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A PROSPECTIVE COMPARATIVE STUDY BETWEEN ORAL CLONIDINE AND PLACEBO IN ATTENUATING HEMODYNAMIC CHANGES DUE TO PNEUMOPERITONIUM AND HYPERCARBIA IN

LAPAROSCOPIC SURGERIES

Dissertation submitted to

THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY In partial fulfillment of the regulations for

The award of the degree of ANAESTHESIOLOGY

M.D. BRANCH – X

Registration Number 201720201

THANJAVUR MEDICAL COLLEGE, THANJAVUR - 613 004.

THE TAMILNADU DR.MGR MEDICAL UNIVERSITY CHENNAI - 600 032.

MAY 2020

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CERTIFICATE

This is to certify that the dissertation entitled “A PROSPECTIVE COMPARATIVE STUDY BETWEEN ORAL CLONIDINE AND PLACEBO IN LAPAROSCOPIC SURGERY TO ATTENUATE THE HEMODYNAMIC CHANGES DUE TO PNEUMOPERITONIUM AND HYPERCARBIA” is a bonafide work of Dr. DHAYANITHY A.G in partial fulfilment of the requirements for M.D branch –X (Anaesthesiology) Examination of the Tamil Nadu Dr. M.G.R medical University to be held in May 2020.The period of study was from August 2017 to October 2019.

Prof. Dr. SHANTHI PAULRAJ M.D., Prof. Dr. KUMUDHA LINGARAJ M.D.,D.A.

Head Of The Department, Dean,

Department Of Anaesthesiology, Thanjavur Medical College, Thanjavur Medical College, Thanjavur – 613004.

Thanjavur – 613004.

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CERTIFICATE – II

This is to certify that this dissertation work titled “A PROSPECTIVE COMPARATIVE STUDY BETWEEN ORAL CLONIDINE AND PLACEBO IN LAPAROSCOPIC SURGERY TO ATTENUATE THE HEMODYNAMIC CHANGES DUE TO PNEUMOPERITONIUM AND HYPERCARBIA” of the candidate Dr. DHAYANITHY A.G with registration Number 201720201 for the award of M.D., in the branch of ANAESTHESIOLOGY X personally verified the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows seven percentage of plagiarism in the dissertation.

Guide & Supervisor with Seal

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DECLARATION

I, Dr. DHAYANITHY A.G solemnly declare that dissertation titled “A PROSPECTIVE COMPARATIVE STUDY BETWEEN ORAL CLONIDINE AND PLACEBO IN LAPAROSCOPIC SURGERY TO ATTENUATE THE HEMODYNAMIC CHANGES DUE TO PNEUMOPERITONIUM AND HYPERCARBIA” is a bonafide work done by me at Thanjavur Medical College, Thanjavur during August 2017 to October 2019 under the guidance and supervision of Prof Dr. SHANTHI PAULRAJ M.D., Professor, Department of Anaesthesiology, Thanjavur Medical College and Hospital, Thanjavur. This dissertation is submitted to Tamilnadu Dr. M.G.R Medical University towards partial fulfilment of requirement for the award of M.D Degree (Branch -X) in Anaesthesiology.

Place: Thanjavur

Date: Dr.DHAYANITHY A.G

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ACKNOWLEDGEMENT

I gratefully acknowledge and express my sincere thanks to Prof.Dr. KUMUDHA LINGARAJ MD, DA., Dean, Thanjavur Medical College and Hospital, Thanjavur for allowing me to do this dissertation and utilizing the institutional facilities.

I am extremely thankful to Prof. Dr. SHANTHI PAULRAJ M.D., Professor and Head of Department of Anaesthesiology for her kind hearted guidance, help and words of encouragement throughout the study.

I express my gratitude to my Co-Guide, Assistant Professor Dr.S.LEO M.D., for his scholarly guidance, constant encouragement, valuable suggestions and time he has rendered to do this work effectively.I would also like to extend my warmest gratitude to all my Assistant Professors for their constant support.

I express my gratitude to the faculty of Department of Surgery for their co-operation and support in conducting this study.I would like to thank all my colleagues and friends who have been a constant source of encouragement to me. Special thanks to all the volunteers who whole heartedly co-operated and participated in this study.

Last but not the least, I would like to express my most sincere gratitude to my parents for their help and constant support for this thesis.

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TABLE OF CONTENTS

S.NO CONTENTS PAGE NO.

1 INTRODUCTION 1

2 AIM AND OBJECTIVE 5

3 PHARMACOLOGY OF CLONIDINE 6 4 PHYSIOLOGICAL CHANGES DURING

LAPAROSCOPIC SURGERIES 15

5 REVIEW OF LITERATURE 28

6 MATERIALS AND METHODS 42

7 RESULTS AND OBSERVATION 46

8 DISCUSSION 66

9 SUMMARY 78

10 CONCLUSION 81

11 BIBLIOGRAPHY 12 ANNEXURES

ABBREVIATIONS PROFORMA CONSENT FORM MASTER CHART

KEY TO MASTER CHART

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INTRODUCTION

“The patient is the centre of the medical universe around which all our works revolve and towards which all our efforts trend”.

J.B.Murphy, 1857–1916, Professor of Surgery, Northwestern University, Chicago, IL, USA.

