Effect of Intravenous Administration of 20% Mannitol on the Optic Nerve Sheath Diameter(ONSD) in Patients With Raised Intracranial Pressure
Conditions: Raised Intracranial Pressure
Sponsor: Tribhuvan University Teaching Hospital, Institute Of Medicine.

1 
 
Effect of intravenous administration of 20% Mannitol on the Optic 
Nerve Sheath Diameter (ONSD) in patients with raised intracranial 
pressure. 
Approval no: 360(6-11)E^2/075/76 
Date: 24 Feb, 2019 

2 
 
1. Proposal Title:  
Effect of intravenous administration of 20% Mannitol on the Optic Nerve Sheath Diameter (ONSD) in 
patients with raised intracranial pressure. 
 
2. Project summary: 
This is a prospective observational cross-sectional study which will determine the extent of change 
brought in the optic nerve sheath diameter by the intravenous administration of 20% Mannitol in patients 
with raised intracranial pressure. The studied patient will be those above the age of 18 years with 
traumatic brain injury, acute stroke or intracranial hemorrhage, with the features of elevated intracranial 
pressure as diagnosed by clinical findings, ONSD value > 5 mm and under 20% Mannitol osmotherapy, 
admitted in the intensive care unit of our institution. Written informed consent will be taken and after the 
eligibility criteria are met, epidemiological data including age, sex, weight, BMI at the time of admission 
will be recorded. Measured baseline observational values including optic nerve sheath diameter, mean 
arterial pressure will also be recorded. Observational variables will be measured after 30 minutes, 60 
minutes and 120 minutes following the intravenous administration of 20% Mannitol. The data will be 
tabulated and analysis performed with SPSS software. The primary outcome will be the change in optic 
nerve sheath diameter, while the correlation between these variables will also be interpreted. 
 
3. Introduction 
Raised intracranial pressure is a common incidence and complication in critically ill patients. There 
have been intense studies and research for understanding the underlying patho-physiology and 
treatment. Much of our understanding of the intracranial pressure is based on the Monro-Kellie 
hypothesis which states that the sum of intracranial volumes of blood, brain, CSF and other 
components is constant, and that an increase in any one of these must be offset by an equal decrease in 
another or else the pressure increases.1 The normal ICP is defined as 5 to 15 mmHg (7.5-20 cmH2O). 
Under normal 
conditions 
the brain is 
able 
to 
auto-regulate its 
blood flow. 
Cerebral 
perfusion pressure (CPP) defined by the equation CPP = MAP – ICP, is the single-most important 
determinant of this auto-regulation. Within a CPP ranging from 50-150 mmHg, the auto-regulation is 
intact. However during any insult/injury this ability of the brain may be impaired or absent thus 
leading to an unregulated change in ICP. Trauma, intracranial hemorrhage, intracranial tumors and 
ischemic stroke are the major causes of such insult and raised intracranial pressure.2 
Prompt diagnosis and treatment of elevated intracranial pressure is the cornerstone of management 
in TBI, intracranial hemorrhages and acute stroke and has been associated with poor outcomes. Care 
based on ICP monitoring has been proved to be associated with frequency of good recovery and 
favorable outcome.3 Such monitoring can be invasive or non-invasive. Currently, invasive ICP 
monitoring is the gold standard. External ventricular drainage and micro-transducer ICP monitoring 
devices are the commonly used modes for ICP monitoring. However there are various hazards  
(infection and hemorrhage) of such invasive procedures and few studies have shown no such 
difference in outcomes with or without invasive monitoring.4, 5 
 
There have been various validated modes of non-invasive ICP monitoring. Trans-cranial Doppler 
ultrasonography (TCD), optic nerve sheath diameter (ONSD), tympanic membrane displacement and 
fundoscopic examinations have been proposed as being surrogates to invasive ICP monitoring.3,4, There 
have been many studies comparing the use of invasive against the use of non-invasive modes of ICP 
monitoring. Among these Optic nerve sheath diameter (ONSD) can be taken as the simplest mode with 
high positive and negative predictive values on detecting rise in intracranial pressure.6 It’s correlation with 
invasively measured intracranial pressure and imaging findings has also been validated7 and used 
extensively in diagnosing episodes of raised intracranial pressure in emergency departments, intensive 
and neurosurgical units.8 
 
 

3 
 
The optic nerve is part of the central nervous system and therefore surrounded by the dural sheath. 
Between the sheath and the white matter is a small 0.1-0.2 mm subarachnoid space which 
communicates with the intracranial subarachnoid space. In cases with raised intracranial pressure the 
pressure is also transmitted into this sheath and expansion occurs. This expansion is appreciable via 
various imaging modalities like CT scans, MRI and ultrasonographic imaging. The feasibility and 
simplicity of this measurement by ultrasonography has made it a efficient tool in diagnosing and 
monitoring in acute care setup.  The major drawbacks are the inter-observer variation in measurement and 
conditions that may confound the finding such as tumors, inflammation, grave’s disease and sarcoidosis. 
Change in ONSD measurements performed before and after interventions including hyperventilation, 
drainage of CSF, administration of Mannitol, tracheal manipulation and lumbar puncture appear to 
correlate well with the induced change in ICP.6, 7 
 
