Does Optimized General Anesthesia Care Reduce Postoperative Delirium In Older Patients Undergoing Hip Fracture Repair?
Phase: NA
Conditions: Hip Fractures, Anesthesia, Delirium
Sponsor: University of Missouri-Columbia

 
 
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Date:    February 20, 2017  
Version Number:   11___________ 
Principal Investigator: _Quinn Johnson, MD_____ 
Application Number: __1212915____ 
Application Title:  
 
Does Optimized General Anesthesia Care Reduce Postoperative Delirium In Older Patients 
Undergoing Hip Fracture Repair? 
 
Protocol 
 
*************************************************************************************************** 
 
 
1. 
Abstract 
 
          The overall objective of this proposal is to determine if optimized general anesthesia care of elderly 
patients undergoing hip fracture surgery will minimize postoperative delirium (POD) and improve 
postoperative outcomes. A proactive geriatric consultation using a multifactorial bundle of pharmacological 
and non-pharmacological strategies in the perioperative period has been shown to effectively reduce POD, 
but even with these perioperative medical interventions, more than 30% of patients undergoing hip fracture 
surgery experience POD.1,2   
             There is tantalizing preliminary evidence suggesting that intraoperative interventions may also 
have the potential to further decrease POD. 3-6  This prospective randomized clinical trial (RCT) will focus 
on the intraoperative optimization of:  1. blood pressure, 2. depth of anesthesia, 3. cerebral oxygenation, 
and 4. postoperative pain management in an effort to further reduce POD.  All of these interventions can 
easily be managed by anesthesia providers during surgery.  A total of 160 patients will be randomized to 
optimal versus usual anesthesia care for hip fracture surgery to determine the impact of this targeted 
anesthesia care bundle on the severity and incidence of POD.  The results of our proposed study are 
intended to enhance patient safety by developing a relatively easily implemented, generalizable anesthesia 
management strategy that can be used by anesthesia providers in both academic and private settings. This 
proposal has the potential to further reduce POD, thereby decreasing patient morbidity and mortality.   
 
 

 
 
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2. 
Objectives (include all primary and secondary objectives) 
 
The primary objective of this proposal is to develop an optimized general anesthetic plan, focusing on 
anesthetic depth, blood pressure control, and cerebral oxygenation for elders undergoing hip fracture 
surgery. This protocol will compare usual care to optimal general anesthesia care to test the following 
hypotheses:  
The use of an optimized general anesthetic technique for elders undergoing hip fracture surgery will: 
• Primary hypothesis:  decrease the severity of POD 
• Secondary hypothesis 1:  decrease the incidence and duration of POD  
• Secondary hypothesis 2:  decrease the length of stay in the hospital  
• Secondary hypothesis 3: to determine if poor performance on preoperative cognitive tests 
or preoperative depression identify patients at high-risk for POD 
• Secondary hypothesis 4:  to determine if the level of preoperative inflammation predicts 
patients at risk for POD 
3. 
Background  
Postoperative delirium (POD) is common in elderly patients and is reported to occur in 35 to 65% 
of patients undergoing hip fracture surgery.8  Despite the fact that delirium is a temporary condition, it is a 
medical and societal stressor from an economic and healthcare standpoint.  POD is independently 
associated with increased morbidity, mortality, length of hospital stay, and placement in long-term care 
institutions.  It increases the cost of hospitalization by $4000 for each patient who develops this 
complication and the total costs attributed to the treatment of delirium in the US are estimated to be as 
high as $152 billion each year.9,10   
The etiology of POD is multifactorial and involves a complex interaction between a vulnerable 
patient with preoperative risk factors who is exposed to numerous precipitating factors in the perioperative 
period.11  Most of the preoperative risk factors such as age, comorbidities and cognitive status are fixed and 
cannot be modified during the perioperative period.  However, there are perioperative factors that are 
directly under the control of the anesthesia provider that could potentially be modified to minimize POD.   