The term ―Laparoscopy is a Greek word meaning, to look into the flanks achieved through the abdominal wall after creation of pneumoperitoneum.4 The Laparoscopic surgery also called as minimally invasive surgery (MIS) is a modern surgical technique in which abdominal surgeries were performed through small (usually 0.5-1.5cm) as compared to larger incisions needed in traditional surgical procedures. Laproscopic procedures have several advantages which includes less tissue trauma, reduced post-operative pain, rapid return to normal activities, reduced hospital stay, cost effectiveness.9

In the last two decades, laparoscopic surgery has got tremendous popularity. The magnitude of laparoscopic technique involves not only in abdominal surgeries but also extended to thoracic, thyroid, urological and gynaecological procedures because of its simplicity and attraction. Laparoscopic surgery can also be extra-peritoneal, can be gasless with abdominal wall retraction and more recently it may be hand assisted. Although laparoscopic surgeries have numerous benefits, it has its own short comings because of increased intra- abdominal pressure created by carbon dioxide insufflation. Even though various

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combination of anaesthetic techniques are trailed all-over the world, controlled ventilation general anaesthesia with endotracheal tube placement is the most preferred anaesthetic technique for upper abdominal laparoscopic surgery. The haemodynamic changes associated with laparoscopic procedure and general anaesthesia are quite detrimental and bit challenging for anaesthesiologist.

PNEUMOPERITONEUM

The hallmark of laparoscopy is Pneumoperitoneum (the peritoneal cavity is insufflated with CO2 gas). This creates a working space between the anterior abdominal wall and the viscera allowing endoscopic access to the peritoneal cavity for the safe manipulation of instruments and organs.19 CO2 is the insufflation gas of choice and can be used safely as it is non-combustible, relatively inert, high diffusion coefficient, highly soluble in blood, readily absorbed by the peritoneal membrane, permitting the use of electro coagulation.

Being a normal metabolic end product, CO2 is rapidly cleared by the lung and so the risk of embolism is reduced. Other alternative gases like helium, argon and Xenon are inert but expensive and have a very low blood gas solubility.9

Carbon dioxide (CO2) insufflation induces a cardiovascular response characterized by abrupt tachycardia, hypertension and increased myocardial oxygen requirements. Haemodynamic changes associated with pneumoperitoneum were first recognized in 1947. Diamant et al reported 35% decrease in cardiac output in dog with a raised intra-abdominal pressure of 40 mm Hg.8,19

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Studies have been focused to evaluate and reduce the various effects of pneumoperitoneum especially on hemodynamic changes. Research fellows have tried beta blockers, alpha 2 agonists, magnesium sulphate, opioids, vasodilators, and gasless approach to negate the hemodynamic variations. There are no known directly mediated alpha-2 adrenoceptor effects on the myocardium. Alpha-2 adrenoceptor reduction in sympathetic tone and increase in parasympathetic tone results in a reduced heart rate, systemic metabolism, myocardial contractility and systemic vascular resistance thereby decreasing the myocardial oxygen requirements. Clonidine lowers the ‘set point’ around which arterial blood pressure is regulated. It also increases the gain of the baroreceptor system, resulting in lower heart rates for a given increase in blood pressure, and widens the range of heart rate responses to changes in blood pressure. These characteristics of alpha 2 agonist are more important and favourable to manage the hemodynamic changes.

Though clonidine is being used as a sedative and as an adjuvant to local anaesthetics in regional anaesthesia and as an anti-hypertensive, their use in laparoscopic surgeries have been studied by few authors only. Recently oral clonidine has been found to have properties which blunt the undesirable hemodynamic changes during laproscopy and intubation. Eventhough dexmedetomidine is a more selective alpha 2 adrenergic short acting drug; it is convenient to use clonidine as oral tablet.

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In view of overcoming the consequences happening during pneumoperitoneum, it was decided to conduct a study with oral clonidine to attenuate the stress response during laparoscopic procedure.

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AIM AND OBJECTIVE

To compare the efficacy of oral clonidine and placebo in attenuating hemodynamic stress response due to pneumoperitoneum and hypercarbia in patients undergoing laparoscopic surgery.

Hemodynamic changes to be monitored 1. Heart rate

2. Systolic Blood pressure 3. Diastolic Blood pressure 4. Mean Arterial pressure 5. Sedation

6. Adverse events

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PHARMACOLOGY OF CLONIDINE

Clonidine is an imidazoline derivative and an alpha 2 adrenergic agonist.

PHARMACODYNAMICS Central Nervous System Effects

Clonidine is a partial agonist with high affinity and high intrinsic activity at alpha 2 receptors, especially alpha 2A subtype in brainstem. Clonidine, is a selective partial agonist for alpha 2 adrenoreceptors, with a ratio of approximately 200:1 (alpha 2 to alpha 1).20 The major haemodynamic effects result from stimulation of alpha 2A receptors present mainly postjunctionally in medulla (vasomotor centre). This decreases discharges in sympathetic preganglionic fibers in the splanchnic nerve and in postganglionic fibers of cardiac nerves → fall in BP and bradycardia. Clonidine also stimulates parasympathetic outflow, which may contribute to the slowing of heart rate as a consequence of increased vagal tone and diminished sympathetic drive. In addition, some of the antihypertensive effects of clonidine may be mediated by activation of presynaptic alpha 2 receptors that suppress the release of NE, ATP, and NPY from postganglionic

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sympathetic nerves. Clonidine decreases the plasma concentration of NE and reduces its excretion in the urine.29

Figure1: Different Physiological Functions Of Alpha 2 Adrenoreceptor

Clonidine and its congeners, as imidazolines, also bind to imidazoline receptors, of which there are three subtypes (I1, I2, and I3) that are widely distributed in the body, including the CNS. Activation of the I1 receptor appears to reduce sympathetic outflow from the CNS. The current hypothesis is that I1 receptors are upstream from the hypotensive alpha 2 receptors in the CNS and work in tandem with them, such that activation of the I1 receptors results in catecholamine release onto the alpha 2 receptors, thereby reducing sympathetic outflow and reducing blood pressure.29

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The use of clonidine as an antihypertensive has been limited by its sedative effects, but offers advantages in anesthetic practice. When clonidine was given in a sufficient dose to produce sleep, the EEG showed an increase in stage 1 and 2 sleep and decrease in rapid eye movement sleep. Alpha-2 adrenoceptor agonists and benzodiazepines produce comparable anxiolysis. Clonidine at high doses can be anxiogenic owing to alpha-1. Clonidine decreases postoperative oxygen consumption and the adrenergic stress response.