The incidence of elevated ICP is more than 50% in patients with ICP ranging as high as 80% in 
patients with traumatic brain injury.10, 11 The fundamental goal of management in TBI is based on 
managing ICP, maintaining adequate CPP and is based upon the Monro-Kellie doctrine and cerebral 
autoregulation.11 Similarly incidence of raised intracranial pressure in patient with intracranial 
hemorrhage ranges from 36% to 80%.12 Malignant cerebral edema leading to raised intra-cranial 
pressure is a major cause of adverse outcome in patients with acute ischemic stroke with an incidence 
of 10-20%. Use of osmotic therapy in such patients has been recommended in both ENLS guidelines 
for management of intra-cerebral hemorrhage and AHA/ASA guidelines. 13 
 
Mannitol, is a polyol (sugar and alcohol) a hyper-osmolar agent that has been used for osmotherapy in 
neurosurgical patients since many years. The proposed mechanism of its action are transient 
hypervolemia thus decreasing blood viscosity, increase in CBF and the microvascular circulation 
leading to autoregulatory vasoconstriction and thus reducing cerebral blood volume.14 However 
there is controversy regarding its mechanism of effect when given as single bolus dose. Its effect in 
red blood cell rheology and improved oxygen delivery/circulation has also been hypothesized for 
explaining its immediate effect in decreasing ICP14. Another hypothesis argues about the ability of 
Mannitol to lower intracranial pressure by reducing brain water content (diuretic effect)9 and 
decreasing CSF production. 
 
Pharmacokinetics of Mannitol:  
Onset of action: 15 minutes 
Half life: 100 minutes 
Osmolarity: 1100 for 20% Mannitol 
Duration of action:  3-6 hours 
Excretion: Urine (80%) 
Time of peak action: 30- 100 minutes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

4 
 
Literature review: 
Launey et. al,15 performed a study to determine the rate of ONSD variation after Mannitol administration 
for increased ICP episodes. They included thirteen patients in their study comparing and correlating the 
changes in ONSD, pulsatility index and invasively monitored ICP. The ONSD significantly decreased 
after Mannitol infusion from 6.3 to 5.56mm (p=0.0007). Concomitantly the intracranial pressure also 
decreased for 35(32-41) to 25(22-29)mmHg (p=0.001) and the CPP increased from 47 to 69 (p=0.003). 
The study concluded that the variations of ONSD appear to be an interesting and effective parameter to 
evaluate the efficacy of osmotherapy for elevated ICP episodes in patients with acute brain injury/SAH. 
 
A study by Li-juan Wang et al16 which included 60 patients who underwent measurement of ONSD prior 
to lumbar puncture on admission and during follow up,  concluded that ICP was strongly correlated with 
ONSD(r=0.758, p<0.001) and this association was independent of all other factors like age, sex, BMI, 
mean arterial pressure and diastolic blood pressure. It also states that ultrasonographic ONSD 
measurements provide a potential noninvasive method to quantify ICP that can be conducted at the 
bedside. 
 
Another study performed in the Indian population by Shirodkar et. al17 evaluated the efficacy of ONSD by 
ultrasonography as a non-invasive method for detecting raised intracranial pressure in intensive care unit 
to compare with CT/MRI findings of raised ICP and to prognosticate ONSD value with treatment. The 
results showed a sensitivity of detecting raised ICP by ONSD to be 84.6% and a specificity approaching 
around 99%. 
 
A study by Joushua E Nash et al18 uses ONSD to diagnose raised ICP along with correlation with CT 
findings. It also reviews the literature from the past and concludes that <0.50 cm ONSD ensured normal 
pressure (95% CI 0.469-0.540, p<0.001). The study also quantifies the inter-observer variability in ONSD 
measurement (0.001-0.002cm). The study also determines the expertise required for measuring ONSD to 
be around 10-25 case examinations and this has been supported by various other studies. 
 
In a prospective convenience sample study, Shushrutha Hedna MD, and colleagues19 enrolled 86 patients 
with stroke from a tertiary care center. They measured ONSD on the day of admission and subsequent 
day, taking longitudinal and transverse measurements of both eyes of each patient. Compared with 
patients who survived, those who died had increased ONSD in both ischemic stroke categories (0.582 vs. 
0.533; P=.0092) and the intracerebral hemorrhage category (0.623 vs. 0.572; P=.0187). With each ONSD 
increase of 0.1 cm, the odds of mortality increased 4.239 times among patients with ischemic stroke (95% 
CI, 1.317-13.642; P=.0155) and 6.222 times among patients with intracerebral hemorrhage (95% CI, 
1.160-33.382; P=.0329). 
 
