PROPOSED TOPIC OF RESEARCH: 

COMPARISON OF EFFECTS OF DEXMEDETOMIDINE AND MIDAZOLAM IN FRAGMENTED SLEEP RELATED GLYCEMIC VARIABILITY IN POST-OPERATIVE INTENSIVE CARE PATIENTS – A SINGLE BLINDED PLACEBO CONTROLLED PROSPECTIVE RANDOMIZED STUDY.

NAME OF THE INVESTIGATORS:

[1] DR ARUN MUTHUKUMAR M K

DEPARTMENT OF ANAESTHESIOLOGY

CALCUTTA NATIONAL MEDICAL COLLEGE, KOLKATA

SUMMARY:

                In general post-operative patients tend to suffer a lot of problems both physically and mentally, compared to the other patients admitted in Intensive care units (ICU) for mild to moderate symptoms like Acute gastroenteritis etc, during their hospital stay. Most of the patients have varied complaints during routine rounds, one such prominent and important complaint is the lack of an adequate 6 to 8 hours sleep at night. The amount of sedatives and opioid analgesics used also vary among different patients. Many patients even after receiving adequate sedation and analgesic tend to suffer sleep fragmentation or deprivation due to multiple factors like continuous exposure to alarm beeps, lightings.

               In order to reduce this problem various drugs have been studied as a means of ICU sedation. More recently even inhalational anaesthetics are also studied as a means of ICU sedation.

                Sleep deprivation in bed bound ICU patients have an significant impact in causing adverse events like altered glycemic variability mostly hyperglycemia and poor immune response and delayed wound healing. This in turn has a major impact in increasing the hospital stay. For these reasons, an ideal maintenance of required daily sleep is essential in any hospitalized patients.

                Still remaining a controversial topic, we in our study will be evaluating two drugs (dexmedetomidine and midazolam) as an effective means of ICU sedation. We also will be evaluating the drug efficacy in preventing hyperglycemic surge in the study subjects which tend to occur most commonly due to sleep fragmentation.

1.     OBJECTIVE OF RESEARCH:  

              GENERAL:

                       To determine whether sleep duration and efficacy are associated with increased risk of Glucose variability in patients admitted in the Intensive Care Units.

               SPECIFIC:

                         To monitor,

-        The routine hemodynamics like Heart rate, Spo2, Blood pressure, ECG during ICU stay

-        Capillary blood sugar and fasting post prandial venous blood sugar of patients during study period

-        Efficacy of the two study drugs in maintaining an adequate sleep cycle per day.

2.     RESEARCH HYPOTHESIS:

          We hypothesized that post-operative patients admitted in the ICU who are suffering from poor sleep quality have a higher risk of developing hyperglycemia and impaired fasting glucose, which becomes one of the important factors predicting the in-hospital outcome. Our main aim in this study will be evaluating the efficacy of two drugs dexmedetomidine and midazolam in attenuating sleep fragmentations related glycemic variability in post-operative patients, mainly laparotomy surgery.

3.     BACK GROUND OF RESEARCH:

a)    Rationale of study:

                    Sleep is a vital for everyday functioning, and yet it is affected invariably in critically ill ICU patients. Sleep is the most importantly altered physiologic phenomena in intensive care set up. The continuous beeps of the alarms from monitors and the multiple entries of the patient’s attenders as well as the necessity of late night drug administration or top up by the nurse in charge also play an important role in hampering the continued sleep cycle. Poor sleep quality results in ventilatory, cardiovascular, immunologic, hormonal and psychological disturbances. Hyperglycemia is common among hospitalized patients, even in those patients who have not been previously diagnosed with diabetes. This in turn is more severe when it comes to in patients admitted in ICU. Hyperglycemia during hospitalization is associated with worse patient outcomes, including higher risk of myocardial infarction and stroke (1). Hence this study evaluates the risk of hyperglycemia in ICU patients with sleep deprivation.

B) Introduction:

                    Sleep is a complex process influenced by biologic and environmental factors. Despite spending one third of our life asleep, the exact physiologic purpose of sleep is still to be elucidated. There is growing evidence that sleep disturbances are associated with adverse outcomes. There are various factors contributing to poor quality of sleep in ICU patients, such as pain, anxiety, noise, light, pre-existing sleep disorder and patient care activities (2). There are many studies which show the effects of sleep deprivation in significantly altering the glycemic control in sick patients.