Cardiovascular SystemEffects

There are both alpha-1 and alpha-2 post-junctional receptors in the arterial and venous vasculature where they both mediate vasoconstriction. The alpha-1 and alpha-2 adrenoceptors differ in their location and their utilization of calcium.

In the arterial vasculature, the alpha-1 adrenoceptors are junctional and the alpha- 2 adrenoceptors are extra-junctional, while the reverse is true of the venous vasculature. Alpha-1 adrenoceptor stimulation produces vasoconstriction by utilizing intracellular calcium while the alpha-2-adrenoceptor mediated vasoconstriction uses extracellular calcium. This makes the alpha-2 adrenoceptor agonist’s pressor response more sensitive to calcium antagonists. Clonidine lowers the blood pressure. It also elevates the gain of the baroreceptor system. It reduces the heart rates for a given increase in blood pressure, and broadens the range of heart rate responses to changes in blood pressure. There are no known directly mediated alpha-2 adrenoceptor effects on the myocardium. Alpha-2 adrenoceptor reduction in sympathetic tone and increase in parasympathetic tone results in a reduced heart rate, systemic metabolism, myocardial contractility and systemic

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vascular resistance thereby decreasing the myocardial oxygen requirements. This may be why clonidine has been successful in the treatment of angina pectoris.9

Rapid i.v. injection of clonidine raises BP transiently due to activation of peripheral postsynaptic vasoconstrictor alpha 2B receptors at the high concentrations so attained. Oral doses producing lower plasma clonidine levels cause only fall in BP, because clonidine has lower intrinsic activity on alpha 2B receptors which predominate in vascular smooth muscle. Probably for the same reason clonidine exhibits the therapeutic window phenomenon: optimum lowering of BP occurs between blood levels of 0.2–2.0 ng/ml. At higher concentrations fall in BP is less marked. On chronic administration of clonidine decrease in cardiac output contributes more to the fall in BP than decrease in T.P.R. Cardiovascular reflexes are affected little

Respiratory System Effects

Alpha-2 adrenoceptors have a minimal effect on ventilation. In humans, clonidine in doses up to 300 mcg seems to cause a small reduction in resting minute ventilation and an increase in expired carbon dioxide. The locus coeruleus is involved in arousal reactions; suppression of its activity by alpha-2 adrenoceptor agonists can result in a state similar to sleep with mild respiratory depression. There is no significant effect on hypercapnic or hypoxic ventilatory drive with alpha-2 adrenoceptor stimulation. The combination of alpha-2 adrenoceptor agonists with opioids does not lead to further ventilatory depression.9

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Renal System Effects

Activation of alpha- 1 receptors in the kidney results in a redistribution of blood from the cortical to medullary areas due to an increase in renal vascular resistance. Stimulation of alpha-2 adrenoceptors has a number of effects that promote diuresis and natriuresis. They decrease the secretion of vasopressin and antagonise its action on renal tubules. Alpha-2 adrenoceptors are also thought to inhibit the release of renin and increase the release of atrial natriuretic factor.9 Neuroendocrine System Effects

The alpha-2 adrenoceptor agonists have a number of neuroendocrine effects, mainly related to their inhibition of sympathetic outflow and the decrease in plasma levels of circulating catecholamines. Stimulation of alpha-2 adrenoceptors located on the beta cells of the islets of Langerhans can temporarily cause direct inhibition of insulin release; clinical hyperglycemia has not proved to be a problem. Alpha-2 receptor agonists also increase the release of growth hormone and inhibit adipose tissue lipolysis. Clonidine can inhibit the secretion of adrenocorticotropic hormone (ACTH) and cortisol during surgery.9

Effects on Platelets

Selective alpha-2 adrenoceptor agonists, as well as adrenaline, are known to stimulate platelet aggregation by stimulating alpha-2c receptors on platelets.

High concentrations of alpha-2 adrenoceptor agonists are required to cause platelet aggregation, as low concentrations of these drugs decrease plasma adrenaline concentration; the net effect may be a reduction in platelet aggregation.

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Alpha-2 receptor stimulation also results in the release of nitric oxide, a potent inhibitor of platelet aggregation. Clonidine does not promote platelet aggregation;

it also blocks adrenaline-induced platelet aggregation.9 Gastrointestinal System Effects

It has been postulated that gastric cholinergic prejunctional alpha-2 adrenoceptors inhibit gastric secretions during stress. Clonidine causes activation of alpha-2 adrenoceptors to inhibit water secretion and increases net absorption in the large bowel; and hence can be used to treat diarrhoea. Stimulation of alpha-2 adrenoceptors is known to reduce salivary secretions and may lead to a dry mouth.9

PHARMACOKINETICS

Clonidine is well absorbed after oral administration, with bioavailability about 100%. Peak concentration in plasma and the maximal hypotensive effect after an oral dose are observed after 1–3 hr. The elimination t1/2 is 6–24 h (mean about 12 h). About half of an administered dose can be recovered unchanged in the urine; the t1/2 of the drug may increase with renal failure. A transdermal delivery patch permits continuous administration of clonidine as an alternative to oral therapy. The drug is released at an approximately constant rate for a week;

3–4 days are required to reach steady-state concentrations in plasma. When the patch is removed, plasma concentrations remain stable for about 8 hr and then decline gradually over a period of several days; this decrease is associated with a rise in blood pressure.30

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USES

Clonidine was a popular antihypertensive in the late 1960s and 1970s, but frequent side effects, risk of withdrawal hypertension and development of tolerance have relegated it to a 3rd or 4th choice drug.30

1. Opioid withdrawal: Opioid and alpha 2 adrenergic systems converge on the same effectors in many systems; both activate the Gi regulatory protein.

Clonidine suppresses sympathetic overactivity of opioid withdrawal syndrome and reduces craving to some extent. Clonidine has also facilitated alcohol withdrawal and smoking cessation.

2. Clonidine has analgesic activity. It has been used to substitute morphine for intrathecal/epidural surgical and postoperative analgesia.

3. Clonidine attenuates vasomotor symptoms of menopausal syndrome.

4. Clonidine has been used to control loose motions due to diabetic neuropathy. It may be acting by alpha 2 receptor mediated enhancement of salt absorption in gut mucosa

5. Acute administration of clonidine has been used in the differential diagnosis of patients with hypertension and suspected pheochromocytoma.

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Clonidine also has apparent efficacy in the off-label treatment of a range of other disorders: Among the other off-label uses of clonidine are30

1. atrial fibrillation, 2. ADHD,

3. constitutional growth delay in children, 4. cyclosporine-associated nephrotoxicity, 5. Tourette syndrome,

6. hyperhidrosis, 7. mania, psychosis 8. post-herpetic neuralgia, 9. restless leg syndrome, 10.ulcerative colitis,

11.allergy-induced inflammatory reactions in patients with extrinsic asthma.

SIDE EFFECTS

Side effects with clonidine are relatively common.30

1. Sedation, mental depression, disturbed sleep; dryness of mouth, nose and eyes (secretion is decreased by central action), constipation (anti-secretory effect on the intestines).

2. Impotence, salt and water retention, bradycardia.

3. Postural hypotension occurs, but is mostly asymptomatic.

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4. Alarming rise in BP, in excess of pretreatment level, with tachycardia, restlessness, anxiety, sweating, headache, nausea and vomiting occur in some patients when doses of clonidine are missed for 1–2 days. The syndrome is very similar to that seen in pheochromocytoma: plasma catecholamine (CA) concentration is increased. This is due to Sudden removal of central sympathetic inhibition resulting in release of large quantities of stored CAs. And also Supersensitivity of peripheral adrenergic structures to CAs that develops due to chronic reduction of sympathetic tone during clonidine therapy.

A combination of α blocker with a β blocker, or a potent vasodilator (nitroprusside) or clonidine itself can be used to treat the syndrome.

These effects of clonidine frequently are related to dose, and their incidence may be lower with transdermal administration of clonidine. About 15%–20% of patients develop contact dermatitis when using the transdermal system. Withdrawal reactions follow abrupt discontinuation of long-term therapy with clonidine in some hypertensive patients.

DRUG INTERACTIONS

Tricyclic antidepressants and chlorpromazine abolish the antihypertensive action of clonidine, probably by blocking α receptors on which clonidine acts.30

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PHYSIOLOGICAL CHANGES DURING LAPAROSCOPIC SURGERIES Both mechanical and neuro-humoral factors contribute to these alterations in cardiovascular and respiratory physiology. The complex cardio-pulmonary changes occurring during laparoscopy are depends mostly on the interaction of patient’s pre-existing cardio-pulmonary status. Several anaesthetic techniques (ventilator technique and anaesthetic agents used) and surgical factors including intra-abdominal pressure, CO2 absorption, patient position and the duration of surgery along with neuro-humoral responses17 also influences these cardio- pulmonary changes. Patient’s discomfort associated with creation of pneumoperitoneum, different positions associated with the procedure and to minimize the risk of acid reflux aspiration19 ,general anaesthesia is considered always even though it by itself causes stress responses during laryngoscopy and intubation.

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FIGURE 2: EFFECTS OF CO2 ON PNEUMOPERITONEUM

CARDIOVASCULAR CHANGES

The increase in intra-abdominal pressure (IAP) produced by pneumoperitoneum, results in direct mechanical effects on blood flow. This is accompanied by the CO2 stimulated release of various vasoactive substances.

Those includes catecholamines, prostaglandins, vasopressin, angiotensin, cortisol, and adreno-corticotropin hormone (ACTH).17

Peritoneal carbon dioxide insufflation to an intraabdominal pressure of 14 mm Hg produces significant hemodynamic changes in healthy patients.8 It results in an increase in mean arterial pressure, decrease in cardiac output and increase in systemic vascular resistance which can lead to altered tissue perfusion. Carbon

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dioxide is readily absorbed from the peritoneal cavity into the circulation resulting in hypercarbia and acidosis. There are reports of life-threatening consequences due to hypercarbia, respiratory acidosis and cardiovascular collapse. Insufflation of CO2 increasing IAP higher than 10 mm hg induces significant alterations of hemodynamics which are characterized by decrease in cardiac output, increase in arterial pressures and elevation of systemic and pulmonary vascular resistances.

The decrease in cardiac output is proportional to IAP. Caval compression, pooling of blood, decrease in venous return and increase in venous resistance is observed by increased IAP. Decline in venous return parallels decrease in cardiac output reflected as decrease in LVEDV. Cardiac filling pressures also rise during peritoneal insufflations. Reflex increase in vagal tone result from sudden stretching of peritoneum results in bradycardia, cardiac arrhythmia and asystole.9

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FIGURE 3: EFFECTS OF ELEVATED INTRA-ABDOMINAL PRESSURE

PULMONARY CHANGES

Different patient positions required for laparoscopic surgery results in various patho-physiological changes. The head down position facilitates the development of atelectasis. Decrease in FRC, TLV, pulmonary compliance manifests in steep head down position which are more marked in elderly, obese and debilitated patients. PNO decreases thoracopulmonary compliance by 30- 50%. Reduction in FRC and development of atelectasis due to elevation of diaphragm and changes in ventilation and perfusion results from increased airway pressure.9

