Clinical Application of Intracranial Pressure Monitoring Based on Flash Visual Evoked Potential in Treatment of Patients with Hypertensive Intracerebral Hemorrhage

Objective To investigate the application value of ash visual evoked potential (FVEP) noninvasive intracranial pressure (nICP) monitoring technology in patients with hypertensive intracerebral hemorrhage (HICH). Methods There were 116 eligible subjects included in the experiment, the nal sample size was 102 for this study. They were randomly divided into FVEP nICP monitoring group (experimental group) and the non-monitoring group (control group). The experimental group were examined lumbar puncture immediately after intracranial pressure was monitored by FVEP. Mannitol was used in reducing the elevated intracranial pressure. The serum concentrations of creatinine and urea nitrogen were recorded to assess the renal function. To evaluate the ecacy of FVEP nICP monitoring technique for clinical adjustment of mannitol. The Glasgow prognosis scores (GOS) were evaluated for patients' prognosis between two groups. Results There was no statistical signicance between FVEP nICP measurement and lumbar puncture intracranial pressure measurement (195.76 ±58.88 mmH2O vs 197.04 ±53.72 mmH2O, P>0.05). Linear correlation analysis indicated that there was a strong positive relationship between the measurements (r=0.950, P<0.01). The duration prescription time and the average usage amount of mannitol in the experimental group was signicantly less than that in the control group (P< 0.05), and the serum creatinine and urea nitrogen concentrations in the two groups were not statistically signicant (P> 0.05). The cure rate of the experimental group was higher than that of the control group (χ 2 =3.889, P=0.048). Conclusion FVEP nICP monitoring technology could replace invasive intracranial pressure monitoring technology in part HICH patients. The application of FVEP nICP technique can reduce the dosage of mannitol and improve the prognosis of patients with HICH. This study showed that there was no statistically signicant difference between the FVEP nICP monitoring values (195.76 ± 58.88 mmH2O) and lumbar puncture measurement values (197.04 ± 53.72 mmH 2 O) in mild to moderate HICH patients (P > 0.05). Pearson correlation analysis demonstrated that FVEP nICP monitoring values was positively correlated with lumbar puncture measurement values, the difference was signicant (r =0.950, P<0.01). Through monitoring the change of ICP values by FVEP nICP monitoring techonology, the duration prescription time and the average usage amount of mannitol in the experimental group was signicantly less than that in the control group. The complications of kidney function impairment caused by drugs were also rare than those in the control group. Our research also showed that the recovery rate of the experimental group was signicantly higher than that of the control group (67.3% vs. 46.0%, P=0.048), and the prognosis of the HICH patients could be improved by closely monitoring the change of ICP value and timely adopting reasonable treatment plan. should not be used prophylactically and should not be used for more than 5 days during rst aid 31,32 . Clinical data showed that mannitol could shorten the incubation period of FVEP N2 wave, and FVEP could observe the changes of ICP after mannitol application 33 . In our experiment, the duration prescription time and the average usage amount of mannitol was signicantly reduced in the experimental group by applying the FVEP nICP monitoring technology. The ICP changes monitored by FVEP nICP monitoring technology conducive to guide clinical treatment.


Abstract
Objective To investigate the application value of ash visual evoked potential (FVEP) noninvasive intracranial pressure (nICP) monitoring technology in patients with hypertensive intracerebral hemorrhage (HICH).
Methods There were 116 eligible subjects included in the experiment, the nal sample size was 102 for this study. They were randomly divided into FVEP nICP monitoring group (experimental group) and the non-monitoring group (control group). The experimental group were examined lumbar puncture immediately after intracranial pressure was monitored by FVEP. Mannitol was used in reducing the elevated intracranial pressure. The serum concentrations of creatinine and urea nitrogen were recorded to assess the renal function. To evaluate the e cacy of FVEP nICP monitoring technique for clinical adjustment of mannitol. The Glasgow prognosis scores (GOS) were evaluated for patients' prognosis between two groups.
Results There was no statistical signi cance between FVEP nICP measurement and lumbar puncture intracranial pressure measurement (195.76 ±58.88 mmH2O vs 197.04 ±53.72 mmH2O, P>0.05). Linear correlation analysis indicated that there was a strong positive relationship between the measurements (r=0.950, P<0.01). The duration prescription time and the average usage amount of mannitol in the experimental group was signi cantly less than that in the control group (P< 0.05), and the serum creatinine and urea nitrogen concentrations in the two groups were not statistically signi cant (P> 0.05).
The cure rate of the experimental group was higher than that of the control group (χ 2 =3.889, P=0.048).
Conclusion FVEP nICP monitoring technology could replace invasive intracranial pressure monitoring technology in part HICH patients. The application of FVEP nICP technique can reduce the dosage of mannitol and improve the prognosis of patients with HICH.