Rajajee et al.20 performed a prospective blinded observational study on 65 patients in the ICU. All 
patients in the study had either had an EVD or intra-parenchymal ICP monitor in situ. The authors used 
individual as well as mean ONSD values to account for possible fluctuation in the ICP during ONSD 
measurement. For the individual ONSD measurements the median was 0.53 cm for ICP > 20 mmHg, and 
was 0.4 cm for ICP < 20 mmHg (p < 0.0001). An ONSD of 0.48 cm demonstrated a sensitivity of 96% 
and specificity of 94% for predicting ICP > 20 mmHg. 
 
Using a described ONSD cut-off of 5 mm, Tayal et al.21 performed a prospective blinded observational 
study in the emergency department on 59 adult patients with a mean age of 38 years, suspected of having 
raised ICP. The mean ONSD in patients with CT evidence of raised ICP was 6.37 mm, and in the group 
without evidence of raised ICP, the mean ONSD was 4.94 mm. Using 5 mm as a cut-off point, the study 
described a sensitivity of 100%, and specificity of 63% for predicting raised ICP. 
 

5 
 
The use of ONSD measurement specifically in the acute phase (within 6 hours) to detect intracranial 
haemorrhage (ICH), was investigated by Skoloudik and colleagues22. This study included 31 patients with 
ICH, comparing them to 31 control patients. Sonographic ONSD measurements were performed at 3 and 
12 mm behind the globe. Relative ONSD enlargement of > 0.66 mm (> 21%) demonstrated an accuracy 
of 90.3% for predicting an ICH volume > 2.5cm3. The authors then used an ONSD value of > 5mm, 
demonstrating a sensitivity of 0.708 (95% CI 0.620 – 0.708), specificity of 1.000 (0.697 – 1.000), positive 
predictive value of 1.000 (95% CI 0.875 – 1.000) and a negative predictive value of 0.500(0.348 – 0.652),  
concluding that enlargement of the ONSD may be detectable in the hyperacute stage of increased ICP. 
The use of ONSD to evaluate the clinical evolution of ICH beyond the acute stage was also later 
confirmed. 
 
A study by Jun IJ and friends23 aimed at studying the effect of mannitol on ONSD as a surrogate for 
intracranial pressure during robot assisted  laparoscopic prostatectomy with pneumo-peritoneum and the 
tredelenburg position. Mannitol (0.5 g/kg) was administered after pneumoperitoneum establishment and 
shifting to the Trendelenburg position. ONSDs were measured at six predetermined time points: 10 
minutes after anesthesia induction (T0); 5 minutes after pneumoperitoneum and the Trendelenburg 
position before Mannitol administration (T1); 30 minutes (T2), 60 minutes (T3), and 90 minutes (T4) 
after completion of Mannitol administration during pneumoperitoneum and the Trendelenburg position; 
and at skin closure in the supine position (T5). Results showed that ONSDs were significantly lower at 
T2, T3, and T4 than at T1 (all p < 0.001), with the greatest decrease observed at T4 compared with T1 
(4.46 ± 0.2 mm vs 4.81 ± 0.3 mm, p < 0.001) while mean arterial blood pressure and heart rate were also 
significantly different. However regional cerebral oxygen saturation, cardiac output, corrected flow time, 
peak velocity, body temperature, arterial CO2 partial pressure, peak airway pressure, plateau airway 
pressure, dynamic compliance, and static compliance were not significantly different during 
pneumoperitoneum and the Trendelenburg position. 
 
 
4. Rationale and Justification of Study 
Optic nerve sheath diameter measurement is a common acute care sonographic procedure. Since the 
change in intracranial pressure is a continuum of event, sonographic monitoring of such an event is 
possible through optic nerve sheath diameter monitoring. Mannitol is a common drug used in 
patients/subjects with raised intracranial pressure either due to trauma, subarachnoid haemorrhage or 
stroke. Its effects on intracranial pressure reduction are well known though the mechanism is not properly 
understood yet. My study/research aims at studying the pattern and extent of change in the optic nerve 
sheath diameter after osmotherapy with intravenous 20% Mannitol within its time of peak effect. 
Monitoring such changes can help tailor the treatment modality and tier according to efficacy. In absence 
of invasive monitoring in a limited setup like ours and in light of the various complications associated 
with invasive monitoring, noninvasive monitoring can help us in improving the outcomes in such 
neurosurgical or neurological cases. 
 
 
 
 
 
 
 
 
 
 
 
 

6 
 
5. Objectives  
General: 
To study the effect of intravenous administration of 20% Mannitol on the optic nerve sheath diameter in 
patients with raised intracranial pressure. 
 