 
 
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     At the present time, only multi-component medical interventions have shown to consistently reduce 
POD.1,12,13  Although it makes sense that neuraxial anesthesia would be associated with less POD than 
general anesthesia (GA), there is no evidence to support this theory, possibly because sedation levels were 
not controlled in these studies.14 There is, however, limited evidence that minimizing anesthetic exposure 
during hip fracture surgery might decrease POD.  Sieber et al.3 randomized elderly patients undergoing hip 
fracture repair with spinal anesthesia to light versus deep propofol sedation for the procedure and found 
that light propofol sedation (BIS  > 80) decreased the incidence of POD by 50% compared with deep 
sedation (BIS =50).  Despite the promising results of this study, the study results have been questioned 
because the two treatment groups were not matched with respect to cognitive and functional status.12  A 
more important issue is that spinal anesthesia is rarely used for patients undergoing hip fracture surgery. A 
large retrospective study of 56,729 patients having hip fracture surgery in the US found that only 28% of 
patients received regional anesthesia and that GA was much more common (72%).15  There are a multitude 
of reasons that anesthesia providers prefer to administer GA for hip fracture surgery including patient 
preference, avoidance of pain during positioning of the patient, difficulty with block placement in elderly 
patients with arthritic spines, and the use of anticoagulation in many elders.  An optimized general 
anesthetic technique is, therefore, needed to improve postoperative outcomes in elders receiving GA for 
this hip fracture surgery.  
Modifiable Intraoperative Factors  
     There is growing evidence that limiting the amount of anesthesia during GA may decrease the 
incidence of POD.  Chan et al.5 prospectively randomized elderly patients undergoing elective major 
surgery to either BIS-guided or routine care anesthesia and found that patients in the BIS-guided group 
received less anesthetic and had a 35% decrease in the incidence of POD.  A second prospective study 
randomized elders undergoing elective surgery and found that intraoperative monitoring with BIS was 
associated with a lower incidence of delirium, “possibly by reducing extreme low BIS values.”6  In a third 
study, a retrospective analysis of patients undergoing general anesthesia found a trend toward less POD 
with BIS-guided compared to end-tidal anesthetic concentration guided protocols.16   

 
 
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     Near-infrared spectroscopy (NIRS) can be used to monitor the balance between cerebral oxygen 
delivery and consumption.17   There is moderate to close correlation between regional cerebral oxygen 
saturation (rScO2) and mixed venous saturation (SvO2) in awake and anesthetized patients, indicating that 
rScO2 is reflective of not only cerebral, but also systemic oxygen balance.18,19 A longitudinal study of 
healthy elderly patients undergoing abdominal surgery found that intraoperative cerebral desaturations 
occurred in 25% of patients and was associated with a higher incidence of early postoperative cognitive 
decline and longer hospital stays.20  Murkin et al.7 randomized 200 patients undergoing coronary artery 
bypass to either NIRS monitoring with active treatment of cerebral desaturations or usual care and found 
that active treatment significantly decreased mortality and major organ morbidity (stroke, myocardial 
infarction, ventilation > 48 hours).  There are no studies evaluating outcomes with the use of NIRS 
monitoring with a predetermined treatment protocol on outcomes after noncardiac surgery. 
         There is conflicting literature as to the relationship between intraoperative hypotension and POD.21,22  
A recent abstract found that nearly half of elderly patients had intraoperative mean arterial BP (MAP) 
decreases of 20% or more from baseline.22  While these investigators did not find a relationship between 
intraoperative hypotension and POD, their findings suggest that intraoperative blood pressure variance may 
have an impact on the occurrence of POD.   
4. 
Study Procedures 
a. Study Design: prospective, randomized, clinical trial with a parallel arm including patients who sign 
the consent to be enrolled in the study but are not randomized because they have a Mini-Mental 
State examination score < 15.  
b. Patient Population: This study will include 160 adults, aged ≥ 65 years, scheduled for surgery to 
repair a hip fracture at the University of Missouri-Columbia hospital.  We plan to recruit 250  
subjects to allow for  90 subjects to be excluded if their surgery is moved to another site or they 
fail the MMSE  prior to completion of the study.  The subjects will be recruited for the study 
after they are admitted to the University hospital for care of their hip fracture.  They will be 
visited during the hospitalization.  After discharge from the hospital, they will be called at home 

 
 