Background
Hypertension intracerebral hemorrhage (HICH) with the characteristic of high morbidity, mortality and disability is one of the major diseases that endanger the health of the elderly 1 . High intracranial pressure (ICP) caused by HICH is a common critical condition in neurology. The elevated ICP leads to the displacement of local brain tissue or the formation of brain herniation, which is the direct cause of the rapid deterioration of patients' condition and even death 2 . Headache, vomiting, and disturbance consciousness are the symptoms of the elevated ICP, but these clinical symptoms are not speci c. At present, most of the ICP monitoring methods are invasive. Some limitations of the invasive methods include short-term monitoring, risk of infection and intracranial hemorrhage, restricted mobility of the subject, etc 3 . Therefore, it is necessary to nd a noninvasive and reliable monitoring method to replace invasive intracranial pressure (iICP) to help clinical diagnosis and treatment. Flash visual evoked potential (FVEP) has been applied in clinical diagnosis due to its noninvasive and easy to perform 4 . Most clinical studies on FVEP noninvasive intracranial pressure (nICP) monitoring technology focus on patients with elevated ICP causd by craniocerebral trauma, subarachnoid hemorrhage and HICH 5,6 . HICH is the most common disease of elevated ICP in neurology department. Mannitol is usually used in reducing the elevated ICP, but it can also cause side effects such as renal function damage and electrolyte disorder. In addition, under pathological conditions, mannitol crystals can form a hypertonic state locally through penetrating the damaged blood-brain barrier and aggravate cerebral edema 7 . The absence of published studies showing that management of elevated ICP has an effect on ICH outcome makes the decision whether to monitor and treat elevated ICP unclear in patients with ICH. Here, we monitored the changes of ICP with FVEP nICP monitoring technology in HICH patients, and evaluate whether the technique is bene cial for clinical practice and reduces complications.

Study design and participants
This study was a prospective registry designed to include consecutive patients with HICH. Only patients with mild to moderate intracerebral hemorrhage were eligible for this study. All subjects were recruited from the emergency department of Neurology, and hospitalized in the department of Neurology and Geriatric department of our hospital from November 2016 to December 2017. All subjects who had a history of hypertension or elevated blood pressure at onset met the diagnostic criteria of the American adult intracerebral hemorrhage treatment guidelines (2015) 8 . They were con rmed by cranial computed tomography (CT) with supratentorial hematoma without or only a small amount of intraventricular hemorrhage, and the amount of hematoma was less than 30 mL according to the Tada (ABC/2) formula 9 , with midline shift < l cm. The vital signs of subjects were relatively stable when they admitted to the hospital. Conservative treatment plan was rst adopted after admission with the consent of the family. Exclusion criteria included local infection of the lumber spine, severe liver and kidney dysfunction, pituitary tumor and all diseases associated with damage to visual pathways. Among 116 patients recruited from the emergency department of Neurology, the nal sample size was 102 for this study.
Because individuals were further excluded for the following reasons: hematoma enlargement requires surgery (n=9), intracranial aneurysm ruptured (n=2), transfer to the superior hospital (n=2), haematuria (n=1). Subjects were randomly divided into FVEP nICP monitoring group (experimental group) and the non-monitoring group (control group). This was in congruence with the local ethics committee requirements. The study was approved by the local ethics committees of our institutions, and subjects informed consent.

Therapeutic methods
All HICH patients with elevated ICP were placed in a recumbent position, with elevation of the head of the bed to 30 degrees, kept the airway unobstructed, took sedatives as appropriate to keep the patients calm and kept the surrounding environment quiet, maintained the body temperature below 38.0 ℃and strictly controlled blood pressure. For HICH patients presenting with SBP between 150 and 220 mmHg and without contraindication to acute BP treatment, acute lowering of the SBP to 140 mmHg. For HICH patients presenting with SBP >220 mmHg, antihypertension agents were intermittent or continuous intravenous administration until SBP to 140 mmHg. Clinical symptoms and signs were observed every 30 minutes. 20% mannitol (Sichuan Kelun Pharmaceutical Co.Ltd, Sichun, China, batch no. A17103207-1) was used in reducing the elevated ICP in patients with HICH. Cranial CT was reviewed within 24h after admission, and were re-examined at any time according to the changes of the patient's condition. Patients of the experimental group received the rst FVEP noninvasive and lumbar puncture iICP measurement within 1 h after admission. ICP values were monitored by FVEP nICP monitoring device within 24 hours, 3th day, 7th day and 14th day after admission, and mannitol dosage was timely adjusted according to the level of ICP. According to ICP values, the cases were divided into groups as normal (5.0 to 15.0mmHg), mildly increased (15.1 to 20.0 mmHg), moderately increased (20.1 to 40.0 mmHg) and severely increased (more than 40.1 mmHg). 1 mmHg is converted to mmH 2 O by multiplying with 13.6.
Patients with mildly elevated ICP were observed closely without using mannitol usually. Patients with moderate elevated ICP lasting more than 10 minutes were offered 125 ml 20% mannitol, every 8 hours. The patients with severely elevated ICP were offered 125 ml 20% mannitol, every 6 hours. ICP values of patients in the control group were not monitored. The usage amount of mannitol was adjusted according to clinical symptoms, signs, hematoma size shown by CT. Mannitol, 125 ml 20% every 6 hours, was used in patients with consciousness disorders and hematoma enlargement by reviewing of cranial CT, and 125 ml 20% mannitol, every 8 hours in the other patients. The usage amount of mannitol and renal function were recorded in both groups. All patients were followed up to 3 months after discharge and their GOS scores were recorded. Lumbar puncture In our work, cerebrospinal uid (CSF) lumbar pressure was used in this protocol as a surrogate measurement of ICP. After FVEP nICP monitoring, the lumbar puncture immediately operated in patients of experimental group in order to evaluate the accuracy of the FVEP nICP monitoring values. The patient was lying horizontally in the left lateral position. Once the appropriate location was palpated, after local anesthesia a non-traumatic lumbar needle was inserted in the L3-L4 or L4-L5 interspinous space and was left in place during the whole procedure. The CSF pressure was measured with a graduated uid transducer. The zero reference pressure was the atmospheric pressure at the level of the foramen of Monro. In our study, local infection of the lumber spine and brain herniation were contraindications to lumbar puncture.

Clinical e cacy evaluation
Prognosis was evaluated using Glasgow Outcome Scale (GOS) standard 10 . level 1: death; Level 2: plant survival state; Level 3: severely disabled, unable to take care of himself; Level 4: mild disability, self-care; Level 5: return to good health and normal life. Level 1 and level 2 were considered invalid, level 3 and level 4 were considered disabled, and level 5 was considered cured. Cure rate = number of patients of level 5 / total number of cases ×100%.

Statistical analysis
Statistical analysis was performed using SPSS software (Version 22.0, Chicago, IL, USA). Measurement data was given as mean ± standard deviation (S.D.) of the mean. Enumeration data was expressed as the count and percentage. Differences between study groups were examined with the χ 2 -test for categorical variables, and t-test for continuous variables. Pearson correlation analysis was used to analyze the correlation of ICP between the experimental group and the control group. P<0.05 was considered statistically signi cant.

Study ow chart
There were 116 eligible subjects included in the experiment, the nal sample size was 102 for this study. They were randomly divided into the experimental group (n=52) and the control group (n=50). FVEP nICP monitoring and lumbar puncture test were performed in the experimental group. Cranial CT was examined and renal function was tested in all subjects. In the two groups, different treatment plans were given according to the severity of patients to reduce intracranial pressure. There was no loss of subjects during the experiment (Figure 1).

Status of patients and and outcome of their monitoring
There were 52 cases in the experimental group including 28 males and 24 females, mean age 61.15 ± 5.84 years. The volume of bleeding was mean 21.16 ± 4.27 mL calculated by Multi-eld formula. There were 50 cases in the control group including 27 males and 23females, mean age 60.82 ± 4.18 years, and the mean bleeding volume was mean 20.73±5.96 mL. There were no statistically signi cant differences in the two groups of patients in age, gender and blood loss. The value of FVEP nICP monitoring was 195.76 ± 58.88 mmH2O and the value of lumbar puncture measurement was 197.04 ± 53.72 mmH2O. There was no statistically signi cant difference (P > 0.05).
Then, we used Pearson correlation analysis to analyze the correlation of FVEP nICP monitoring values and lumbar puncture measurement values. The analyses via Pearson's correlation coe cient demonstrated that FVEP nICP monitoring values was positively correlated with lumbar puncture measurement values (r =0.950), the difference was signi cantly signi cant (P<0.01) (Figure 2).

Comparison of renal function and mannitol treatment between two groups
There were two cases who suffered kidney dysfunction in the control group, manifested as elevated creatinine and urea nitrogen values, but no statistical signi cance was found between the experimental group and the control group (P > 0.05). Compared with the control group, the duration prescription time and the average of mannitol usage in the experimental group was signi cantly decreased (P < 0.05) ( Table 1).

Comparison of GOS scores between two groups
There were 35 patients with GOS grade 5 in the experimental group and 23 patients with GOS grade 5 in the control group. The cure rate in the experimental group was higher than that in the control group (67.3% vs. 46.0%, χ 2 =3.889, P=0.048) ( Table 2). experimental group was signi cantly less than that in the control group. The complications of kidney function impairment caused by drugs were also rare than those in the control group. Our research also showed that the recovery rate of the experimental group was signi cantly higher than that of the control group (67.3% vs. 46.0%, P=0.048), and the prognosis of the HICH patients could be improved by closely monitoring the change of ICP value and timely adopting reasonable treatment plan.
HICH is an acute and severe disease in department of neurology. Elevated ICP after intracerebral hemorrhage plays an important role in secondary brain injury and is associated with increased mortality 11 . Timely detecting of ICP changes is the key to successful rescue of critically ill patients. Nowadays, most methods of ICP monitoring are invasive, but it's more likely to occur intracranial infection, intracranial hemorrhage and other complications 12,13,14 . Mizutani et al. 15 attempted to evaluate the sizes of intracranial hematoma, subdural hematoma, ventricular, and the degrees of subarachnoid hemorrhage and brain trauma injury through CT imaging, and established the relationship equation between CT imaging and elevated ICP by applying multiple regression analysis. But the results showed that the difference of ICP value was more than 40 mmH 2 O. Magnetic resonance imaging (MRI) examination is not convenient to be used in critically ill patients, nor can it be used to monitor ICP in a timely and dynamic manner 16,17 . FVEP nICP monitoring technology had been applied in clinical practice since 1986 18 . FVEP is the electrical activity generated by the occipital cortex to the visual stimulation induced by the diffuse non-mode light source. The delay time of the second negative wave (N2 wave) of the brain FVEP is directly related to ICP 19 . A microcomputer device can be used to perform visual stimulation and measure the delay time of N2 wave, then we can obtained the ICP value by comparing the relation table of N2 wave delay time and ICP value 20 . York et al. con rmed in the study of pediatric hydrocephalus and nonopen craniocerebral trauma that there was a strong linear relationship between elevated ICP and prolonged latency of N2 wave of visual evoked potential (the correlation coe cient was 0.8-0.9) 19 . Visual evoked potential is best predicted when cranial hypertension is greater than or equal to 300 mmH 2 O 21 .
When a technique is applied to the clinic practice, the rst consideration is accuracy. The correlation coe cient between nICP and ICP describes Whether nICP is a good proxy for the ICP. To assess the accuracy of a noninvasive method, the Association of Advancement of Medical Instrumentation stated that when the ICP that ranges between 0 20 mmHg, a difference of 2 mmHg is acceptable when compared to an invasive method 22 . Our study showed that the difference between the invasive and noninvasive ICP value within 2mmHg. Therefore, we can admit that FVEP nICP monitoring technology is accurate.
Similar to our research, ultrasonographic optic nerve sheath diameter (ONSD) is another noninvasive ICP monitoring technology through detecting optic nerve. Though it is a simple bedside ocular ultrasound used in detecting the elevated ICP, the ONSD is moderately correlated with ICP in both right and left eyes respectively and Pearson correlation of ONSD between two eyes (right and left) was 0.749 and 0.726 23 .
The optimal ONSD cut-off for the identi cation of ICP has controversial, it uctuates from 0.48-0.5cm 24,25 .
The majority of patients with intracerebral hemorrhage experienced further increase in ICP due to hematoma enlargement within 24h after the onset of intracerebral hemorrhage. Some researchers showed that the increase of ICP is signi cantly earlier than the clinically observed changes in consciousness and vital signs 26.27 . Especially applicable to patients with mild to moderate HICH without invasive ICP monitoring, FVEP nICP monitoring technology can be used as an effective means of early warning of further increase of ICP and further enlargement of hematoma 28 . Moreover, lumbar puncture manometry has been limited due to contraindications and clinical complications 29 . Therefore, the use of FVEP nICP monitoring is particularly important for HICH patients, especially for monitoring the change of ICP on the hematoma side and for early evaluating the degree of cerebral hemorrhage and cerebral edema.
In HICH patients, intracranial hematoma and cerebral edema will lead to elevated intracranial hypertension in 70% of patients. If not timely intervention will seriously affect the recovery of neurological function and prognosis of patients. Mannitol is the most commonly dehydrating agents which lower ICP by reducing blood viscosity and increasing plasma osmotic pressure 30 . However, clinical usage amount lacks scienti c standards and often relies only on clinical experience, as for mannitol to achieve the expected effect is more di cult to determine. In addition, mannitol can cause kidney function damage and electrolyte disturbance. In order to reduce the possible damage caused by using of high doses of mannitol blindly, the American stroke Association recommends that mannitol should not be used prophylactically and should not be used for more than 5 days during rst aid 31,32 . Clinical data showed that mannitol could shorten the incubation period of FVEP N2 wave, and FVEP could observe the changes of ICP after mannitol application 33 . In our experiment, the duration prescription time and the average usage amount of mannitol was signi cantly reduced in the experimental group by applying the FVEP nICP monitoring technology. The ICP changes monitored by FVEP nICP monitoring technology conducive to guide clinical treatment.

Limitations
Certain limitations of this report need to be acknowledged. Firstly, the study was performed in a small population and in a limited area. There may be a bias in drawing conclusions . Secondly, this study only carried out in mild to moderate HICH patients, and the application of FVEP nICP monitoring technology in critically ill patients has not been experienced, so further experiments can be attempted.

Conclusions
Our research showed that the recovery rate of the experimental group was signi cantly higher than that of the control group, and the prognosis of the HICH patients could be improved by closely monitoring the change of ICP value and timely adopting reasonable treatment plan. Based on the noninvasive and security of FVEP nICP monitoring technology, it can be considered to be applied to HICH patients with relatively mild to moderate clinical conditions, good patient compliance, and stability of the disease. The dynamic monitoring of ICP in HICH patients can guide the clinical timely adjustment of the dosage of mannitol and improve the condition and prognosis of HICH patients. However, the limitations and in uencing factors of FEVP nICP monitoring technology should also be considered during clinical use, so as to better understand its indications and provide more reliable methods and means for clinical treatment of patients with HICH intracranial hypertension.

Declarations
Ethics approval and consent to participate The study was approved by the Ethics Committee of the Songjiang Hospital A liated to Shanghai Jiaotong University School of Medicine. Written informed consent was obtained from all participants following a detailed explanation of the study. The study was done in accordance with the principles outlined in the Declaration of Helsinki (1964).

Consent for publication
Not applicable.

Availability of data and materials
The data supporting our ndings can be found in our article and its additional les.

Competing interests
The authors declare that they have no competing interests.

Funding
The OPENS trial is funded by the Shanghai science and technology commission (16411973000). The funder had no involvement in developing the protocol but approved the nal submission.
Authors' contributions FP-Y participated in the design of the study, statistical analysis, and drafted the manuscript. YC-Z participated in the design and conduct of the study. Y-Z carried out the operation of the experiment. Y-W provided management and operational assistance to the patients. XH-L helped to modify the manuscript. All authors read and approved the nal manuscript.