Specific: 
• 
To compare the changes in optic nerve sheath diameter brought about by administration of Mannitol 
within the time of its peak effect. 
• 
To correlate and compare the extent of change in ONSD (ΔONSD) at 30, 60 and 120 minutes in 
relation with dose of mannitol administered and change in Mean Arterial Pressure (ΔMAP). 
• 
To correlate the changes in ONSD in relation with PIP and PEEP in patients on Mechanical 
ventilation. 
 
6. Research Questions/Hypothesis: 
 
Null Hypothesis (H0): Serial Optic nerve sheath diameter monitoring with a cut-off value of 5.0 mm can 
reflect changes due to IV administration of 20% Mannitol in patients with raised ICP. 
 
Alternate Hypothesis (H1): Serial Optic nerve sheath diameter monitoring with a cut-off value of 5.0 mm 
cannot reflect changes due to IV administration of 20% Mannitol in patients with raised ICP. 
 
Expected outcome: H0≠ H1 
 
 
 
7. Research Design and Methodology 
7.1. Research Method 
Quantitative 
 
7.2 Types of study 
Prospective, observational, cross-sectional 
 
7.3 Study Population: 
All adults in the intensive care unit admitted with the diagnosis of Traumatic brain injury, 
SAH and acute stroke under treatment with IV 20% Mannitol. 
 
7.4 Study site and its justification:  Intensive care unit of TUTH, IOM.   
Optic nerve sheath diameter has been used for the evaluation of patients with neurological lesion or 
injuries and in acute care settings. However no studies have been performed on its usefulness in our 
institute. It can be used to guide the treatment of acute episodes of raised intracranial pressure in the 
intensive care units and to quantify the efficacy of measures taken to reduce raised intracranial pressure. 
The examination is easy and is non-interventional, so examination can be made mandatory in such 
cases. 
 
 
 
 
 
 
 
 

7 
 
 
7.5 Sampling Method 
Probability sampling 
 
7.6 Sample size 
Basis and method of determination including power of the study, level of significance etc. 
Power of study: 80% (1-β = 0.84) 
Level of significance: 95% (α = 0.05) 
Assuming mean difference and standard deviation of differences (σ) of 0.24 and 0.49 respectively, effect 
size (Δ) was 0.49 as derived from previous study23, 
Using the formula 
 
 
 
The sample size required would be 35. 
Assuming a dropout of 10%, the required sample size would be 40. 
 
 
7.7 Inclusion and Exclusion Criteria 
 
Inclusion criteria:  
• Age > 18 yrs 
• Gender: any 
• H/o traumatic brain injury/ subarachnoid hemorrhage/ acute stroke 
• Mean optic nerve sheath diameter > 5mm (0.5cm) 
• Under osmotherapy with 20% Mannitol. 
 
Exclusion criteria: 
• Baseline ocular pathology like tumors, Grave’s disease and Sarcoidosis 
• Previous ocular surgery 
• Decompressive cranial surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

8 
 
 
 
 
 
7.8 Study Variables: 
 
Epidemiological variables: 
Age 
Gender 
Weight 
BMI 
 
Measured base line variables: 
GCS score  
Mean arterial pressure 
Optic nerve sheath diameter, T1 (mean of 3 measurements in each eye)  
Ventilator parameters (PIP and PEEP) in patients on mechanical ventilation. 
 
 
Measured variables after infusion of 20% Mannitol: 
 
Dose of 20% mannitol administered 
Mean arterial pressure 
Optic nerve sheath diameter (mean of 3 measurements in each eye) after 30mins(T2), 60 mins(T3) 
and 120 mins(T4). 
 
 
7.9 Primary outcomes: 
 
Change in the optic nerve sheath diameter (ΔONSD) at T2, T3 and T4. 
 
7.10 Secondary outcomes: 
 
Change in the mean arterial pressure before and after mannitol administration. 
Comparison and correlation between the extent of change in ONSD (ΔONSD) with  
dose of mannitol and change in MAP(ΔMAP). 
Correlation between ΔONSD with PIP and PEEP in mechanically ventilated patients 
 
 
 
 
 
 
 
 
 
7.10 Expected Duration of the Study: 6 months 
 
7.11 Tools and techniques for data collection: 
 
Tools: 
6-10 Hz linear array USG probe (Sonosite M-Turbo) 
Ultrasound coupling jelly 
Transparent dressing (Tegaderm) 
Cleaning gauze pieces 
Proforma 
Arterial blood pressure monitor (invasive or non-invasive) 
 
 
 

9 
 
 
 
 
 
 
 
 
 
 
 
Methodology: 
 
• 
Included patients will be those above 18 years, admitted in the ICU of TUTH, Maharajgunj, with 
the diagnosis of traumatic brain injury, acute stroke or intracranial hemorrhage and under 
osmotherapy with 20% Mannitol. 
 