                    Sleep deprivation can affect the immune system, hormone levels, pulmonary and ventilatory mechanics, and neurocognition. Studies have shown a modulation of immune function secondary to changes in sleep patterns (3). Sleep deprivation causes changes to homeostatic mechanisms and alters neuroendocrine abnormalities and has been shown to cause increases in thyroid hormone, norepinephrine, and cortisol levels with decreases in growth hormone levels and insulin resistance (4). The impact of sleep disturbance on glucose metabolism is critical because glucose regulation can have an impact on patient morbidity and mortality in select ICU populations. A target capillary as well as venous glucose levels of 140- 180 mg/dl is considered normal (normoglycemic) for ICU patients according the American Diabetic Association (ADA). Any patient, if found having high sugar levels during the time of ICU stay is more prone for adverse events and complications. In patients with high glucose levels who required basal insulin or oral hypoglycemic agents were found having comparatively more poor outcomes than normoglycemic patients. This rate of complications were much more higher in patients who required insulin infusion for maintaining sugar levels.

                 ICU sedation is an on going topic of discussion where the safety and efficacy were evaluated according to the type of drug administered. Initially propofol and midazolam gained so much popularity in giving adequate sedation and a quality sleep for bed bound patients. Moreover post surgical stress also is a major factor

                    Multiple studies have compared the efficacies of dexmedetomidine and midazolam, in which they concluded that patient and operator satisfaction was better in dexmedetomidine group, with similar hemodynamic and respiratory safety profiles (12).

C) Review of literature:

                   We have gathered various literature supporting the objective and rationale of our study,

                    Stamatakis KA and Punjabi NM in 2009 studied the effects of sleep fragmentation on glucose metabolism in normal subjects and concluded that fragmentation of sleep across all stages is associated with a decrease in insulin sensitivity (6).

                    De Pietro et al in 2017 studied the association between inpatient sleep loss and hyperglycemia and concluded that among medical inpatients, both shorter sleep duration and worse sleep efficiency were independently associated with greater proportional odds of hyperglycemia and impaired fasting glucose. (5)

                       Cauter EV et al in 1991 studied roles of circadian rhythmicity and sleep on the 24-h variation in glucose tolerance and concluded that that both circadian rhythmicity and sleep are important physiological regulators of glucose tolerance in a normal man. (7)

                       During the period of 2011-2014 many studies were conducted comparing effects of intravenous propofol and midazolam in ICU sedation, while some studies even compared inhalational sevoflurane with propofol infusion. In a study conducted by Weinbroum et al in 1997 which included 67 patients showed that midazolam is better in maintaining the sedation and less cardiovascular depression than propofol. But the prospective randomized study conducted by Zhou et al in 2014, which included 135 patients showed that cost benefit ratio was higher when midazolam-propofol combination was used instead of either of drugs alone. After this came the era, where the usage of inhalational agents like sevoflurane were argued for ICU sedation.

                        In a randomized study conducted by Mesnil et al in 2011, showed that extubation times and opioid requirements were less when inhalational sevoflurane was used for ICU sedation. Followed by which Jareth et al in 2015 designed a study called volatile anaesthetic agents for long-term critical care sedation (VALTS) trial, which was started as a pilot study for further researches.   

                        But later in a systemic review by Jerath et al in 2017, which combined multiple trials explained the presence of heterogeneity and a positive publication bias and a difficulty in feasibility of the mentioned procedure. They also warranted further more studies to clearly pick a definitive outcome. Still many more studies are going on regarding this controversy (10).

                        Barends et al in 2017, in a systematic review and meta analysis study commented that Dexmedetomidine as a better alternative to midazolam in ICU sedation. It was also found superior to the previously used lorazepam, remifentanyl and propofol and had beneficial effects in reducing ICU related deilirium and had excellent and promising patient tolerability (11).