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FIGURE 4: PULMONARY CHANGES DURING LAPROSCOPY

GASTROINTESTINAL EFFECTS

Trochar insertion can damage viscera, particularly distended stomach, probably caused by manual ventilation during intubation. Therefore, nasogastric aspiration should always be done prior to trochar insertion. Increased incidence of nausea and vomiting has been associated with the laparoscopic surgery, so regular antiemetic drugs may be considered. Though increased IAP may be considered to increase the chances of regurgitation but it also increases the barrier pressure thus preventing chances of regurgitation.9

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EFFECTS ON OTHER SYSTEMS

Pneumoperitoneum, changes in patient position, reductions in cardiac output, and systemic CO2 absorption influence splanchnic, renal, and cerebral blood flow during minimal access procedures. Numerous regional circulatory changes also occur during laparoscopy including increased cerebral blood flow and intracranial pressure, decreased total hepatic blood flow, reduced bowel circulation resulting in decreased gastric intramucosal pH (suggesting reduced gut perfusion), reduction in renal blood flow and urine output (because of increase in renal vascular resistance, reduction in glomerular filtration gradient and decrease in cardiac output), and decreased femoral vein blood flow which may increase the risk of deep vein thrombosis. Carboperitoneum causes a hemodynamic stress response and decreases urine output because of an activated renin angiotensin- aldosterone system (RAAS) Massive elevation in IAP produces lactic acidosis, probably by severely lowering cardiac output and by impairing hepatic clearance of blood lactate9

Pneumoperitoneum beyond pressures of 18 mmHg may result in a compartment like syndrome and a fall in venous return to the heart. Absorption of CO2 into the third spaces causes oozing from surgical sites and blood loss.

Although these physiological changes are well tolerated by most of the healthy patients, they can have adverse consequences in elderly patients with multiple co-morbid conditions, the very young, the morbidly obese, pregnant women, the critically ill and the patients with limited cardiac reserve.

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PATIENT POSITIONING

Various patho-physiological changes occurring during laparoscopic surgeries were also due to different patient positioning. Patients are often placed in the Trendelenberg position for laparoscopic gynaecologic procedures while laparoscopic cholecystectomy usually change to steep reverse Trendelenberg, with left lateral tilt to facilitate retraction of the gallbladder fundus and to minimize the diaphragmatic dysfunction associated with the induced pneumoperitoneum.

Trendelenberg position is commonly requested during insertion of Verres needle and cannula. Patient tilt should be reduced as much as possible (should not exceed 15 to 20º) and must be slow and progressive to avoid sudden hemodynamic and respiratory changes. With Trendelenberg position and pneumoperitoneum, cardiac output fall by 60% and there are no changes in heart rate. Though preload is increased, MAP remains unchanged or decreases. Moderate fall in stroke volume occurs. Stroke index and cardiac index fall by 42%. Total peripheral resistance increases. These seemingly paradoxical responses may be explained by carotid and aortic baroreceptor-mediated reflexes. The reverse Trendelenberg position decreases preload, cardiac output. Venous congestion of head and neck may compromise cerebral perfusion and produce intra-cerebral and intraocular hypertension. Anaesthetic agents may blunt these effects. There is also an increase in left ventricular end-systolic wall stress and decreased left ventricular end- diastolic area but left ventricular ejection fraction was maintained during a study by trans-oesophageal echocardiography. In head up position for upper abdominal surgery, there is improved pulmonary function at expense of decreased cardiac

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function. Nerve compression is a potential complication during the head down position. Overextension of the arm must be avoided. Shoulder braces should be used with great caution and must not impinge on the brachial plexus. Lower limb neuropathies have been reported after laparoscopy. Prolonged lithotomy position, as required for some operative procedures, can result in lower extremity compartment syndrome.9

ANAESTHESIA AND LAPAROSCOPY

An optimal anesthetic technique should provide excellent intraoperative conditions while ensuring rapid recovery, low incidence of adverse effects, and early return to daily activities. Anaesthetic approaches to laparoscopic surgery include infiltration of local anaesthetic with an intravenous sedative, epidural or spinal anesthesia, or general anaesthesia. General anesthesia with muscle paralysis and tracheal intubation with positive pressure ventilation remains the preferred technique for most laparoscopic procedures for many reasons

1. Increased risk of regurgitation from increased intra-abdominal pressure during insufflation

2. The necessity for controlled ventilation to prevent hypercapnia 3. The relatively high peak inspiratory pressures required because

of the pneumoperitoneum

4. The need for neuromuscular blockade during surgery to allow lower insufflation pressures, provide better visualization, and prevent unexpected patient movement

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5. The placement of nasogastric tube and gastric decompression to minimize the risk of visceral perforation during trocar introduction and optimize visualization.

Ventilatory settings have to be adjusted according to respiratory and hemodynamic response of the patient. Large tidal volumes (12 to 15 mL/kg) prevent progressive atelectasis and hypoxemia and allows for more effective alveolar ventilation and CO2 elimination. However this may cause excessive increase in intrathoracic pressure and thus deleterious cardiovascular effects that will result in an increased alveolar dead space.9

MONITORING DURING LAPAROSCOPY

Routine intraoperative monitors include ECG, pulse oximetry, blood pressure, pulse rate, and EtCO2 (End Tidal carbon dioxide) are essential.

