EVALUATION OF EFFICACY OF INTRAVENOUS

DEXMEDETOMIDINE IN POST OPERATIVE CARE OF CARDIAC

SURGERY PATIENTS- A PROSPECTIVE STUDY.

BY

MAJ (Dr.) SHISHIR KUMAR

SYNOPSIS FOR REGISTRATION OF SUBJECT FOR DISSERTATION

TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

IN PARTIAL FULFILLMENT OF REGULATIONS FOR THE

AWARD OF

DOCTOR OF MEDICINE

IN

ANAESTHESIOLOGY

DEPARTMENT OF ANAESTHESIOLOGY

COMMAND HOSPITAL (AIR FORCE), BANGALORE – 560 007

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE, KARNATAKA

RAJIV GANDHI UNIVERSITY OF HEALTH

SCIENCES

SYNOPSIS

DISSERTATION TOPIC

EVALUATION OF EFFICACY OF INTRAVENOUS

DEXMEDETOMIDINE IN POST OPERATIVE CARE OF CARDIAC

SURGERY PATIENTS- A PROSPECTIVE STUDY.

By

MAJ (Dr.) SHISHIR KUMAR

PG student (Anaesthesiology)

Command Hospital (Air Force),

Bangalore.

Course

2013-2016

Rajiv Gandhi University of Health Sciences, Bangalore, Karnataka.

Annexure-A

1.Name of candidate :Maj (Dr.) Shishir Kumar

2. Name of Institution :Command Hospital (Air Force), Bangalore

3. Course of study and subject :M.D. (Anaesthesiology)

4. Date of admission :Jul 2013

5. Title Of Topic :Evaluation Of Efficacy Of Intravenous Dexmedetomidine In Post-Operative Care Of Cardiac Surgery Patients- A Prospective Study.

6. Brief resume of intended work Need for the study : APPENDIX ‘A’ Objective of study : APPENDIX ‘B’ Review of literature : APPENDIX ‘C’

7. Material and Methods : APPENDIX 'D' Source of data : APPENDIX ‘D’ Method of collection of data : APPENDIX ‘D’ 8. Does the study require any investigation and interventions to be conducted on patients or other animals? : YES/NO Has ethical clearance been obtained from your institution? : YES/NO

9 . Patient Performa : APPENDIX ‘E’ 10. Statistical Analysis : APPENDIX ’F’11. List Of References : APPENDIX ‘G’12. Patient Consent Form : APPENDIX ‘H’13. Study Information Sheet : APPENDIX ‘I’

14. Signature Of Candidate

15. Remarks of guide An interesting study which will highlight the efficacy of intra-venous Dexmedetomidine in cardiac surgery patients.

16. Name and designations

Guide Gp Capt (Dr.) Sachin ShoucheSenior Advisor & Cardiac AnaesthesiologistDept of Anaesthesiology

& Critical CareCommand Hospital (Air Force)

Bangalore Signature

17. Head of the Department Col (Dr.) K Prabhakaran Senior Advisor & Head of Dept of Anaesthesiology & Critical Care Command Hospital (Air Force) Bangalore

Signature

18. Remarks of the chairman and principal

Signature

Appendix ‘A’ Need for the study

Approximately 7 million invasive cardiovascular procedures are performed

worldwide each year.1 The major complication rates for valve and coronary artery

bypass graft (CABG) procedures are as high as 30.1% in Society of Thoracic

Surgeons (STS) reports.2 Postoperative delirium, infection, acute renal failure, and

major adverse cardio cerebral events (MACEs), which include permanent or

transient stroke, coma, perioperative myocardial infarction (MI), heart block, and

cardiac arrest, represent major postoperative complications.3–5 These complications

translate into increased mortality and prolonged hospital stays with increased

expenditure. The reasons for these adverse events are multifactorial, but a major

contributing factor is the surgical stress response that results in increasing plasma

levels of epinephrine and norepinephrine with consequent myocardial oxygen

supply demand imbalance and myocardial ischemia.6 More than 50% of all

perioperative complications are related to adverse cardiovascular events.7

The α-2 receptor agonists (clonidine, Dexmedetomidine) currently used in clinical

practice have many desirable effects, including analgesia, anxiolysis, inhibition of

central sympathetic outflow, and reduction of systemic norepinephrine release, that

improve hemodynamic stability, positively affect myocardial oxygen supply and

demand, and may provide myocardial protection.8,9. Dexmedetomidine is a highly

selective, shorter-acting intravenous α-2 agonist with an α-2 to alpha-1 selectivity

ratio of 1600:1.10 At our institution, Dexmedetomidine is used for transition of

cardiac surgical patients from the operating room to the intensive care unit (ICU)

and to provide sedation before extubation. Studies evaluating the hemodynamic

stabilizing and sympatholytic effects have shown that α-2 agonists can potentially

reduce postoperative cardiovascular complications. These include studies of

clonidine in cardiac surgery patients and dexmedetomidine in vascular and

noncardiac surgery patients.11-14 Multiple studies have reported that

dexmedetomidine has a protective effect on specific organs, including the heart,

brain, kidney, and lungs.15-19 In addition, dexmedetomidine has been shown to have

anti-inflammatory properties, decreasing mortality and attenuating plasma cytokine

concentrations in laboratory animals exposed to endotoxin in a dose-dependent

fashion.20 Therefore, this study will examine the potential impact of

dexmedetomidine on other major end points such as hemodynamic stability ,

arousability, congestive heart failure, myocardial ischemia, arrhythmia, stroke,

delirium, infection, and acute renal failure during the postoperative period for

patients undergoing cardiac surgery.

Appendix 'B'

Objectives of study

The objectives of the study are

(i) Primary outcome measures

aa) Hemodynamic stability, mortality and postoperative major adverse

cardio cerebral events (stroke, coma, perioperative myocardial infarction,

heart block, or cardiac arrest).

ii) Secondary outcome measures

aa) To concurrently calculate incidence of renal failure, sepsis, delirium,

postoperative ventilation hours, length of hospital stay, and 30-day

readmission.

Appendix ‘C

Review of literature

Cardiac surgery is associated with a high risk of cardiovascular and

other complications that translate into increased mortality and

healthcare costs. The major complication rates for valve and coronary

artery bypass graft (CABG) procedures are as high as 30.1% in

Society of Thoracic Surgeons (STS) reports.2

Dexmedetomidine is a highly selective, shorter-acting intravenous α-2

agonist with an α-2 to alpha-1 selectivity ratio of 1600:1.10 It is

currently used in clinical practice and has many desirable effects,

including analgesia, anxiolysis, inhibition of central sympathetic

outflow, and reduction of systemic norepinephrine release, that

improve hemodynamic stability, positively affect myocardial oxygen

supply and demand, and may provide myocardial protection.9,10.

Multiple studies have reported that dexmedetomidine has a protective

effect on specific organs, including the heart, brain, kidney, and

lungs.15-19

This study is designed to determine whether the post-operative use of

dexmedetomidine could reduce the incidence of complications and

mortality after cardiac surgery.

Appendix ‘D’

Materials and Methods

The project is a prospective study which will run for Two years. All patients undergoing cardiac surgeries will be selected and admitted to ICU will be monitored

a. Inclusion Criteria i) CABG or valve surgery

ii) CABG or valve surgery combined with other procedures.

b. Exclusion criteria:

i) Patients undergoing emergency surgery

ii) Off-pump surgery

iii) Surgery requiring deep hypothermic circulatory arrest

iv) Surgery involving the thoracic aorta

For these surgical patients, after standard monitoring, general anesthesia will be administered with Midazolam as pre medication, induction with Fentanyl (2 µg/kg) along with Thiopentone/Etomidate, skeletal muscle relaxation with Rocuronium and maintained with oxygen and sevoflurane according to the patient’s hemodynamic responses. Ventilation will be controlled to an end-tidal CO2 of 35 to 45 mm Hg by adjustment of tidal volume and respiratory rate. Monitoring in form of invasive intra-arterial BP, Pulmonary arterial occlusive pressure (only in CABG patients), CVP (all valve surgeries), transesophageal echocardiography, cardiac output monitoring by Flowtrac will be used as indicated in valve repair surgeries and patients with poor LV function respectively.

Post-operative Dexmedetomidine use is defined as an intravenous infusion (0.24 to 0.5 μg·kg−1·h−1) initiated without loading dose after cardio- pulmonary bypass before sternal closure titrated to conscious sedation and continued for <24 hours postoperatively till 15 minutes post-extubation in the ICU. The infusion rate of Dexmedetomidine will be adjusted according to the manufacturer’s package insert and in response to the patients’ hemodynamic changes in response to stimulation.

Appendix ‘E’

Patient Proforma

Pt Name:…………………………..Age/Sex……………….Wt……….....................Sr. No……

Diagnosis……………………………………………………………………………………………

ASA …………………………………………………………………………………………….…

MONITORS:

TIME

(hhmm)

TEMP

(0F)

PULSE

(/min)

RR

(/min)

IBP

(mm

Hg)

PAOP

(mm

Hg)

SPO2

(%)

CVP

(cm H2O)

DEXEMEDOTI

MIDINE

DOSE (mcg/kg/h)

VENTIATOR SETTINGS:

TIME

(HHMM)

MODE FiO2 (%) RATE

(/min)

P SUPPORT/CPAP

(cm of H2O)

VTE (ml)

EXTUBATED AT _______________________________

DEXEMEDOTIMIDINE STOPPED AT ________________________________

EFFECT ON POST-OP COMPLICATIONS AND MORTALITY:

COMPLICATIONS YES NO

PERI-OP MI

CARDIAC ARREST REQUIRING

PHARMACOLOGICAL INTERVENTION

HEART BLOCK

SIGNIFICANT HYPOTENSION REQUIRING

PHARMACOLOGICAL INTERVENTION

SIGNIFICANT BRADYCARDIA REQUIRING

PHARMACOLOGICAL INTERVENTION

RESPIRATORY DEPRESSION REQUIRING

VENTILATORY SUPPORT (INVASIVE/ NON

INVASIVE)

STROKE

COMA

DELIRIUM

SEPSIS

POST-OP RF

POST-OP DIALYSIS

30 DAY RE-ADM

IN HOSP MORTALITY

MORTALITY WITHIN 30 DAYS

Appendix ‘F’

Statistical analysis

Statistical analysis will be done using student–t test, Chi-square test.

Statistical significance is assumed for P<0.05.

Appendix ‘G’

References

1. Patel MR, Jneid H, Derdeyn CP, Klein LW, Levine GN, Lookstein RA,

White CJ, Yeghiazarians Y, Rosenfield K; American Heart Association

Diagnostic and Interventional Cardiac Catheterization Committee of the

Council on Clinical Cardiology, Council on Cardiovascular Radiology and

Intervention, Council on Peripheral Vascular Disease, Council on

Cardiovascular Surgery and Anesthesia, and Stroke Council. Arteriotomy

closure devices for cardiovascular procedures: a scientific statement from

the American Heart Association. Circulation. 2010;122:1882–1893.

2. Shahian DM, O’Brien SM, Filardo G, Ferraris VA, Haan CK, Rich JB,

Normand SL, DeLong ER, Shewan CM, Dokholyan RS, Peterson ED,

Edwards FH, Anderson RP; Society of Thoracic Surgeons Quality

Measurement Task Force. The Society of Thoracic Surgeons 2008 cardiac

surgery risk models, part 3: valve plus coronary artery bypass grafting

surgery. Ann Thorac Surg. 2009;88(suppl):S43–S62.

3. Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo

IM. Association of perioperative myocardial ischemia with cardiac

morbidity and mortality in men undergoing noncardiac surgery: the Study of

Perioperative Ischemia Research Group. N Engl J Med. 1990;323:1781–

1788.

4. Mangano DT. Perioperative cardiac morbidity. Anesthesiology.

1990;72:153–184.

5. Cao L, Young N, Liu H, Silvestry S, Sun W, Zhao N, Diehl J, Sun J.

Preoperative aspirin use and outcomes in cardiac surgery patients. Ann Surg.

2012;255:399–404.

6. Halter JB, Pflug AE, Porte D Jr. Mechanism of plasma catecholamine

increases during surgical stress in man. J Clin Endocrinol Metab. 1977;45:936–

944.

7. Dawood MM, Gutpa DK, Southern J, Walia A, Atkinson JB, Eagle KA.

Pathology of fatal perioperative myocardial infarction: implications regarding

pathophysiology and prevention. Int J Cardiol. 1996;57:37–44.

8. Muzi M, Goff DR, Kampine JP, Roerig DL, Ebert TJ. Clonidine reduces

sympathetic activity but maintains baroreflex responses in normotensive humans.

Anesthesiology. 1992;77:864–871.

9. Ellis JE, Drijvers G, Pedlow S, Laff SP, Sorrentino MJ, Foss JF, Shah M,

Busse JR, Mantha S, McKinsey JF. Premedication with oral and transder- mal

clonidine provides safe and efficacious postoperative sympatholysis. Anesth

Analg. 1994;79:1133–1140.

10. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor

agonists: their pharmacology and therapeutic role. Anaesthesia. 1999;54:146–165.

11. Nishina K, Mikawa K, Uesugi T, Obara H, Maekawa M, Kamae I, Nishi N.

Efficacy of clonidine for prevention of perioperative myocardial ischemia: a

critical appraisal and meta-analysis of the literature. Anesthesiology. 2002;96:323–

329.

12. Wijeysundera DN, Naik JS, Beattie WS. Alpha-2 adrenergic agonists to

prevent perioperative cardiovascular complications: a meta-analysis. Am J Med.

2003;114:742–752.

13. Biccard BM, Goga S, de Beurs J. Dexmedetomidine and cardiac protec-

tion for non-cardiac surgery: a meta-analysis of randomised controlled tri- als.

Anaesthesia. 2008;63:4–14.

14. Yeh YC, Sun WZ, Ko WJ, Chan WS, Fan SZ, Tsai JC, Lin TY.

Dexmedetomidine prevents alterations of intestinal microcirculation that are

induced by surgical stress and pain in a novel rat model. Anesth Analg.

2012;115:46–53.

15. Wijeysundera DN, Bender JS, Beattie WS. Alpha-2 adrenergic agonists for

the prevention of cardiac complications among patients undergoing surgery

[review]. Cochrane Database Syst Rev. 2009; 7:CD004126.

16. Yang CL, Chen CH, Tsai PS, Wang TY, Huang CJ. Protective effects of

dexmedetomidine-ketamine combination against ventilator-induced lung injury in

endotoxemia rats. J Surg Res. 2011;167:e273–e281.

17. Gu J, Sun P, Zhao H, Watts HR, Sanders RD, Terrando N, Xia P, Maze M,

Ma D. Dexmedetomidine provides renoprotection against ischemia-reper- fusion

injury in mice. Crit Care. 2011;15:R153.

18. Sanders RD, Xu J, Shu Y, Januszewski A, Halder S, Fidalgo A, Sun P,

Hossain M, Ma D, Maze M. Dexmedetomidine attenuates isoflurane- induced

neurocognitive impairment in neonatal rats. Anesthesiology. 2009;110:1077–1085.

19. Okada H, Kurita T, Mochizuki T, Morita K, Sato S. The cardioprotec- tive

effect of dexmedetomidine on global ischaemia in isolated rat hearts.

Resuscitation. 2007;74:538–545.

20. Taniguchi T, Kurita A, Kobayashi K, Yamamoto K, Inaba H. Dose- and

time-related effects of dexmedetomidine on mortality and in- flammatory

responses to endotoxin-induced shock in rats. J Anesth. 2008;22:221–228.

Appendix ‘H’

COMMAND HOSPITAL AIR FORCE, BANGALORE 560007CONSENT FORM

Patient’s name……………………Age…….Rank………………….. Unit………………………………Ward………………………………

I hereby authorize the performance of the following procedures upon myself/my relative (name of the patient ………………………………)- Administration of intravenous Dexmedotimidine in cardiac surgery.

The kind of procedure to be performed has been fully explained to me and all my questions and doubts about the procedure have been cleared to my satisfaction. All the risks involved have been explained to me and I understand those risks and I accept them.

I understand that the procedure and the medication have their own advantages and disadvantages and each is associated with its own share of risks. I understand that all due care will be taken during the above said procedure.

I understand that though best efforts will be put into the present condition no guarantee of the outcome can be given.

I agree to cooperate fully with my doctor and to follow the instructions to best of my ability.

This consent to be of my own free act of will

Signature of Witness Signature of patient/NOK

Appendix ‘I’

Study Information Sheet for Patients/NOK

Title: Evaluation Of Efficacy Of Intravenous Dexmedetomidine In Post-

Operative Care Of Cardiac Surgery Patients- A Prospective Study.

Investigator: Maj Shishir Kumar

Dear Sir/Madam

You/your relation are suffering from an illness which requires invasive

surgery and further medical management for cardiac hemodynamic stability.

The method proposed in this study is administration of intravenous

dexmedetomidine for conscious sedation and management until extubation.

Multiple studies have reported that dexmedetomidine has a protective effect

on specific organs, including the heart, brain, kidney, and lungs.

We seek your consent to participate in this study.

Alternative to participation:

The patient is free not to participate in the study. If the patient chooses not to

participate in the study he will not be administered dexmedetomidine.

Confidentiality

All information that will be provided during the study will be kept

confidential.

Contacts

If you have any further questions, any time during the course of the study

you can contact the following

Maj Shishir Kumar

Resident

Dept. of Anaesthesiology and Critical Care

Command Hospital Air force

Bangalore 560007

Gp Capt Sachin Shouche

Senior Advisor & Cardiac Anaesthetist

Dept. of Anaesthesiology and Critical Care

Command Hospital Air force

Bangalore 560007

CERTIFICATE FROM THE HEAD OF THE INSTITUTION

Permission is hereby accorded to the student Maj (Dr.) Shishir Kumar, to

undergo MD (Anaesthesiology) course being conducted at Command Hospital (Air

Force) Bangalore affiliated to the Rajiv Gandhi University of Health Sciences

commencing from Jul 2013 under the guidance of Gp Capt (Dr.) Sachin Shouche

(Senior Advisor & Cardiac Anaesthesiologist), Dept of Anaesthesiology,

Command Hospital (Air Force) Bangalore.

Date: (R Bhalwar)

Air Vice Marshal

Commandant and Principal

Command Hospital, Air Force

Bangalore – 560007

CERTIFICATE FROM ETHICAL COMMITTEE

1. The committee has examined the scope including the need, objectives, methods

and human /animal interventions and the follow-up study to be carried out by Maj

(Dr.) Shishir Kumar, MD student (Anesthesiology) under guidance of Gp Capt

Sachin Shouche, the title of which is Evaluation Of Efficacy Of Intravenous

Dexmedetomidine In Post-Operative Care Of Cardiac Surgery Patients- A

Prospective Study.

2. The committee has no objections for undertaking this study at Command

Hospital (Air Force) Bangalore.

(MS Prakash) (SC Dash) (SK Jha) (H Sahni)Brig Col Col Gp Capt Prof and HOD Prof and HOD OIC OICDept of medicine Dept of Surgery PG Cell AFMRCMember Member Member Member Secretary

(S Kaistha) (Shalini chaudhary) (Dr.V.Sinha) (Mrs.Vasanta kishore) Wg Cdr Sqn Ldr Scientist Counsellor Rep of AFWWA OIC, Legal Cell Physiologist E-Support Member Member Member Member

(MK Bedi) Air Cmde AOC, MTC Chairman Ethical Committee Command Hospital (Air Force) Bangalore- 560007

CERTIFICATE OF ACCEPTANCE BY THE GUIDE

1. I, Gp Capt Sachin Shouche, hereby accept Maj Shishir Kumar as a

candidate of MD (Anesthesiology) course. The title of his dissertation is as

follows:-

“ Evaluation Of Efficacy Of Intravenous Dexmedetomidine In Post-

Operative Care Of Cardiac Surgery Patients- A Prospective Study.”

2. He will be under my guidance during the period of his study and thesis

work.

Date: Gp Capt (Dr.) Sachin Shouche

Senior Advisor & Cardiac Anesthesiologist

Dept of Anesthesiology &

Critical Care

Command Hospital Air Force

Bangalore 560007