                       A large multicenter trial involving 200859 patients done by Dr Simon Cichoz and Clara Schaarup in 2017 discussing hyperglycemia as a predictor of ICU related adverse events showed that the mortality rate among ICU patients without diabetes was 17.3% for observed hyperglycemia and 6.6% for patients without hyperglycemia (P < .001). They also added that length of ICU stay had a median of 2.7 days (hyperglycemia) and 1.6 (no hyperglycemia) (P < .001)

                        Numerous sleep sedation scales were devised in the past with so many ongoing researches still evaluating the efficacies of various scales. Rasheed et al in 2019 in a cross-sectional study involving 425 patients showed that Richmond Agitation Sedation scale (RASS), is comparatively better to Richmond Sedation scale in assessing sleep in intensive care patients. So, we will be employing RASS scale as a reliable means of assessing the sleep depth and adequacy

d) Research questions:

1)    How effective are the two drugs in maintaining sleep depth and adequacy?

2)    How an adequate day to day sleep cycle will be useful in reducing the hyperglycemic episodes?

3)    Will it be useful in reducing adverse events related to hyperglycemia induced adverse events?

4)    How efficiently post-operative patients are able to tolerate the sedation?

5)    Which among the study drug is more effective in maintaining a proper 6 to 8 hourly sleep cycle in study patients?

6)    Can the two study drugs be used as an effective means of ICU sedation?

            These are the questions which will help us amalgamate the result of the mentioned study.

e) Relevance and expected outcome of proposed study:

                        We assumed both the drug administered were equally effective in providing a better quality sleep in ICU patients. The main outcome expected will be the efficacy of the two drugs in reducing the sleep fragmentation related hyperglycemia in these patients.

5) METHODOLOGY  

a) Study design / Experiment design:

                A prospective interventional single blinded placebo controlled randomized study.

b) Study setting and timelines: Admitted patients in SICU and MICU, of CNMC&H, Kolkata. For each study subject approximate time will be 10 days. Total duration of study: 5 months.

b)    Place of study: - Surgical Intensive Care Unit and Medical Intensive care Units of Calcutta National Medical College and Hospital, Kolkata.   

d) Period of study: January 2022- May 2022                        

e) Study population:  Patients admitted in SICU, MICU of CNMC&H, during the study period.                      

f) Sample size / design: An Approximated calculation with a total of 240 patients divided randomly in three groups, Group M and Group D and Group P with 80 study subjects in each group, who met the inclusion criteria were included.

g) Sample distribution:  The sample size was calculated approximated to be 180 and were equally and randomly distributed among three groups assuming a beta error of 20 percent. With a power of 0.8, the sample size for our required study would be 80 patients in each group with 95% confidence interval

h) Case, control required or not: Group P will act as a control to the other two groups (M and D).

    Case definition:

        Group M: Patient who receive Inf midazolam at rate of 0.05 mg/kg/hr over 6 hours from 11 pm to 5 am during the study period.

         Group D: Patient who receive Inf dexmedetomidine at rate of 0.2 mcg/kg/hr over 6 hours from 11 pm to 5 am during the study period

and Group P: Patient who receive Inf normal saline at the rate of 0.5 ml/hr over 6 hours from 11 pm to 5 am during the study period, as a placebo

i) Inclusion criteria:

1.     Patient and their relatives who consented for the study

2.     Adults of the age 18-55 years of age

3.     Patients who got admitted in SICU, MICU following post-operative emergency surgeries.

4.     Patient who received Non-invasive ventilation in form of Cpap and BiPap with better prognosis.

5.     Patients who were studied within 72 hours of surgery performed.

.

   Exclusion criteria

1.     Patients refused to give consent

2.     Known prior diabetic history, or under Oral hypoglycemics or Insulin during or before hospital stay.

3.     Paediatric patients (<18 years)

4.     Patients with allergy to study drugs 

5.     Liver dysfunction or confirmed renal impairment (CKD, DCLD)

6.     Patients who had known neurological (Epilepsy, Guillian Barre syndrome etc) or endocrinological (cushings disease, addisons disease etc.) disorders prior to the study.