• 
Written informed consent will be taken from the patient or patient’s responsible guardian. 
Conscious patients will be explained about the procedure. 
 
• 
The patient’s diagnosis, epidemiological variables and baseline variables will be recorded. 
 
• 
Baseline ventilator parameters will be noted and the ICU staffs instructed not to change those 
variables over the study period until deemed necessary by the treating physician. 
 
• 
Positioning of the patient will be done: supine, 30o head elevated. 
 
• 
Mean arterial blood pressure will be noted from arterial line readings or NIBP reading as 
appropriate or available. 
 
• 
A protective transparent dressing will be placed over the closed eyelid in sedated or ventilated 
patients as an additional measure to prevent any irritation of the conjunctiva. 
 
• 
For ONSD measurement, generous amount of coupling gel will be applied over the closed upper 
eyelid. 
 
• 
The probe will be held with a pincer grasp between the thumb and index finger, using the 
remaining fingers for stability by resting them on the maxilla or supraorbital ridge. 
 
• 
The depth will be adjusted to optimize the visualization of the intended structures, i.e. the optic 
nerve, the surrounding CSF space and the ONS. The gain will be adjusted to create a hypoechoic 
posterior chamber. 
 
• 
The mechanical index will be adjusted as per the recommended values for the eye, in order to 
limit the amount of energy absorbed by the eye. 
 
• 
Values will be noted 0.3 cm posterior to the retinal surface after optimal visualization of the entry 
of optic nerve in the orbit. 
 

10 
 
• 
Mean will be obtained after taking 3 readings in each eye. Only patients with mean ONSD > 
0.5cm will be included and the baseline value designated as T1. 
 
• 
Intravenous 20% Mannitol as prescribed will be administered via a dedicated IV line over 20 
minutes. 
 
• 
Mean arterial pressure and Optic nerve sheath diameter readings will be performed as previously 
described and noted at 30(T2), 60(T3) and 120(T4) minutes after completion of IV administration. 
 
• 
The coupling gel will be removed gently after each measurement and the protective adhesive 
dressing will be removed at the end of the study. 
 
 
7.12 Management protocol of patients/participants if applicable: 
All patients will be managed according to the current ICU protocol abiding with the ENLS and Brain 
Trauma Foundation guidelines for TBI and intra-cerebral hemorrhage and AHA/ASA guidelines for acute 
ischemic stroke. In subjects with persistently elevated intracranial pressure and ONSD findings above 5.0 
mm despite the administration of 20% Mannitol, decision for further treatment will rest upon the treating 
physician. 
 
7.13 Plan for Data Management and Statistical Analysis 
• 
Data will be entered by the investigator and resident on duty in the intensive care unit and will be 
destroyed after the completion of the study, however the results and conclusions will be stored 
without hampering the subject/ patient’s privacy or rights. 
• 
Power of the study is based on the primary outcome which is the change in ONSD following infusion 
of 20% Mannitol. 
• 
Paired t test, chi square test will be used for data analysis. 
• 
Data will be analysed by using SPSS 20 software version 
• 
The value of p<0.05 will be considered as statistically significant. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

11 
 
 
 
 
 
7.14 A graphic outline of the study design and procedures using a flow diagram including the 
timing of assessments. 
 
 
 
8. Biases: 
Data collection by on duty MD anesthesiology Resident or DM Critical Care Residents will reduce 
observer and performance bias. 
 
9. Limitation of the study: 
Single centered 
Open label 
No control group 
 
 
 
 

12 
 
10. Safety considerations: 
Regarding the safety concerns during the measurement of optic nerve sheath diameter subjects with 
ocular injury, glaucoma are being excluded. The acoustic energy used for diagnostic purposes has no 
described adverse effects. The recent bioeffects and safety report by the American Institute of Ultrasound 
in Medicine (AIUM) makes no specific mention of the eye. The United States Food and Drug 
Administration Center for Devices and Radiological Health (US FDA/CDRH) describes an output 
intensity limit for all eye exposure of 50 mW/cm2, recommending the use of a mechanical index (MI) < 
0.23, and a thermal index (TI) < 1. The definition of an experienced operator differs, but studies have 
defined an experienced operator as having performed more than 25 prior transorbital ultrasound 
examinations. 
11. Plan for Supervision and Monitoring: 
The research will be continuously supervised by the co-guides Dr. Pramesh Sundar Shrestha and Dr. 
Arjun Gurung and will be conducted under the guidance of Dr. Subhash P. Acharya. 
12. Expected outcome of the Research: 
Optic nerve sheath diameter changes are expected to be associated with the administration of 20% 
Mannitol  in patients with raised intracranial pressure. Such an outcome would have various 
benefits in terms of usefulness of the optic nerve sheath diameter monitoring. 
13. Plan for Dissemination of Research: 
Research results will be submitted to the Department of Anaesthesiology and Research department, 
IOM. 
Research results will also be submitted for publication in national and international journals of 
repute. 
 