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at 1 year after surgery and this will be the final subject contact during the study.  They will not 
be required to return to the hospital for the purposes of this study.   
c. Intraoperative care – All patients will be monitored with standard ASA monitors and normocarbia 
and normothermia will be maintained during surgery.  None of the patients will be given 
benzodiazepine premedication.  All patients will receive a fascia iliaca compartment block in 
the holding area prior to surgery unless contraindicated (patient refusal, anticoagulation).  
Patients will be randomized to one of two intraoperative anesthesia care groups.  The patients, 
surgeons, and research personnel performing the confusion assessments will be blinded to the 
study group.  The anesthesia providers will be aware of the study group.  For the remainder of 
their intraoperative anesthesia care, patients will be randomized to: 
1. Usual care – General anesthesia will be induced with the medications commonly used for general 
anesthesia for this type of surgery namely, iv propofol or etomidate, iv fentanyl, and iv neuromuscular 
blocking agents to facilitate endotracheal intubation.  Patients will be ventilated with air/oxygen 
mixtures during surgery and anesthesia will be maintained with sevoflurane.  Anesthetic administration 
will be titrated on the basis of clinical judgment. A BIS® (Covidien) monitor and Fore-Sight® cerebral 
oximeter (CASMED) will be placed on the patients in the usual care arm, but the anesthesia team will 
be blinded to this monitoring data.  This data will not be used to treat the patient, but it will be analyzed 
to determine differences in intraoperative hemodynamics, cerebral oxygenation, and depth of anesthesia 
between groups.    
2. Optimized general anesthesia care (OP Care) – The anesthesia providers will be trained on the OP 
care protocol prior to the start of the study.  The same anesthetic agents will be used for induction and 
maintenance as in the usual care group, but the maintenance anesthesia will be titrated to achieve a BIS 
value between 40 and 60.  Non-invasive cerebral oximetry (Fore-Sight) will be placed before the 
induction of anesthesia and resting baseline rScO2 and BIS levels will be obtained on room air prior to 
sedation.  Intraoperative interventions will be performed for: 

 
 
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a. Cerebral desaturations - defined as an rScO2 < 50% or a 15% bilateral or unilateral reduction from 
baseline values.  If a desaturation occurs, patients will be treated using an algorithm developed by 
Denault et al.23   This algorithm brings BP to baseline values, increases oxygen delivery, and 
corrects head position, hypoventilation, and anemia.  
b. BP aberrations – any intraoperative systolic BP change greater than 20% from preoperative values 
and/or systolic BP < 90 mm Hg will be treated.  The initial treatment of hypotension will include 
fluid bolus followed by vasoactive agents (phenylephrine, ephedrine, glycopyrrolate) if needed.  
Vasoactive drugs (hydralazine, beta blockers) will be used to treat hypertension.  The 
anesthesiologist will use clinical judgment to determine the treatment regimen.  
IV. Perioperative assessments 
1. Hip Fracture Management Protocol – all patients will be managed by the Hip Fracture Improvement 
Team according to the hip fracture management protocol.  Postoperative pain management is 
outlined in this protocol. 
2. Cognitive and functional assessments – at baseline prior to surgery (This is a research procedure) 
a. 
Mini-Mental State Examination (MMSE-2)24 - a widely used screening tool for 
assessing global cognition (maximum score is 30);  Controlled Oral Word Association 
(COWA)25 –a brief measure of lexical fluency in which the subject must generate words 
beginning with specific letters; and Trails Making Test25 –a cognitive flexibility task. 
b. 
Depression will be measured using the Geriatric Depression – Short Form.26 
c. 
Pre-injury functional status will be evaluated using 7 instrumental and 7 basic activities 
of daily living (ADL).27 
d. 
Fragility Risk Analysis Index (RAI)28 - The RAI is a novel frailty index for use in 
surgical populations.   It is a 14-item questionnaire that takes less than 2 minutes to complete 
and generates scores ranging from 0 to 81. 

 
 