Anaesthetic gases concentration and patient’s temperature can be monitored depending upon the availability. EtCO2 is most commonly used as a non-invasive substitute for PaCO2 in evaluating the adequacy of ventilation during laparoscopic surgery. However, EtCO2 may differ considerably from PaCO2 because of ventilation-perfusion (V/Q) mismatching, and erroneous clinical decisions may be reached if the two values are assumed to be equal, to change proportionally, or even to change in the same direction. EtCO2 monitor is also useful for early detection of gas embolus. For hemodynamically unstable or compromised patient and patients with cardio-respiratory chronic diseases and obese patients, careful monitoring of cardiovascular and blood gases is indicated. Radial artery

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cannulation for continuous blood pressure recording and frequent ABG analysis should be considered in patients with preoperative cardiorespiratory disease and in situations where intra-operative hypoxemia, high airway pressures, or elevated EtCO2 are encountered. There is a need for a urinary bladder catheter and nasogastric tubes to decompress the viscera and thus avoid injury to intra- abdominal contents during trocar insertion.9

COMPLICATIONS OF LAPAROSCOPY PROCEDURE

Awareness of the potential complications associated with laparoscopic procedures should allow early detection and treatment, and improve patient care and safety. The complications associated with laparoscopy include those related to surgical instrumentation, creation of the pneumoperitoneum, and patient’s positioning.9

INTRAOPERATIVE COMPLICATIONS9 Complications from surgical instrumentation

1. Misplacement of verres needle 2. Uncontrolled haemorrhage Cardiovascular complications

1. Cardiac dysrhythmias 2. Myocardial dysfunction 3. Cardiac tamponade 4. Venous gas Embolism

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Pulmonary complications 1. Hypoxemia, Hypercarbia 2. Hypoventilation

3. Pneumothorax

4. Pneumo-mediastinum Subcutaneous emphysema 1. Significant hypercarbia 2. Respiratory Acidosis 3. Hypothermia

Postoperative Complications Impaired postoperative ventilation from residual anesthetics and/or neuromuscular blockade may result in significant hypercapnia. In patients with significant respiratory dysfunction and restricted CO2 clearance, positive pressure ventilation may be required in the postoperative period until the patient can eliminate the CO2 load with resumption of spontaneous respiration. Increased IAP during pneumoperitoneum has been reported to cause venous stasis that can increase the potential for deep vein thrombosis and pulmonary embolism.9

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METHODS TO STABILIZE HEMODYNAMIC CHANGES

The decline in cardiac output and venous return can be attenuated by volume infusion before pneumoperitoneum. However, an increase in MAP and SVR requires therapeutic intervention. Techniques like reduction in intra- abdominal pressure during pneumoperitoneum and gasless laparoscopy using abdominal elevators have been tried to counteract these detrimental effects of pneumoperitoneum. Pharmacological agents like β-blocker, opioids, increasing concentration of inhalational anaesthetic agents, Nitroglycerine, and alpha-2 adrenergic agonist have been used to minimize these hemodynamic derangements during laparoscopy with varied results.

The increase in SVR is associated with a marked release of vasopressin and catecholamines. Clonidine given before PNO reduces this release of catecholamines and provides intraoperative hemodynamic stability.

Thus, there is a need to modify the anaesthetic technique to allow these novel surgical procedures to be performed safely with minimal complications and rapid recovery. To counteract the influences of pneumoperitoneum on various systems, various modalities have been considered. These include17

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Non-pharmacological methods

1. Gasless technique (Abdominal wall lift method)

2. Helium and Argon have been tried to replace CO2 for creating pneumoperitoneum.

3. Low pressure insufflation.

4. gasless laparoscopic surgery.

Various pharmacological agents such as

1. beta blocker (esmolol, metoprolol and propranlol), 2. alpha2-agonist (clonidine, dexmetedomidine), 3. vasodilators (magnesium sulphate),

4. opioids (remifentanil),

5. vasodilating anaesthetic agents (isoflurane) or

6. direct vasodilating drugs (nitroglycerin or nicardipine) agents

have been used to suppress the haemodynamic changes associated with pneumoperitoneum.

Clonidine before PNP reduces catecholamine release and attenuates hemodynamic changes during laparoscopy. In another study it has been concluded that Clonidine inhibits the release of catecholamine and vasopressin and thus modulates the hemodynamic changes induced by pneumoperitoneum.

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REVIEW OF LITERATURE

Sung et al28 (2000) conducted a prospective, randomized, single-blind, comparative study in which one hundred and ten patients, scheduled for elective laparoscopic cholecystectomy, were recruited and randomly allotted to either of the placebo or clonidine group. Patients of the placebo group were premedicated with oral antacid (alugel hydroxide 300 mg), while those in the clonidine group were given oral clonidine 150 mcg, 60 to 90 min before the anticipated time of induction of anesthesia. Haemodynamic response and other parameters in 24hours were noted. Patients in the clonidine group showed greater hemodynamic stability perioperatively and the isoflurane requirement was reduced (30% less).

In a study conducted by uchida et al31 (2004), 60 adult patients (ASA physical status I) were randomly assigned to one of two groups- control and clonidine group. Control group patients were given famotidine 20 mg orally 90 min before the induction of anesthesia, whereas the clonidine group patients received clonidine 5mcg/kg and famotidine 20mg. The baseline measurements including mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), and plasma catecholamine concentration were recoreded during normocapnia (an end- tidal carbon dioxide partial pressure of 30–35 mmHg).

MAP, CI and HR responses to hypercapnia in the clonidine-propofol subgroup were significantly decreased compared with those in the other three subgroups. Plasma norepinephrine concentrations (but not epinephrine concentration) were significantly lower in clonidine-propofol patients. The

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cardiovascular effects of hypercapnia are suppressed in patients given clonidine prior to propofol anesthesia, perhaps due to the profound suppression of sympathetic nervous system activity. The hemodynamic response to hypercapnia depends on the level and extent of any sympathetic blockade. The interaction between the basal anesthetic agent and clonidine (given as a premedicant) can apparently modify the hemodynamic response to hypercapnia to a significant extent.

In a study conducted by Das M et al8 (2007), Sixty adult patients of ASA physical status I & II, scheduled for elective laparoscopic cholecystectomy were recruited for a prospective randomized, double-blinded comparative study. They were randomly allocated to one of the two groups to receive either oral clonidine 150 mcg (Group C) or ranitidine 150 mg (Group P), 90 minutes before induction of anaesthesia. Perioperative hemodynamic parameters were recorded at various time intervals. They concluded that premedication with 150 mcg oral clonidine, has been found to be relatively safe and effective method that provides stable haemodynamics and protection against stress response triggered by pneumoperitoneum in patients undergoing laparoscopic cholecystectomy.

Clonidine also affords an added advantage of reduction in postoperative complications such as nausea-vomiting and shivering.

In a study conducted by Passi et al21 (2009), fifty adult patients belonging to ASA physical status I or II, scheduled for laparoscopic Cholecystectomy were selected and randomly allocated to two groups A & B. Group A (clonidine)

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received Tab. clonidine 150mcg orally and Group B (Control) received Tab.

vitamin B complex orally as premedication 60-90 minutes before scheduled laparoscopy. Heart rate and mean blood pressure were recorded prior to intubation, 15 min after endotracheal intubation, at skin incision, 15 min and 30 min after creation of pneumoperitoneum and 15 min after release of pneumoperitoneum. Mean heart rate varied from 92 ± 8 to 96 ± 12 (Mean ± SD) in group A while in group B it varied from 94 ± 13 to 111 ± 17 (Mean ± SD).

Changes in mean blood pressure ranged between 88 ± 9 to 95 ± 9 (Mean ± SD) in the group A and between 97 ± 14 to 106 ± 5 (Mean ± SD). They have concluded that premedication with oral clonidine 150 mcg 60- 90 min before scheduled laparoscopic cholecystectomy provides stable hemodynamics and protection against stress response triggered by pneumoperitoneum.

Singh S et al26 (2011) studied the clinical efficacy of oral clonidine premedication in fifty patients who were scheduled for elective laparoscopic cholecystectomy under general anaesthesia. They were randomly allocated into

two groups of 25 each, to receive premedication with oral clonidine and vitamin C. Group I patients were received clonidine 150 mcg PO 90 min before

induction and Group II patients were given Vitamin C tablets 100 mg po 90min before induction. The two groups were compared with respect to haemodynamic parameters, isoflurane concentration, pain and sedation scores, and these parameters was recorded at prior to induction, 1 min after endotracheal intubation, 5 min after endotracheal intubation, at skin incision, start of pneumoperitoneum,

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15 and 30 min after institution of CO2 pneumoperitoneum and 15 min after release of pneumoperitoneum.

Heart rate was significantly low in clonidine premedicated patients compared to placebo group at 5mins after intubation, at skin incision, following start of pneumoperitoneum and 15 min after pneumoperitoneum (79.28 ± 9.50 to 85.84 ± 10.12). Mean arterial pressure was low in clonidine group at all time points except at 15 mins after the release of pneumoperitoneum (88.77 ± 7.99 to 102.41 ± 10.35). They have concluded that administration of oral clonidine 150 mcg as a pre-medicant in patients undergoing laparoscopic cholecystectomy results in improved perioperative haemodynamic stability, having an isoflurane sparing effect and a reduction in the intra-operative anaesthetic and post-operative analgesic requirements.

A randomized doubleblind study conducted by Chandrashekaraiah MM et al5 (2011) with sixty patients undergoing elective laparoscopic cholecystectomy were enrolled for the study and received either tab clonidine 150mcg [group C-30]

or placebo drug tab lorazepam 2mg [group L- 30] orally one hour before the induction. Heart rate, systolic blood pressure, diastolic pressure and mean arterial pressure were recorded at baseline, pre induction, 5 minutes after intubation, post pneumoperitoneum, 5 minutes, 10 minutes, 15 minutes, 30 minutes and 60 minutes. There was a decrease in HR, SBP, DBP and MAP can be seen from base line to pre-induction (p<0.001) in the study group C and they found that oral

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clonidine 150mcg can effectively counteract the cardiovascular changes induced by pneumoperitoneum.

Bhandari D et al3 (2012) conducted a study in which 100 adult ASA I and II patients scheduled for elective laparoscopic cholecystectomy were selected and randomly allocated to one of the two groups to receive either oral clonidine 150 micrograms (Group C) or ranitidine 150 mg (group B) 90 minutes prior to induction of anaesthesia. Systemic arterial pressure including the systolic, diastolic and mean arterial pressure, heart rate, SPO2, EtCO2 and electrocardiography (ECG) with ST segment analysis were recorded at the baseline prior to premedication, Prior to induction, three minutes after endotracheal intubation, before pneumoperitoneum, fifteen minutes after pneumoperitoneum, thirty minutes after pneumoperitoneum, ten minutes after release of CO2 and ten minutes after extubation. Mean heart rate varied from 76.8

± 10.99 to 111.14 ± 13.13 bpm in group B and in group C it varied from 77.04 ± 9.78 to 83.24 ± 8.36 bpm. Upon statistical comparison in two groups of patients, significant variation was seen in the blood pressure throughout the intra-operative period except for the baseline value where no significant variation was observed.

14 out of 50 patients (28%) required intra-operative NTG drip for control of hypertension in group B whereas no patient required NTG drip in group C. p value was 0.000 (p <0.05) and thus the difference was statistically significant.

Postoperatively there were increased number of patients in group C who were more sedated (OAS score 2 & 3 = 20), as compared to group B (OAS score 2 &

3= 8).

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They concluded that premedication with 150 micrograms of oral clonidine in ASA I and II patients has been found to be relatively safe and effective method to provide stable hemodynamics intraoperatively and as protection against stress response triggered by pneumoperitoneum in patients undergoing laparoscopic cholecystectomy. Oral clonidine premedication also helps in the reduction of postoperative complications such as pain, nausea- vomiting, and shivering.