14. Plan for Utilization of the Research Findings: 
The research results would help us in the care of patients in the neurosurgical and neurological 
intensive care units with non-invasive monitoring. 
 
 

13 
 
15. Work Plan  
 
S.N 
Activities 
2018 AD 
2019 AD 
Nov  
Dec 
 
Jan 
Feb 
Mar 
Apr 
1 
Problem identification 
 
 
 
 
 
 
2 
Literature review  
 
 
 
 
 
 
3 
Topic selection 
 
 
 
 
 
 
4 
Writing thesis proposal 
 
 
 
 
 
 
5 
Presentation to sub 
committee 
 
 
 
 
 
 
6 
Review thesis proposal 
 
 
 
 
 
 
7 
Submission to IRB 
 
 
 
 
 
 
8 
Approval from IRB 
 
 
 
 
 
 
9 
Data collection  
 
 
 
 
 
 
10 
Data analysis 
 
 
 
 
 
 
11 
Final thesis writing 
 
 
 
 
 
 
12 
Final correction and 
submission 
 
 
 
 
 
 
 
 

14 
 
 
16. Ethical Consideration  
 
 
 
 
 
 
 
 
 
Research is based on human optic nerve sheath diameter.  
Approval by IRB. 
Verbal consent from patients relatives and/or legal guardian would suffice as the study is non-
interventional and non-invasive with no effect on patients safety. 
Confidentiality will be maintained. 
 
17. Obtaining the Consent 
Patients legal guardian will be well counseled and no information will be withheld. 
 
 
 
18. Budget 
The expenditure during the study will be made by the principal investigator. 
Transparent dressing (Tegaderm): 50 pcs: Rs. 2400 
Data statistician: Rs. 8000 
Stationary: Rs. 4000 
Photocopies of proforma and information sheet: Rs.2000 
Binding: Rs. 4000 
Total: Rs 20400 
 
 
 
 
 
 
 
 
 
 
 
 

15 
 
19. Annexes: 
                                              INFORMED CONSENT  
                                                       Department of Anaesthesiology  
                               Tribhuvan University, Institute of Medicine, Kathmandu, Nepal, 
Study Title: Effect of intravenous administration of Mannitol 20% on the Optic nerve sheath diameter(ONSD) 
in patients with raised intracranial pressure 
Study Number:                                                                       Subject’s Initials: _______________  
Subject’s Name:_______________  
Date of Birth / Age: _________________                         
(i) I confirm that I have read and understood the information sheet and consent form dated  for the   above study 
and have had the opportunity to ask questions.  
(ii) I understand that my participation in the study is voluntary and that I am free to withdraw at any time, 
without giving any reason, without my medical care or legal rights being affected.  
(iii) I understand that the researchers and the IRB and other regulatory authorities will not need my permission 
to look at my health records both in respect of the current study and any further research that may be conducted 
in relation to it, even if I withdraw from the trial. I agree to this access. However, I understand that my identity 
will not be revealed in any information released to third parties or published.  
(iv)I agree not to restrict the use of any data or results that arise from this study provided such a use is only for 
scientific purpose(s)  
(v) I agree to take part in the above study.  
Signature (or Thumb impression) of the Subject/Legal Guardian: 
 
 
 
Signatory’s Name:________________                         Signature of the Investigator:       
Date:_____/_____/______                                          Study Investigator’s Name: ______________ 
                                                                                Date:_____/_____/_______ 
Signature of the Witness: 
Name of the Witness: ____________________ 
Date:_____/_____/_______ 

16 
 
                            सुसूचित मन्जुरीनामा 
म ______________________________(उमेर _______वर्ष)ले ‘Study on the effect of 
intravenous administration of 20% Mannitol on the Optic nerve sheath diameter(ONSD) in patients with 
raised intracranial pressure’ शिर्षकको अनुसन्धान सम्बन्धी संलग्न शमतत २०७   /    /     को 
'जानकारी पत्र/पुस्ततका' सुनेर/पढेर र प्रश्नोत्तर समेत गरेर यो अध्ययन-अनुसन्धान सम्बन्धमा 
जानकारी प्राप्त भयो। यो अनुसन्धान कायषमा मेरो सहभाचगता मेरो व्यस्ततगत इच्छामा भर पने 
र मैले िाहेको खण्डमा कुनै पतन बेला यो अनुसन्धान प्रक्रियाबाट बाहहररन पाउने भन्ने कुरा मैले 
बुझेको छु। यसको लाचग मैले कुनै कारण हिनु नपने र त्यसबाट मैले पाउने सेवा र मेरो कानुनी 
अचधकारमा असर नपने समेत मलाई बुझाईएकोछ। यस अनुसन्धानको प्रततवेिन वा सम्बस्न्धत 
प्रकाशित कृततहरुमा मेरो कुनै व्यस्ततगत पररिय खुल्ने जानकारी प्रकाशित हुने छैन भन्ने कुरा 
मैले बुझेकोछु। 
सहभागीको बुढीऔंलाको ल्याप्िे 
 