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e. 
Grip strength measured by the JAMAR handgrip dynamometer29 – an instrument for 
measuring the maximal isometric strength of the hand and forearm muscles.  The subjects 
are verbally encouraged to produce their maximal grip strength for 2-4 seconds for a total of 
3 trials.  This measurement can be completed in one minute or less. The maximal value will 
be used for analysis.Pain assessments –  
3. 
Patients will be asked to verbally rate their pain at each delirium assessment using a 
numerical rating scale from 0 (no pain) to 10 (worst imaginable pain).  (This is a research 
procedure).  Patients will also be assessed using the Critical-Care Pain Observation Tool (CPOT).  
This assessment can be used in intubated or delirious patients who cannot verbally rate their pain 
and will be performed by the member of the research team during the research visits.   
4. 
Delirium assessments - During the preoperative interview, the presence of delirium will 
be measured using the Confusion Assessment Method (CAM) and observation (appendix).  The 
CAM 30 uses 4 clinical criteria to diagnose delirium: acute onset and fluctuating course, inattention, 
disorganized thinking, and altered level of consciousness. The CAM was developed to be 
administered by nonpsychiatric clinicians and, across studies, has a pooled sensitivity of 86% and 
specificity of 93%, a positive and negative predictive accuracy of greater than 90%, and high inter-
rater reliability (kappa = .81 to 1.0.28 If the subject has a positive CAM at preoperative testing, 
he/she will be excluded from the study. For the first five postoperative days, subjects will be visited 
daily by a trained research technician.  The patients will be assessed daily using the CAM, the 
CAM-ICU and the 3D-CAM.  If the CAM is positive, the diagnosis of delirium will be confirmed 
by a second investigator who has specialty training in evaluating delirium and is unaware of the 
treatment assignment for the subject and the baseline cognitive test scores.  The specialist will 
administer the Delirium Rating Scale-Revised-98 (DSR-R98) daily until the delirium resolves or the 
patient is discharged.34  The severity and duration of delirium will be recorded.  (This is a research 
procedure.) 

 
 
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5. Systemic Inflammatory Response (SIRS) markers: 
The subjects will undergo venipuncture on the morning of surgery (prior to the start of 
anesthesia) and a total of 6 ml blood will be collected (for whole blood, serum, plasma). Blood 
will also be drawn at the end of surgery and on postoperative day 2 so a total of 18 ml of blood 
will be collected for study purposes.  All blood will be treated as follows: whole blood will be 
stimulated ex vivo with LPS for 24 hours at 37 °C, as described by Riyaz with 10 ng/ml (final 
concentration) Escherichia coli lipopolysaccharide (Difco, Detroit, MI).  Serum and plasma 
samples will be spun at 3000 rpm for 15 minutes and the supernatant stored at -80 °C until 
analyses are performed.  After 24 hours, the TruCulture incubation will be terminated, as 
described and samples stored until analyses.  The resulting plasma samples (+/- LPS) will be 
used for cytokine analyses.  These blood samples will be stored until funding is obtained for 
analysis of the inflammatory response. (This is a research procedure to obtain pilot data on the 
relationship between preoperative inflammatory state and POD. 
6. Postoperative follow up:  patients will be contacted at 3 months and 1 year after surgery to 
determine postoperative complications, functional status, and living environment (independent 
versus assisted living or nursing home).   
5. 
Inclusion/Exclusion Criteria 
Inclusion Criteria: a. Subject or legal representative has voluntarily signed the informed consent 
approved by the IRB, b. hip fracture surgery scheduled under general anesthesia, c. subject is 65 
years or older on the day of surgery 
Exclusion Criteria: a. Inability to follow directions or comprehend the English language, b. Severe 
uncorrected visual or auditory handicaps, c. delirium at screening or baseline, , d. emergency 
surgery in which the preoperative care of the patient is not optimized by the hip fracture or primary 
care team.   
Parallel arm 1:  During the initial hospital visit, we ask the patient to state his/her name and the 
year.  If they can correctly answer these questions, we explain the protocol and attempt to obtain 

 
 
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informed consent.  If the patient is unable to answer these two questions, we do not attempt to enroll 
the patient because he/she would not be able to follow directions to take the preoperative cognitive 
tests.  The nurses caring for these patients do CAM screening several times each day to assess the 
patient for delirium.  After the patient is discharged from the hospital, we will perform a 
retrospective chart review to determine the incidence of postoperative delirium (as assessed by the 
nursing staff) in this patient population.    
Parallel arm 2: If a patient is enrolled in the study, but scores < 15 on the MMSE, they will remain 
in the study but will not be randomized to one of the treatment groups.  They will be given the 
depression (GDS) and activities of daily living (ADL) questionnaires, but will not be administered 
the COWA or the Trail-making tests. However, they will receive the same type of general 
anesthesia for their hip fracture surgery and will be assessed for pain and delirium after surgery as 
described in 3 and 4 above. They will not be monitored with BIS or cerebral oximetry during the 
surgical procedure.    
6. 
Drugs/ Substances/ Devices 
 