7.     Patients who were diagnosed with sepsis according to the recent SIRS guidelines.

8.     Pregnant patients and lactating mothers

9.     Patients who were on opioids like tramadol, fentanyl infusion during the study period.

10.  Known prior cardiac illness like A-V block, previous MI, pacemaker implantation.

11.  Patient who are ventilated and have poor prognosis.

12.  Patients who are on additional muscle relaxant infusion

13.  Patients who require vasopressor like Noradrenaline or dopamine infusions to maintain Mean arterial pressure above 65 mm Hg

14.  Patients admitted for severe burns or road traffic accidents

15.  Patients with BMI >30 and severely obese patients

i) Study variables

1. Demographic variables (Age, Sex, Body weight, BMI)

2. Capillary blood glucose thrice per day

3. Fasting blood glucose, post prandial glucose every alternate day during ICU stay

4. Hemodynamic Variables (HR, BP, Spo2, ECG) – continuous monitoring

j) Data collection and interpretation: 

                       Data will be collected during the stay of the patient in ICU, by trained nursing assistant or on call doctor. Data will be analyzed by appropriate statistical software.

k) Laboratory investigations:

                                   Including all the required investigations like,

·       Blood for Haemoglobin, Total leucocyte count, Differential leukocyte count, Platelets, alternate day.

·       Blood sugar at serial intervals (CBG thrice per day)

·       Fasting and post prandial venous blood sugar on alternate days

·       Hba1c on Day 1 and Day 15 in ICU

·       ECG (a 12 lead ECG once in 5 days apart from running 24 hours monitor)

·       Blood urea and creatinine every once in three days

·       Coagulation profiling including PT, APTT and INR

·       Chest X-ray PA or AP view, (mostly bedside)

·       Ultrasound Whole abdomen

·       Urine R/E every once in three days; C/S on day 1 and 15

·       LFTs including albumin and total protein done once in 5 days

·       ABG (every day at morning if ventilated)

·       Serological reports (HIV1 & 2, HCV, HBSAG)

·       COVID 19 RTPCR

·       Central venous catheter tip sample for C/S if required

l) Parameters and Procedures:

After Ethics committee clearance and getting written informed consent, patients will be randomly selected in accordance with our inclusion criteria.

Study patients will be randomly allocated into 3 groups: Group M and Group P and Group D using computer generated randomisation table. Patients in group M will receive Injection Midazolam 0.05mg/kg/h over 6 hours and group P will receive placebo ie. Normal saline at 0.5 ml/hr infusion over 6 hours and group D will receive dexmedetomidine at 0.2 mcg/kg/hr continuous infusion over same time period of 6 hours.

The infusions were administered as in order to maintain a Richmond agitation sedation scale range of 0 to -3 (except for the Group P).

An independent assistant not involved in the study will check morning CBG. Blood for Fasting blood glucose, Post-prandial blood glucose will also be sampled on alternate days. All the data will be collected and analysed with statistical analysis.

m) Outcome definition and parameters:

                     Glucose levels of >180 mg/dl will be considered abnormal. Incidence of hyperglycemia (will be considered as primary outcome variable. The secondary outcome variables include severity of adverse events like nausea vomiting, degree of sedation, hemodynamic variables and average duration of hospital stay.

n)  Statistical analysis:

                       Data will be entered in MS Excel and analyzed by SPSS Version 23.0, IBM, Chicago USA.

            To test hypotheses about the difference in frequency, the chi-squared test was used. The t-test was used for testing hypothesis about difference of arithmetic means between the 2 groups. Repeat Measures ANOVA will be used to compare between groups at different time interval. A p-value of ≤0.05 will be considered significant.

o) WORK PLAN:

               Formation of research hypothesis

                        Review of Literature

                        Formation of title of research

                       Patient selection & determination of methodology                     7 months.

                       Ethics clearance& Submission of synopsis 

                       Procedure of the study

                       Data collection      

                       Result and Analysis                                                                       1 month

                       Conclusion.

REFERENCES

1. Levetan C. Controlling hyperglycemia in the hospital: A matter of life and death. Clin Diabetes 2000;18:17–25

2.     Kamdar BB, Needham DM, Collop NA. Sleep deprivation in critical illness: its role in physical and psychological recovery. J Intensive Care Med. (2012) 27:97–111. 10.1177/0885066610394322

3.     Benedict C, Dimitrov S, Marshall L, Born J. Sleep enhances serum interleukin-7 concentrations in humans. Brain Behav Immun 2007;21:1058–1062.