 
 
िायाँ 
बायाँ 
यी सबै कुराहरु जानी-बुझी, म यस अध्ययन-अनुसन्धानमा सहभागी हुन तवेच्छाले राजी भई यो 
सुसूचित मन्जुरीनामामा सहहछाप गरेकोछु।  
सहभागीको सही_______________ 
सहभागीको नाम थर _________________________ 
शमतत २०७  /  /   
साक्षीको सही________________________________________ 
साक्षीको नाम थर _____________________________________  
                       

17 
 
 
 
                                                         Proforma 
“Study on the effect of intravenous administration of 20% Mannitol on the Optic nerve sheath diameter 
(ONSD) in patients with episodes of raised intracranial pressure.” 
Participant serial no.:  
 
 
IP no.:  
 
 
 
Date: 
Name:  
 
 
 
 
Age/sex: 
 
 
 
Weight: 
Height: 
 
 
 
            BMI: 
Diagnosis: 
 
 
 
 
Admission date: 
 
 
Ventilator parameters at time of baseline measurement 
PIP:             cmH2O 
PEEP:          cmH2O 
Time of 20% Mannitol administration: 
Dose of 20% Mannitol administered: 
Time of measurement: 30 minutes: 
 
 
           60 minutes: 
 
 
           120 minutes: 
 
MEASURED VARIABLES: 
VARIABLES 
BASELINE 
(T1) 
POST-MANNITOL 
(30MINUTES: T2) 
60  MINUTE 
(T3) 
120 MINUTES 
(T4) 
MEAN 
ARTERIAL 
PRESSURE 
     mmHg 
                     mmHg                   mmHg 
                    mmHg 
OPTIC 
NERVE 
SHEATH 
DIAMETER 
RIGHT:          mm 
RIGHT:            mm 
RIGHT:        mm 
RIGHT:           mm 
LEFT:             mm 
LEFT:               mm LEFT:           mm 
LEFT:              mm 
MEAN:           mm 
MEAN:           mm 
MEAN:         mm 
MEAN:            mm 
GLASGOW 
COMA SCALE 
E: 
V: 
M: 
E: 
V: 
M: 
E: 
V: 
M: 
E: 
V: 
M: 
 
 
 

18 
 
List of Abbreviations: 
ICP 
Intracranial pressure 
TBI 
Traumatic brain injury 
SAH 
Subarachnoid hemorrhage 
ONSD 
Optic nerve sheath diameter 
CPP 
Cerebral perfusion pressure 
CBF 
Cerebral Blood Flow 
MAP 
Mean arterial pressure 
GCS 
Glasgow Coma Scale 
USG 
Ultrasonography 
ICU 
Intensive care unit 
IOM 
Institute of medicine 
TUTH 
Tribhuwan University Teaching Hospital 
IV 
Intravenous  
BMI 
Body Mass Index 
ASA/AHA 
American Heart Association/American Stroke 
Association 
SPSS 
Statistical Package for the Social Sciences  
TCD 
Transcranial Doppler 
cmH2O 
Centimeter of water 
COR 
Class of recommendation 
LOE 
Level of evidence 
MI 
Mechanical index 
TI 
Thermal index 
US FDA/CDRH 
United States Food and Drug Administration/ 
Center for Devices and Radiological Health 
AIUM 
American Institute Of Ultrasound In Medicine 
ENLS 
Emergency Neurological Life Support  
CI 
Confidence Interval 
PIP 
Peak Inspiratory Pressure 
PEEP 
Positive End Expiratory Pressure 
 
 

19 
 
REFERENCES:  
1. Miller JD, Sullivan HG. Severe intracranial hypertension. Int Anesthesiol Clin. 1979;17(2-3):19-75. 
2. Rangel-Castilla, L., Gopinath, S. & Robertson, C. S.. 2008. Management of intracranial hypertension. Neurol 
Clin 26: 521-41, x. doi: 10.1016/j.ncl.2008.02.003. 
3. Geeraerts T, Launey Y, Martin L, Pottecher J, Vigué B, Duranteau J, et al. Ultrasonography of the optic nerve 
sheath may be useful for detecting raised intracranial pressure after severe brain injury. Intensive Care 
Medicine. 2007Jan;33(10):1704–11 
4. Legrand A, Jeanjean P, Delanghe F, Peltier J, Lecat B, Dupont H. Estimation of optic nerve sheath diameter 
on an initial brain computed tomography scan can contribute prognostic information in traumatic brain injury 
patients. Critical Care. 2013;17(2) 
5. Chesnut RM, Temkin N, Carney N, et al. A Trial of Intracranial-Pressure Monitoring in Traumatic Brain 
Injury. The New England journal of medicine. 2012;367(26):2471-2481. doi:10.1056/NEJMoa1207363. 
 
6. Williams P. Optic Nerve Sheath Diameter as a Bedside Assessment for Elevated Intracranial Pressure. Case 
Reports in Critical Care. 2017;2017:1–2 
 
7. Kimberly H, Shah S, Marill K, Noble V. Correlation of Optic Nerve Sheath Diameter with 
Direct Measurement of Intracranial Pressure. Academic Emergency Medicine. 2007Jan;14 (5 Supplement 1). 
 
8. Soldatos T, Karakitsos D, Chatzimichail K, Papathanasiou M, Gouliamos A, Karabinis A. Optic nerve 
sonography in the diagnostic evaluation of adult brain injury. Crit Care. 2008;12(3):R67. 
 
9. Diringer MN, Scalfani MT, Zazulia AR, Videen TO, Dhar R, Powers WJ. Effect of mannitol on cerebral 
blood volume in patients with head injury. Neurosurgery. 2012;70(5):1215-8; discussion 9. 
 
10. Hlatky R, Valadka AB, Robertson CS. Intracranial hypertension and cerebral ischemia after severe traumatic 
brain injury. Neurosurg Focus. 2003;14(4):e2. 
 
11. Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, et al. Guidelines for the 
Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017;80(1):6-15. 
 
12. Zoerle T, Lombardo A, Colombo A, Longhi L, Zanier ER, Rampini P, et al. Intracranial pressure after 
subarachnoid hemorrhage. Crit Care Med. 2015;43(1):168-76. 
 
 

20 
 
13. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 Guidelines for 
the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From 
the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110. 
 
14. Sakowitz OW, Stover JF, Sarrafzadeh AS, Unterberg AW, Kiening KL. Effects of mannitol bolus 
administration on intracranial pressure, cerebral extracellular metabolites, and tissue oxygenation in severely 
head-injured patients. J Trauma. 2007;62(2):292-8. 
 
15. Launey Y, Nesseler N, Le Maguet P, Malledant Y, Seguin P. Effect of osmotherapy on optic nerve sheath 
diameter in patients with increased intracranial pressure. J Neurotrauma. 2014;31(10):984-8. 
16. Wang LJ, Chen LM, Chen Y, Bao LY, Zheng NN, Wang YZ, et al. Ultrasonography Assessments of Optic 
Nerve Sheath Diameter as a Noninvasive and Dynamic Method of Detecting Changes in Intracranial Pressure. 
JAMA Ophthalmol. 2018;136(3):250-6. doi: 10.1001/jamaophthalmol.2017.6560. 
17. Shirodkar CG, Rao SM, Mutkule DP, Harde YR, Venkategowda PM, Mahesh MU. Optic nerve sheath 
diameter as a marker for evaluation and prognostication of intracranial pressure in Indian patients: An 
observational study. Indian J Crit Care Med. 2014;18(11):728-34. 
18. Nash, J. E., O’Rourke, C., & Moorman, M. L. (2016). Transocular ultrasound measurement of the optinerve 
sheath diameter can identify elevated intracranial pressure in trauma patients. Trauma, 18(1),28–34.  
https://doi.org/10.1177/1460408615606752 
19. Shushrutha Hedna, Vishnumurthy, Rastogi, Vaibhav, Weeks, Emily & Patel, Rohit P. 2015. 
Abstract WMP83: Use of Optic Nerve Sheath Diameter in Emergency Department to Predict Stroke Outcome. 
Stroke 46: AWMP83-AWMP83. 
20. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised 
intracranial pressure. Neurocrit Care. 2011;15(3):506-15. 
21. Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic 
measurement of optic nerve sheath diameter to detect findings of increased intracranial pressure in adult head 
injury patients. Ann Emerg Med. 2007;49(4):508-14. 
22. Skoloudik D, Herzig R, Fadrna T, Bar M, Hradilek P, Roubec M, et al. Distal enlargement of the optic nerve 
sheath in the hyperacute stage of intracerebral haemorrhage. Br J Ophthalmol. 2011;95(2):217-21. 
23. Jun I-J, Kim M, Lee J, Park S-U, Hwang J-H, Hong JH, et al. Effect of Mannitol on Ultrasonographically 
Measured Optic Nerve Sheath Diameter as a Surrogate for Intracranial Pressure During Robot-Assisted 
Laparoscopic Prostatectomy with Pneumoperitoneum and the Trendelenburg Position. J Endourol. 2018 
Jul;32(7):608–13. 

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