a. Drug selection:  We are using the anesthetic agents routinely used during anesthesia care for hip 
fracture in both study groups.  The anesthetic management is routine care.  The only difference 
is that in the optimized anesthesia care group, the amount of intraoperative anesthetic given will 
be titrated using a depth of anesthesia (BIS) monitor.  All of the drugs used in this protocol are 
being administered in approved dosages for FDA approved indications.  The use of the BIS and 
Fore-Sight monitors are for the purposes of the research.  
b. Device selection:  We are using the depth of anesthesia device (BIS) that is already available in 
the University Hospital operating rooms.  However, most clinicians prefer to follow clinical 
signs such as BP and heart rate to adjust the anesthetic depth and the anesthesia providers at the 
University Hospital do not routinely use the BIS for this purpose.  The BIS is a FDA approved 
monitor intended depth of anesthesia monitoring, but it is not a standard of care.  The cerebral 
oxygenation monitor (Fore-Sight) is often used to monitor oxygenation of the brain during 

 
 
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cardiac surgery.  It is a FDA approved monitor and has an indication linking its’ use to 
improved patients outcomes after surgery.  
7. 
Study Statistics 
 
Outcome Variables: 
 
     To assess the primary hypothesis, the DRS-R98, a 16-item clinician-rated scale with 13 severity items 
and 3 diagnostic items (maximum total score of 46 and a maximum severity score of 39 points) will be 
utilized.31   The DRS-R98 is widely utilized in clinical and research situations when a sensitive, valid 
standardized measurement of delirium is needed.  For the secondary hypotheses, we will collect data on 
the incidence of POD which will be a dichotomous outcome.  The duration of delirium episodes and length 
of stay in the hospital will be measured in days and analyzed as a continuous variable.   
Statistical Analysis:  Group comparisons on the delirium severity score and length of stay will be made 
using the Wilcoxon Rank Sum Test (WRST).  The WRST is a nonparametric alternative to the two sample 
t-test.  The standard assumptions of the t-test are normality and equal variances, neither of which is 
required for the WRST.  Hospital length of stay (LOS) is typically a highly skewed outcome due to a 
relatively few patients having atypically long LOS.  Thus the WRST will also be used for a simple two-
group comparison and results reported in terms of median LOS.  Log-transformed LOS will be the 
dependent variable if regression analysis is needed for covariate adjustment. 
Randomization only guarantees homogeneous groups when randomizing a very large number of 
subjects.  Thus, preliminary comparison of the baseline characteristics of the usual care and study group 
will be performed to confirm that randomization did indeed produce similar groups with respect to 
demographics and initial cognitive status.  Any statistically significant (p < 0.05) differences that are also 
judged to be clinically meaningful will shift the analytical approach to an analysis of covariance using 
either parametric or non-parametric regression methods most appropriate to the specific outcome.  
We will also collect data on intraoperative variables including the average BIS and BP as well as 
the proportion of time that the BP and BIS is in the recommended range.  This information will be analyzed 
as a quality control measure to ensure compliance with the treatment protocol in the optimal care group.  

 
 
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Data for the treatment group (OP Care) will be analyzed after the first 5 patients and then after each 
additional 15 patients are treated to ensure compliance with the treatment protocol (BP and BIS in 
recommended range).  Patients will be followed daily during the hospitalization and charts reviewed to 
determine transfusion requirements and prevalence and types of postoperative complications.   
Power Analysis: The primary hypothesis states that optimized anesthesia care will decrease the severity of 
POD compared to usual care.  We expect that the severity score in the optimized group will be 14 ± 3 
versus 18 ± 4 in the usual care group similar to that seen in previous treatment studies.35 To have 80% 
power to detect such a difference when testing a two sided alternative and alpha of 0.05 will require 22 
subjects per group.  This is the number of subjects that qualify as confused.   Only patients with POD 
contribute to the DRS severity sample, so if 30% of subjects are expected to experience delirium, then the 
total sample size for the study would have to be 44/.3 = 148, or 74 per group. We plan to enroll 80 patients 
per group for a total sample size of 160.   
Interim Analysis:  There will be no interim analyses and no safety monitoring board so there are no early 
stopping rules. 
Data management 
The data collected on the data collection forms developed for this study, will be obtained 
specifically for research purposes.  Research data will be stored in a locked research office in the 
Department of Anesthesiology at the University Hospital.  All patient identifiable information will be 
stored in a locked file cabinet in this locked research office or stored on a secure server in this locked 
office.  Only research personnel listed on the IRB proposal will know the log in and password information 
for this server.  The demographic, hemodynamic, laboratory and historical data that are collected at the 
time of the intraoperative study are part of the routine medical record documenting the patient’s care in the 
perioperative period.  The patient’s identity will be specifically protected and confidentiality will be 
maintained in any publication of data.   
 