4.     Schmid SM, Hallschmid M, Jauch-Chara K, Bandorf N, Born J, Schultes B. Sleep loss alters basal metabolic hormone secretion and modulates the dynamic counterregulatory response to hypoglycemia. J Clin Endocrinol Metab 2007;92:3044–3051

5.     DePietro RH, Knutson KL, Spampinato L, Anderson AL, Meltzer DO,Cauter EV, Arora VM. Association between inpatient sleep loss and hyperglycemia of hospitalization. Diabetes Care 2017 Feb; 40(2):  188-193

6.     Stamatakis KA, Punjabi NM. Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest. (2010) 137:95–101. 10.1378/chest.09-0791 

7.     Van Cauter E., Blackman J., Roland D., Spire J.-P., Refetoff S., Polonsky K. Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep. J. Clin. Invest. 1991; 88: 934–942.

8.     Zhou Y, Jin X, Kang Y, Liang G, Liu T, Deng N. Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study. Crit Care. 2014 Jun 16;18(3):R122. doi: 10.1186/cc13922. PMID: 24935517; PMCID: PMC4095601.

9.     Mesnil M, Capdevila X, Bringuier S, Trine PO, Falquet Y, Charbit J, Roustan JP, Chanques G, Jaber S. Long-term sedation in intensive care unit: a randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam. Intensive Care Med. 2011 Jun;37(6):933-41. doi: 10.1007/s00134-011-2187-3. Epub 2011 Mar 29. PMID: 21445642.

10.  Jerath A, Panckhurst J, Parotto M, Lightfoot N, Wasowicz M, Ferguson ND, Steel A, Beattie WS. Safety and Efficacy of Volatile Anesthetic Agents Compared With Standard Intravenous Midazolam/Propofol Sedation in Ventilated Critical Care Patients: A Meta-analysis and Systematic Review of Prospective Trials. Anesth Analg. 2017 Apr;124(4):1190-1199. doi: 10.1213/ANE.0000000000001634. PMID: 27828800.

11.  Barends CR, Absalom A, van Minnen B, Vissink A, Visser A. Dexmedetomidine versus Midazolam in Procedural Sedation. A Systematic Review of Efficacy and Safety. PLoS One. 2017 Jan 20;12(1):e0169525. doi: 10.1371/journal.pone.0169525. PMID: 28107373; PMCID: PMC5249234.

12.  Barends CRM, Absalom A, van Minnen B, Vissink A, Visser A (2017) Dexmedetomidine versus Midazolam in Procedural Sedation. A Systematic Review of Efficacy and Safety. PLoS ONE 12(1): e0169525. https://doi.org/10.1371/journal.pone.0169525

13.  Cichosz SL, Schaarup C. Hyperglycemia as a Predictor for Adverse Outcome in ICU Patients With and Without Diabetes. J Diabetes Sci Technol. 2017 Nov;11(6):1272-1273. doi: 10.1177/1932296817721937. Epub 2017 Jul 21. PMID: 28728435; PMCID: PMC5951053.

14.  Gunst J, De Bruyn A, Van den Berghe G. Glucose control in the ICU. Curr Opin Anaesthesiol. 2019 Apr;32(2):156-162. doi: 10.1097/ACO.0000000000000706. PMID: 30817388; PMCID: PMC6774765.

15.  Rasheed AM, Amirah MF, Abdallah M, P J P, Issa M, Alharthy A. Ramsay Sedation Scale and Richmond Agitation Sedation Scale: A Cross-sectional Study. Dimens Crit Care Nurs. 2019 Mar/Apr;38(2):90-95. doi: 10.1097/DCC.0000000000000346. PMID: 30702478.

CONSENT FORM

I,

Mr. /Mrs. ---------------------------------------------------------------,

Father’s/Husband’s name --------------------------------------------------,

Address---------------------------------------------------------------------------------------------,

               IAm aware of the research work to be done by Dr Arun Muthukumar M K, Department of Anaesthesiology, Calcutta National College & Hospital, Kolkata. Dr Arun Muthukumar, has explained to me in detail about the procedure to be undertaken, which is also a part of my treatment. He has also informed me about the possible effects and side effects of this study. He has also promised that the observational data will be kept secret. I have been explained all these in my own language clearly.

               I, hereby declare that I am voluntarily giving my consent to participate in this. I also have the right to withdraw from the study anytime if I desire so.

