Key words : Comatose patients, Deceased donor, Eyeball transverse diameter, Glasgow Coma Scale, Intracranial pressure

Introduction

Brain death is defined as loss of brainstem reflexes, apnea, and irreversible coma. Increased intracranial pressure (ICP) has been shown to be a critical step in the pathophysiology of brain death.¹ Therefore, it is of great importance to measure ICP in comatose patients.² In addition to invasive techniques, noninvasive techniques can be used to measure ICP. The optic nerve sheath is an extension of the dura mater, under which the subarachnoid space continues forward to the back of the eyeball. It has been revealed that normal optic nerve sheath diameter (ONSD) values are 4.0 mm for children aged <1 year, 4.5 mm for those aged 1 to 18 years, and up to 5.0 mm for adults.^3,4 Sonographically measured enlargement of ONSD may be detectable in the hyperacute stage of increased ICP.⁵ In patients with intracranial hemorrhage and subarachnoid hemorrhage, a value of ONSD greater than a threshold of 5.5 mm has been shown to be significantly indicative of elevated ICP measured invasively.⁶

In Turkey, the number of deceased donor organ transplants in 2019 was 619, whereas the number of transplants from living donors was 4348. Thus, the number of deceased donor organ transplants per million population is 7.59; despite the gradual increase in the number of transplants, unfortunately, the primary source of organs for transplant is not deceased donors, probably because brain death is often overlooked or undiagnosed. Therefore, to identify potential organ donors as soon as possible and to avoid delay of the diagnosis of possible brain death, patients with a Glasgow Coma Scale (GCS) score of 7 or less and a likelihood of poor prognosis should be closely monitored in terms of a potential donor candidate in our country. Also, various studies have suggested that elevated ICP and progression to brain death in these patients can be detected with techniques such as computed tomography (CT) at admission or optic nerve sheath ultrasonography during follow-up.⁷

We aimed to investigate whether changes in ONSD secondary to increased ICP on the initial brain CT scans of patients diagnosed with intracranial hemorrhage can be used as a precursor for identi-fication of patients who will develop brain death.

Materials and Methods

Approval was obtained from the Bursa Uludag University Faculty of Medicine Non-Interventional Research Ethics Committee (2021-1/27), and patient information was derived from the hospital’s data recording system.

The study was conducted on patients admitted to the intensive care unit (ICU) of Private Medicabil Hospital with a bed capacity of 27 between January 1, 2019, and December 1, 2020. Patients are admitted to our ICU through mobile emergency care services. The initial brain CT scan taken in the emergency room before ICU admission is always evaluated by the neurosurgeon, and the opinion is added to the medical record.

The study included patients who had not yet received surgical intervention and who were admitted to the ICU with intracranial hemorrhage, had a GCS score of 7 or less, and had received mechanical ventilation support. Patients younger than 18 years of age, patients with neurological disorders secondary to intoxication, hypercarbia, and sepsis, patients who had undergone decompression surgery, and those with maxillofacial trauma, skull base fracture, and length of stay in the ICU of less than 24 hours were not included in the study.

The patients included in the study were divided into 3 groups: brain death group (patients who were diagnosed with brain death and died), hemorrhage group (patients without brain death who died due to secondary causes), and survivor group (patients who presented with hemorrhage and were discharged from ICU).

According to the Ministry of Health regulation for organ and tissue transplantation, the absence of brainstem reflexes, coma status that has been confirmed not to be induced by hypothermia or drugs, and a positive apnea test result were evaluated in favor of the diagnosis of brain death. To perform the apnea test, the patient was disconnected from the mechanical ventilator and given intratracheal oxygen to prevent auto-triggering of cardiac origin after providing normothermia, normotension, normovolemia, and PaCO₂ of 35 to 45 mm Hg and PaO₂ of >200 mm Hg. The apnea test was considered positive if spontaneous breathing was absent despite a PaCO₂ value ≥60 mm Hg and/or an increase in PaCO₂ of 20 mm Hg or more from baseline at the end of the test. Patients underwent cerebral CT angiography to confirm brain death and to detect the absence of intracranial blood flow. Patients without intracranial blood flow were considered brain dead.

The ONSD was measured at a distance of 3 mm behind the globe on transverse slices of the cranial CT taken at ICU admission of patients, and the eyeball transverse diameter (ETD) was recorded.

Statistical analyses
The Shapiro-Wilk test was used to check whether continuous variables followed a normal distribution. Depending on the results of the normality test, continuous variables were presented with median, interquartile range, minimum and maximum values. Categorical variables were expressed as numbers and related percentages. The Kruskal-Wallis test was used for the comparison of continuous and discrete variables between the study groups, and in the case of obtaining general significance, subgroup analyses were conducted using the Dunn-Bonferroni test. The chi-square and Fisher-Freeman-Halton tests were used to compare categorical variables between groups. A receiver operating characteristic (ROC) curve analysis was performed to estimate the sensitivity and specificity of the ONSD and the ONSD/ETD ratio for prediction of the presence of brain death. The independent risk factors for progression to brain death were examined by logistic regression analysis. Statistical analyses of the study were performed using SPSS software (version 23.0; IBM), and the type I error rate was considered 5% in statistical comparisons.

Results

A total of 312 patients were admitted to the ICU with a diagnosis of cranial hemorrhage during the study period. Due to missing data and exclusion criteria, 88 patients were excluded from the study groups. Patients who developed brain death were significantly younger than those in the hemorrhage and survivor groups (P = .004 for both). There was no difference in the age distribution between the patients in the hemorrhage and survivor groups (P > .05). The sex ratios and comorbidity rates were similar in all patient groups.

Although the GCS scores of the brain death and hemorrhage groups were lower than the GCS scores of the survivor group (P < .001 and P < .001, respectively), there was no difference in GCS scores between the brain death and hemorrhage groups (P > .99). The demographic data, comorbidities, and GCS scores of the patients are shown in Table 1.

Given the ONSD values on cranial CT, the median ONSD was higher in patients with brain death versus those in the hemorrhage and survivor groups (P < .001 and P < .001, respectively), and the hemor-rhage group had higher ONSD values than the survivor group (P < .001) (Table 2).

On cranial CT, ETD was higher in the survivor group than in the hemorrhage group (P = .031). The other comparisons showed similar ETD values between the groups (Table 2).

The calculation of the ratio of ONSD to ETD was higher in patients with brain death versus those in the hemorrhage group and the survivor group (P < .001 and P < .001, respectively). Moreover, the ONSD/ETD ratio of the hemorrhage group was also higher than that of the survivor group (P < .001) (Table 2).

The ROC curve analysis was performed to estimate the sensitivity and specificity of ONSD for prediction of the presence of brain death, and the cutoff point for ONSD was determined as >6.62 mm. The area under the curve for ONSD was 0.85 (sensitivity 66.20%, specificity 90%; P < .001), showing that ONSD >6.62 mm was significantly related to an increased risk of the presence of brain death (Figure 1).

The ROC curve analysis was performed to estimate the sensitivity and specificity of the ONSD/ETS ratio for prediction of the presence of brain death, and the cutoff point for ONSD/ETD was determined as >0.29. The area under the curve for ONSD was 0.80 (sensitivity 60.56%, specificity 87.14%; P < .001), showing that ONSD/ETD >0.29 was significantly related to an increased risk of the presence of brain death (Figure 2).

The variables included in Table 3 were first examined with univariate logistic regression analysis to determine the independent risk factors affecting brain death. The variables that met the condition of P < .25 as a result of univariate analyses were included in the multivariate logistic analysis. The results of the analysis are presented in Table 3. In the multivariate logistic regression analysis, the forward selection method was adopted as the variable selection method, and the model obtained in the final step was found to be significant (P < .001) and consistent with the data (P = .554). The analysis revealed a 25.529-fold increased risk of developing brain death in the patient group with an optic nerve diameter greater than 6.62 mm.

Discussion

Our study demonstrated that ONSD measured on initial cranial CT scans of patients admitted to the ICU with a diagnosis of intracranial hemorrhage and a GCS score of 7 or less may be an important marker for determining the likelihood of developing brain death.

It has been suggested that the probability of developing brain death is higher in patients admitted to the ICU with a low GCS score, whereas the probability is lower in older patients.⁸ The results of our study also showed that GCS score was lower in patients with brain death versus other groups, and the patients in the brain death group were younger than the patients in the other groups.

Increased ICP is a common condition in brain death. The diagnosis of brain death before damage to the potential donor organs is vitally important in transplantation. Recently, numerous studies have shown that measurements of ONSD can be used as a noninvasive marker to determine ICP. McLaughlin and colleagues reported a strong correlation between ONSD and ICP measured on initial cranial CT scans.⁷ Liu and colleagues revealed a correlation between ONSD and ICP calculations based on the cranial CT scans of patients who presented to the emergency room with traumatic brain injury, suggesting that the use of ONSD would be a strong parameter for indication of surgery.⁹ Bender and colleagues showed that ONSD evaluation in the acute stage of patients who were followed up with intracranial hemorrhage was effective for prediction of clinical outcomes.¹⁰ In a series of 223 patients with subarachnoid hemorrhage, ONSD was shown to have an important predictive value for poor neurological outcomes. The method of ONSD measurement by cranial CT has been useful in combination with clinical rating scales to improve prognosis in patients with subarachnoid hemorrhage.¹¹ A study investigating the significance of changes in the optic nerve sheath to predict malig-nant progression in ischemic stroke demonstrated that changes in the ratio of ONSD to ETD from baseline on cranial CT could be a predictor of late malignant progression along with midline shift.¹²

Our study indicated that ONSD values were higher in the brain death group and that evidence of ONSD greater than 6.62 mm could be a useful method to demonstrate brain death. Toscano and colleagues reported significantly increased ICP in adult ICU patients who had been diagnosed with brain death and received invasive ICP monitoring after the diagnosis of brain death. Toscano and colleagues detected a strong correlation between ICP values measured by invasive techniques and ONSD measured by ultrasonography.¹³ In another study, they emphasized the importance of intermittent ONSD measurements in comatose patients for early detection of brain death and reported significantly higher ONSD values in patients with brain death compared with comatose patients.¹⁴ Lovrencic-Huzjan and colleagues demonstrated higher ONSD measurements in patients with brain death.¹⁵ The results of our study revealed similar ONSD values in groups with and without brain death, with ONSD being statistically significantly higher in both groups compared with survivors.

Repeated measurements of the ONSD/ETD ratio have been associated with low GCS in patients followed up for intracranial hemorrhage.⁶ The ONSD/ETD ratio was shown to be a valuable marker for late bleeding rather than early bleeding in patients with ischemic stroke.¹² Zhu and colleagues found that ONSD/ETD ratios higher than 0.25 were associated with poor neurological outcomes.¹⁶ The results of our study also showed a higher ONSD/ETD ratio in the brain death group, with a higher risk of brain death for patients with ONSD/ETD above 0.29.

Tommasino and colleagues showed a higher probability brain death in patients with a GCS score below 8 and reported a higher frequency of brain death in patients with a GCS score of 3.¹⁷ In our study, GCS values were lower in the brain death group, which is similar to the aforementioned study. An increase in ONSD diameter has been associated with an 8-fold greater risk of traumatic brain injury.18 The results of our study showed a very high rate of brain death in patients with ONSD above 6.62 mm.

The major limitations of our study are the lack of randomization and the prospective design.

Conclusions

We suggest that ONSD measured to be higher on initial cranial CT of patients admitted to the ICU with a diagnosis of intracranial hemorrhage is a strong marker for the evaluation of progression to brain death.

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