8. 
Risks 
 

 
 
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         This study will enroll 160 patients scheduled for surgery for repair of a hip fracture.  All subjects will 
have an injury requiring surgery and general anesthesia is routinely used at the University of Missouri-
Columbia for repair of a hip fracture. The anesthesia used in the protocol is routine care and does not add 
additional risk to the patients.  In the optimized care group, we will apply two additional monitors, a 
cerebral oximeter and a depth of anesthesia monitor.  Both of these monitors are non-invasive and FDA 
approved for use in the operating room so the additional risk of using these monitors is minimal.  Both 
devices use a bandage-like sensor applied to the forehead.  There are no reports of allergies or rashes from 
these sensors.   
          The Hip Fracture Improvement Team evaluates all patients who are admitted to the University 
Hospital with this type of injury and they will evaluate all of the patients in the study and adhere to the Hip 
Fracture Management Protocol in the perioperative period.  Thus, the perioperative care of the patient will 
be unchanged for patients enrolled in this study.     
          Elderly patients with hip fractures may have cognitive impairment and ensuring informed consent 
can be a challenge in this type of patients.  Patients will not be enrolled in the study if they are delirious 
when approached and will be excluded from the study if they exhibit significant cognitive impairment as 
evidenced by a score < 18 on the baseline MMSE.  However, inclusion of older adults with cognitive 
impairment in research studies in necessary because preoperative cognitive impairment is one of the 
primary risk factors for POD.32,31   We will request IRB approval to obtain consent from a legally 
authorized representative (as outlined in a Missouri statute) if a subject’s decision-making capacities are in 
question.  If the subject agrees to the research protocol, but we are unsure of his/her ability to fully 
understand the research, we will obtain additional informed consent from a family member or legal 
representative.   
           The baseline cognitive and functional tests and questionnaires are brief and are not adverse.  These 
tests, however, can be frustrating for older subjects.  To prevent this problem, the test battery is limited to 
approximately 15 min and we will ask the subject if he/she needs a break during testing.  We will also have 

 
 
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water, soda and snacks available for the subjects during testing.  If a subject wants to stop the testing at any 
time, we will not continue testing him/her. 
     There are always risks associated with the breach of a subject’s confidentiality.  To minimize this risk, 
research data will be stored in a locked research office in the Department of Anesthesiology at the 
University Hospital.  All patient identifiable information will be stored in a locked file cabinet in this 
locked research office or stored on a secure server in this locked office.  Only research personnel listed on 
the IRB proposal will know the log in and password information for this server.  The demographic, 
hemodynamic, laboratory and historical data that are collected at the time of the intraoperative study are 
part of the routine medical record documenting the patient’s care in the perioperative period.  The patient’s 
identity will be specifically protected and confidentiality will be maintained in any publication of data.   
9. 
Benefits 
 
          In general, the research procedures will not benefit the individual participant.  Subjects in both 
groups will be monitored closely and will receive the type of general anesthesia that would be used if they 
were not enrolled in the study.  It is possible that patients in the optimized anesthesia care group will have 
better outcomes, but this is not known. The primary benefit of this project is to society as a whole, from the 
new information that will be obtained regarding the role of optimized anesthesia care in preventing POD 
and improving postoperative outcomes. 
10. 
Payment and Remuneration 
 
      There will be no compensation or payments to participants in this study.  
 
11. 
Costs 
   
 
 
         The subjects in the study will not be responsible for any of the additional costs associated with the 
research procedures.  The additional costs in the study include the costs of the sensors for the BIS and Fore-
Sight monitors.  These sensors will be paid for by research funds in the Department of Anesthesiology at 
the University of Missouri.  Funding will be sought for analysis of the blood samples for the inflammatory 
response.  The blood samples will be stored until this funding is obtained. 
 
12. 
References 

 
 
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1. 
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2. 
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