Date:                                                                                             Signature of patient                                      

Signature Of investigator

Signature of witness

अनुमति पत्र

मै,

श्री / श्रीमती ..................................................,

पिता / माता के नाम .......................................................,

ठीकाना ..........................................................................................................................,

मेरे चिकित्सा से सम्बंध युक्त डाक्टर के अध्ययन के बारे मे पूरा जानकारि प्राप्त किया और स्वतंत्र दिमाग और खुद कि पुर्ण मर्जी से इसअध्ययन के हिस्सा बनने के लिये राज़ि हो रहे हय । उनहोने मुझे खुल के पुरा काम और उसके अन्चाहे बुरी परिणाम के बारे मे बताये है। उनहोने ये भि बताये हय के ये सभि जानकारी जो उन्होने इस अध्ययन मे सामिल करेंगे, वो सब छुपाके रखा जायेगा । मै ये भी खुलकर बता देता हूँ के मेरा ये अधिकार है के मै इस अध्यन से बिना कोइ कारण बताये किसी भी वक़्त मे निकाल सक्ता हूँ ।

मरीजका नाम और पूर्ण दस्तखत......................................................................

साक्शी का नाम और पूर्ण दस्तखत ......................................................................

चिकित्सक का नाम और पूर्ण दस्तखत ......................................................................

दिनांक ..............................................

स्थान.................................................

INVESTIGATOR’S UNDERTAKING

I hereby, declare that, I, Dr. Arun Muthukumar, Post Graduate Trainee (Session 2018-2021), currently SR in the department of Anaesthesiology, Calcutta National Medical College & Hospital, Kolkata, am doing the study entitled “COMPARISON OF EFFECTS OF DEXMEDETOMIDINE AND MIDAZOLAM IN FRAGMENTED SLEEP RELATED GLYCEMIC VARIABILITY IN POST-OPERATIVE INTENSIVE CARE PATIENTS – A SINGLE BLINDED PLACEBO CONTROLLED PROSPECTIVE RANDOMIZED STUDY”. I shall be liable to bring to notice of the Ethics Committee regarding this study including any adverse outcome. The protocol will be in parity with the present standards maintained in this hospital. The investigations and treatment will be done in Govt. hospital setup.

                                                                                                       Dr. Arun Muthukumar,

                                                                                         Senior resident MD Anaesthesiology,

                                                                                                    Department of Anaesthesia

                                                                                                                        CNMCH, Kolkata

PATIENT INFORMATION BROCHURE

However with any of the above study procedure, complications e.g. sudden haemodynamic changes such as hypotension, bradycardia, hypertension, visual side effects, nausea and vomiting etc. can occur any time during the study period. Experienced Intensivists will be present in the SICU, MICU, HDU to deal with such cases. In any case, patient may deny getting involved in this study at any time. The investigator may exclude any patient from this study without his / her consent. 

Signature of participant

Signature of Study Investigator

PATIENT RECORD FORM

PATIENT DETAILS:

               Name-                                                          Age-                 Sex-

                REG. no-                                                      DOA:

                Body weight (Kg) -                                     Height (Metre)-                BMI

 EXAMINATION-

➢     HISTORY-

➢     DIAGNOSIS –

➢     SURGERY PERFORMED:

➢     TYPE OF ANAESTHESIA USED:

➢     GENERAL PHYSICAL EXAMINATION-

➢     SYSTEMIC EXAMINATION-

➢     INVESTIGATIONS-

➢     BASELINE FBS, PPBS -

RELEVANT PARAMETERS:         

GROUP TO WHICH THE PATIENT BELONGS:

a)     Group M:                               b) Group D:                                       c) Group P:

RASS SCALE :

1)     CBC        

                                          Day 1                Day 4                      Day 7                Day 10       

Hg:              

TlC:                   

DLC

Platelets:      

2)     Blood sugar examination:

                          Day 1              Day 3                Day 5             Day 7                 Day 9              Day 11    

Fasting:

Post prandial:

3)     Coagulation profile:

PT:

APTT:

INR:

4)     Liver Function Tests:

                                                  Day 1                        Day 5                        Day 10                        

  Total bilirubin:                       

            Direct:                                    

            Indirect:

  Total protein:

            Albumin:  

            A/G ratio:

  Total cholesterol:

            LDL:                

            HDL:

            VLDL:

5)     Renal function tests:

6)     Urine R/E:

7)     STUDY VARIABLES: