mei Medical Center, Tainan, Taiwan

3
 Departments of Neurology, Chi-Mei Medical Center, Tainan, Taiwan

4
 Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan;




Corresponding author: Kao-Chang, Lin MD, Department of Neurology, Chi-Mei Medical

Center, 901 Chung Hwa Road, Yung Kang City, Tainan, Taiwan 710




Tel: 886-6-2812811; Fax: 886-6-2828928


E-mail: kuo.ox@msa.hinet.net




                                                1
Abstract


Background/ Purpose: Although several prognostic factors for TBI have been evaluated, a

useful predictive scoring model for outcome has yet been developed for TBI patients. The aim

for this study, therefore, was to determine independent predictors and develop a multivariate

logistic regression equation to determine prognosis in TBI patients.


Methods: A total of 13 different variables were evaluated. All 84 patients in this study were

retrospectively evaluated between October 2003 and January 2008 and all underwent

craniectomy or craniotomy for haematoma removal and were fitted with intracranial pressure

(ICP) microsensor monitors. By using univariate, multiple logistic regression and prognostic

regression scoring equations it was possible to draw receiver-operating characteristic curves

to predict Glasgow Outcome Scale (GOS) 6 months after TBI.


Results: It was shown that older patients in particular those over 40 years of age,

unresponsive pre-op pupil reaction, higher pre-op midline shift, higher injury severity score

(ISS) and craniectomy were factors associated with poor outcome in patients with traumatic

brain injury.


Conclusions: These 5 variables can be used as independent predictors to predict the 6 months

GOS in traumatic brain injury patients. Also, the five variables derived from multivariate

logistic equation are clinically useful in predicting outcome in daily practice and act as a

guideline in deciding whether or not to avoid performing decompressive craniectomy.




Key words: traumatic brain injury, craniectomy, injury severity score, pupillary reaction,

midline shift, prognositic factors



                                               2
Introduction


 Traumatic brain injury (TBI), remains a critical public health challenge. 1 The annually TBI-

related death is 19.4 of 100,000 persons. 1 The prognosis of TBI can be predicted by a wide

range of variables: age, neurological assessment (Glasgow coma scale), pupillary light reflex,

injury severity score (ISS), 2 imaging study (degree of midline shift in computed tomography).

3-6
      time elapsed from injury to surgery, 7 intra-operative cerebral perfusion pressure (CPP), 8

                                                                                9, 10
and whether or not the patient has undergone decompressive craniectomy.                 However, a

useful outcome predictive scoring model has not been well established for TBI patients. The

aim of this study is to determine independent predictors and develop a multivariate logistic

regression equation to predict the prognosis in traumatic brain injury patients. These

predictive variables are age, sex, injury severity score, neurological assessment, preoperative

and postoperative imaging studies, and hemodynamic change during operation.


Material and method


      Patients with TBI were retrospectively evaluated and enrolled from Oct 2003 to Jan 2008,

in a medical center in southern Taiwan. This study was approved by the ethics committee of

our hospital. A complete history was taken and a neurological assessment was performed on

each patient. All patients received neuroimaging with computerized tomography (CT) and

were evaluated for the initial GCS in the emergency room. They all underwent craniectomy or

craniotomy for haematoma removal and an intracranial pressure (ICP) microsensor (Codman

and Shurtlef, Inc., Rayman, MA, USA) was placed in the parenchyma of the ipsilateral frontal

lobe of each patient.


      The key indications for craniectomy were as follows: a thickness of more than 1cm in cases

of extracerebral hematoma and a volume more than 30 ml in cases of intracerebral hematoma,


                                                 3
a deviation of supratentorial midline shift > 5mm with lateral ventricle compression,

disappearance of the basal cistern, and clinical aggravation. The mean arterial blood pressure

(MAP) was monitored using standard pressure transducers. Cerebral perfusion pressure (CPP),

                                             11
cerebral circulatory-pressure index (CCPI)        and MAP values were recorded when the scalp

was closed. Postoperatively, patients underwent CPP-guided management, with the aim of

obtaining a CPP of 60 mmHg or more and ICP of 25 mmHg or less.


 The relationship between age, sex, injury severity score (ISS), admission Glasgow coma

scale (GCS), preoperative GCS, preoperative brain CT midline shift, time interval from injury

to operation, the values of MAP, ICP, CPP, and CCPI when scalp was closed, postoperative

midline shift, postoperative cerebral infarction and Glasgow outcome score (GOS) at 6

months after TBI were evaluated.


 The midline shift on the CT scan was defined as the absolute distance (mm) that the septum

pellucidum of the brain was displaced away from the midline, which was determined as an

average by calculating the distance between both inner tables inside the skull.12


  For convenience of data analysis, the presence of a fixed pupil was defined as unresponsive

(<1 mm) to a light stimulus. The pupillary light reflex was divided into three categories

including one pupil fixed, both pupils fixed and both pupils reactive.


 Time elapsed between injury and surgery was classified as very early surgery (less than 6

hours after injury), early surgery (between 6 and 24 hours) and late surgery (after 24 hours).


  The outcome of the patients at 6 months after injury was categorized according to the

Glasgow outcome scale as: (1) death; (2) persistent vegetative state; (3) severe disability

(conscious but disabled); (4) moderate disability (disabled but independent) and (5) good




                                                  4
recovery.13 A score of 4 to 5 was considered a favorable outcome (moderate disability or less)

and a score of 1 to 3 was considered unfavorable (severe disability or death).


  Data were expressed as a mean ± standard deviation in some items. Student’s t-test, or chi-

square test were used to assess statistical significance among all groups. Multiple logistic

regression models were used for correlation between two continuous or categorical variables

and the independent risk factors for poor outcome defined. Finally, logistic regression

analysis was then used to establish a prognostic model and a receiver-operating characteristic

curve 14 was then drawn based on the prognostic scoring model All data were analyzed using

qualified statistical software (SPSS for Windows, Version 16, SPSS Inc., Chicago, Illinois,

USA). A P-value of less than 0.05 was considered significant.


Results


 In total, 84 traumatic brain injury patients were retrospectively evaluated. Traffic accidents

had occurred in 74.0% of the cases. The mean age of the 84 patients (56 male and 28 female)

was 40.8±18.6 years (range, 12–78 years). Male patients were significantly predominant at

66.7%. There were subdural hemorrhages in 52.4 % of the cases, epidural hemorrhages in

8.3 %, intracranial hematomas in 11.9 %, and mixed hemorrhages in 15.4 %. The average ISS

was 27± 4.1. The overall 6 months GOS was 3.0±1.7. Patients and their clinical

characteristics are summarized in Table 1.


  Table 2 shows that age (P<0.001), admission GCS (P<0.001), preoperative GCS (P<0.001),

preoperative midline shift (P<0.001), postoperative midline shift (P<0.001), and ISS (P=0.005)

were significantly associated with GOS at 6 months after injury by using student’s t-test for

continuous variables. When chi-square or Fisher's exact statistics were used for categorical

variables, it showed that pre-op pupil reaction (P <0.001), time interval from injury to


                                               5
operation (P=0.002) and craniectomy (P=0.005) were significantly associated with 6 months

GOS (Table 3).


 Multivariate logistic regression was then performed on the significant variables extracted

from the previous step to determine the independent association of each variable with GOS at

6 months after injury. Thus, the final model contained five variables: age, pupil reaction, ISS,

preoperative midline shift and decompressive craniectomy. These results showed age (OR=

1.12, CI= 1.05-1.19, P<0.001), pupil reaction (OR= 78.68, CI= 6.39-968.6, P= 0.001),

preoperative midline shift (OR= 16.17, CI= 2.07-126.39, P=0.008), ISS (OR= 1.48, CI= 1.11-

1.97, P=0.007) and craniectomy ([OR= 1.19, CI= 1.0-1.42, P<0.05) were independent of

associations to GOS (Table 4).


     At the same time, a predicted probability (P) of having an unfavorable outcome was

estimated by the multiple logistic regression model: Ln(P/1-P) = -19.86 + 2.78 x (craniectomy

or craniotomy) + 0.11x (age in years) + 4.37x (pupil reaction) + 0.17x (preoperative midline

shift in mm) + 0.39 x (ISS). The predictors of the model were selected by stepwise procedure.

Using the receiver operating characteristic curve analysis (ROC) based on the prognostic

model scoring, a cut point for prediction to an unfavorable outcome of P was defined as a

value >=0.6. The equation’ sensitivity was 97.5%, and specificity 90.7% in predicting the

unfavorable outcome at 6 months after TBI (AUC=0.96, 95% confidence interval 0.91-1.00)

(Figure 1).


Discussion


  A significant relationship between age and post-traumatic outcome has been reported.15, 16

Ono et al have demonstrated 15 in patients fewer than 40 years of age, the percentage of good

outcome ranged from 33.9% to 48.7% in different lesions. On the other hand, poor outcome


                                               6
ranging from 66.7% to 94.4% was predominant in patients over 40 years of age. In our study,

in univariate analysis, the result showed age 32.6 ± 15.1 years in favorable and 48.5 ± 18.3

years in unfavorable outcome (P <0.001)). By multiple logistic regression models, the

adjusted odd ratio (OR) in predicting the poor outcome was significant with age (OR= 1.12,

CI= 1.05-1.19, P<0.001). In subgroup analysis, patients under 40 years of age, the percentage

of good outcome was 67.5%. On the other hand, poor outcome was 70.5% in patients over 40

years of age. Our results revealed that age is an independent predictor to GOS in traumatic

brain injury, which is consistent with the previous reports.


  Pupil reactivity to light stimulus correlated to outcomes that have been reported in several


reports. Bilaterally absent pupillary light reflex was associated with a 56–90% mortality.17

Kuo et al demonstrated pupil reactivity to light has the most significant correlation with GOS

(ρ= 0.727, P < 0:0001) when compared with coagulopathy and midline shift. It is believed

                                                                                                  18
that most patients classified as having both pupils fixed would have very poor outcome.

However, Carter et al reported that nearly 20% of patients with bilaterally absent pupillary

                                                                  19
response had favorable outcomes in a study of 89 cases.                The present study reveals the

percentage of unfavorable outcome was 28.6% in both reactive pupils, 52.6% in one fixed

pupil and 91.3% in both fixed pupils (P< 0.001). Table 4 disclosed the adjusted odd ratio

(OR= 78.68, CI= 6.39-968.6, P= 0.001) in both fixed pupils versus at least one reactive pupil.

These results were consistent to previous reports. In the subgroup analysis, 95% (GOS 1 30%,

GOS 2+3 65%) unfavorable outcomes occurred in patients with unresponsive pupillary

reaction in both pupils when undergoing life saving decompressive craniectomy. From our

results, we recommended avoiding decompressive craniectomy procedure in such cases,

because there is only very little benefit to neurologic status.




                                                 7
  The prognosis of TBI can be predicted by GCS has been reported. 20 However, in our study,

by multiple logistic regression modle, it disclosed that GCS is not independent predictor to

GOS. In the subgroup analysis, we dichotomized preoperative GCS to binary variable by cut

point 6, it revealed significantly correlated to favorable / unfavorable outcome (P < 0.001,

chi-square test). Furthermore, GCS was also strongly correlated to pupil reaction (P < 0.001,

chi-square test). Base on the strong correlation between GCS and pupil reaction finding, in

model selection procedure, pupil reaction rather than GCS was selected into multiple

regression analysis.


   The distance of brain CT midline shift is generally considered to indicate the severity of

injury and has a risk factor with poor outcome. 21 Mass et al showed midline shift (1-5 mm,

OR 1.36; CI 1.09-1.68; > 5mm, OR 2.20; CI 1.64-2.96) were strongly related to poor

outcome. However, Lin et al contradicted it with results of (distance of midline shift ≧5 Vs

< 5 mm, OR 2.63; CI 6.0-43.67, P=0.499). 22 In the present study, the results revealing poor

outcome was significant with a preoperative midline shift on brain CT (OR= 1.19, CI= 1.00-

1.42, P= 0.050). This discrepancy might be due to the existence of another independent

factor which plays a more important role than midline shift but is in someway strongly

correlated to it. However, in our study, results support the concept that the distance of brain

CT midline shift is an index for severity of injury and is a risk factor for poor outcome.


   Injury severity score (ISS) is an index of overall severity useful for persons sustaining

multiple injuries 2; and is one of the most important factors in predicting outcome after acute

head injury.4 However, Ucar et al has not supported the idea.24 In our study, the result

showed ISS 26.1± 2.7 for favorable and 28.6±4.8 for unfavorable outcomes (p=0.005). By

multiple logistic regression models, the adjusted odd ratio (OR) in predicting the poor

outcome was significant with ISS (OR= 1.48, CI= 1.11-1.97, P=0.007).This result provided

                                               8
other evidence to support the idea that patients with a higher ISS would be at higher risk for

secondary brain insult. This result also implies that no injuries in a primary and secondary

survey for the trauma team in an emergency room should be overlooked because these

extracranial insults could lead to irreversible secondary brain damage.


  Decompressive craniectomy has been historically considered a salvage procedure in TBI.

Skoglund et al24 showed 68% patients of TBI had favorable outcome. However, Jiang et al         25



showed 60.2% and Ucar et al    23
                                    indicated 84% of patients’ experienced unfavorable outcome

after decompressive craniectomy. In our study, the overall mortality rate and unfavorable

outcome in craniectomy patients was 33.3% and 62.7% respectively. When comparing

craniectomy with craniotomy patients, it shows craniectomy patients have a lower

preoperative GCS (P=0.012); more unresponsive pupil reaction (P=0.013); higher ICP

(P=0.001), lower CPP (P=0.011) and lower CCPI (P<0.001) when the scalp was closed, and

higher postoperative cerebral infarction (P=0.037). These results seem to support the notion

that the perioperative neurological status in decompressive craniectomy patients is more

severe than in craniotomy. These results might explain why patients who underwent

craniectomy in our study will lead to poor outcome and craniectomy is an independent

predictive variable in GOS after TBI. To avoid under or over-estimated causal – effect

relationships in univariate analysis resulting from confounders, multiple logistic regression

model was performed to estimate the adjusted odd ratio. Craniectomy rather than craniotomy

was more likely to get an unfavorable outcome after adjustment for age, pupil reaction, pre-

operative midline shift and ISS.


   In addition to the single factor analysis and multi-factorial prognostic analysis, in our study,

we further combined an ROC curve and the multivariate logistic regression equation to

evaluate the predictive accuracy of five variables in GOS. These results disclosed all five

                                                9
variables, which had previously been shown to be related to survival, had strong accuracy in

prognostic judgment with sensitivity 97.5% and specificity 90.7% in GOS. Since these five

variables in the scoring model are clinically simple to attain in the acute stage after TBI, we

consider therefore, that the derived equation is clinically useful to predict outcome in daily

practice.


  There are limitations to these results because of the nature of the retrospective design. One

of our significant findings from our study is patients with craniectomy rather than craniotomy

were more likely to get an unfavorable outcome after adjustment for age, pupil reaction, pre-

operative midline shift and ISS. Clearly, the strategy of surgical procedure may be affected by

experience of surgeons and patients’ condition. This issue needs to be addressed in

prospective studies.


  Another limitation of this study is small sample size and heterogeneity of the patient

population. Actually, the different types of TBI such as epidural hematoma, subdural

hematoma and contusion hemorrhage have different outcomes. In our study, there were

subdural hemorrhages in 52.4 % of the cases, epidural hemorrhages in 8.3 %, intracranial

hematoma in 11.9 %, and mixed hemorrhages in 15.4 %. However, in our study, the outcome

predictors such as age, sex, injury severity score, neurological assessment, preoperative and

postoperative imaging studies, and hemodynamic change during operation are all important

factors in any types of brain insults. In general, it seems reasonable to group these patients

together. However, the subgroup analysis of an enriched population of different types of

hemorrhage patients is needed to clarify the issue.


Conclusions




                                              10
  Based on our findings, we conclude that the five factors; old age, unresponsive pre-op pupil

reaction, higher pre-op midline shift, higher ISS and underwent craniectomy are factors

associated with poor outcome in patients with traumatic brain injury. They can be used as

independent predictors in assessing the 6-month GOS in traumatic brain injury patients. The

five variables derived multivariate logistic equation is clinically useful to predict outcome in

daily practice also.




                                              11
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 ACKNOWLEDGMENTS


  The authors wish to express their gratitude to all of the participants from neurology,

neurosurgery, emergency critical medicine, and the intensive care unit. They also thank Ms.

Lin, Wen-Chun for her help on the statistical analysis.




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