Patel et al22 (2015) conducted a prospective randomized controlled study of 60 patients undergoing laparoscopic cholecystectomy. They were divided into two groups of which Group CL premedicated with tablet Clonidine 3 mcg/kg, 90 min before induction while Group C were not given any oral premedication. All hemodynamic parameters were observed intraoperatively and for two hrs postoperatively. In both the groups preoperative baseline parameters such as pulse rate, SBP, DBP, MAP, respiratory rate and SpO2 were comparable. Pulse rate in Group CL was low compared to baseline throughout intraoperatively (76.2 ± 7.015 bpm to 88.3 ± 5.4 bpm). Significant rise in SBP in Group C compare to Group CL was seen before induction, remained high intraoperatively and even after extubation (128.33 ± 6.59 mmHg to 159.6 ± 12.33 mmHg). While in in Group CL, SBP was decreased compared to baseline, no rise was seen after intubation, extubation or during pneumoperitoneum (110.8 ± 9.1 mmHg to 128.13

± 5.7 mmHg). DBP increased highly significantly in Group C before intubation and remained high intraoperatively till deflation of pneumoperitoneum (82.13 ±

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3.23 to 99.47 ± 9.0), while in Group CL, decrease in DBP in to that of baseline was seen.

They concluded that with clonidine 3mcg/kg there is no rise in pulse rate and BP throughout laparoscopic cholecystectomy at various stages. Patients remain haemodynamically stable throughout laparoscopic surgery with clonidine.

Clonidine also decreased the requirement of inhalation agent. No significant perioperative complications were found with the use of clonidine.

Singh R et al25 (2015) conducted a study in which 100 patients of ASA grade I–II, scheduled for elective laparoscopic cholecystectomy under general anaesthesia were randomly allocated to receive premedication with either oral clonidine 150 mcg (Group I, n = 50) or placebo (Group II, n = 50) 90 minutes prior to induction. Both groups were compared in aspects of haemodynamic parameters, pain and sedation scores and incidence of adverse effects.

Haemodynamic parameters i.e. pulse rate, systolic blood pressure, mean arterial pressure and diastolic blood pressure were significantly lower and stable in the Group I as compared to Group II. Significantly less number of patients in Group I required NTG infusion than in Group II. Anxiety level of the patients in the Group I was significantly lower as compared to the patients in the Group II.

The patients in the Group I had higher sedation score but they were easily arousable. They concluded that clonidine in dose of 150 mcg can be used effectively and safely in ASA class I & II patients to control the haemodynamic changes which occur during laparoscopic cholecystectomy.

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A similar study conducted by Aasim SA et al1 (2016) in which 60 ASA grade I and II patients of age between 20 to 60 years, scheduled for laparoscopic cholecystectomy surgeries were randomly allocated to receive premedication with either oral clonidine 150 mcg (Group I, n=30) or placebo- tab. vitamin c 100 mg (Group II, n=30) 90 minutes prior to induction. These two groups were compared with respect to haemodynamic parameters, requirement of isoflurane concentration at prior to induction, 1 min after endotracheal intubation, 5 min after endotracheal intubation, at skin incision, start of pneumoperitoneum, 15 and 30 min after intubation of CO2 pneumoperitoneum and 15 min after release of pneumoperitoneum.The basal hemodynamic parameters were not comparable. At skin incision, following start of pneumoperitoneum and 15 min after pneumoperitoneum changes in mean heart rate between the two groups was statistically significant (p value < 0.05). The difference in the MAP value between the two groups at all time intervals was significant except at 15 min after the release of pneumoperitoneum when it became not significant.

Hypertension and tachycardia were noted during the application of CO2

pneumoperitoneum in the placebo group while patients on premedication with clonidine had more stable haemodynamics. Clonidine premedication effectively blunted the cardiovascular response to surgical stress, especially during pneumoperitoneum. They concluded that premedication with oral clonidine was found to be significantly better in maintaining haemodynamic stability and it also having an isoflurane sparing effect in patients and a reduction in intra-operative

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anaesthetic requirements compared to control group undergoing laparoscopic cholecystectomy surgeries.

Karmegam G et al15 (2016) conducted a prospective, randomized, double- blind, control study on 30 patients in two groups, one receiving placebo and the other receiving clonidine 5 mcg/kg 90 min before induction was carried out.

Intraoperative heart rate (HR) and non-invasive blood pressure (BP), post- operative complications such as nausea and vomiting were monitored at preinduction, at scopy 1 and 5 min thereafter, and with pneumoperitoneum every 5 min intraoperatively for the first 30 min and 15 min thereafter. Hemodynamic stability was remarkable with Group C as seen by the comparisons with Group P and the increase in HR and BP seen in the placebo group during intubation and insufflation was not seen in the clonidine group. Post-operative nausea/vomiting and respiratory depression were negligible. They concluded that oral clonidine was found to be an excellent premedicant in laparoscopic surgery with a good hemodynamic control and it is better avoided or used with caution in patients with airway obstruction, obesity, and extremes of age as it may cause excessive sedation.

A similar study was conducted on 60 adult patients belonging to ASA physical status I & II by Rao AS et al24 (2016) in which the patients were randomly assigned to 2 groups of 30 each. Group C received oral clonidine 150 mcg 90 minutes before surgery and group P received oral ranitidine 150 mg 90 minutes before surgery. Sedation score was noted on arrival to operation theatre.

All vital parameters (Systemic blood pressures including the systolic, diastolic and

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mean arterial pressure, heart rate, SpO2, ETCO2 and electrocardiography (ECG) with ST segment analysis ) were recorded at regular intervals-prior to induction , 3 minutes after tracheal intubation, before pneumoperitoneum , 15 minutes after pneumoperitoneum, 30 minutes after pneumoperitoneum, 10 minutes after release of carbon dioxide and 10 minutes after extubation. Changes in heart rate, blood pressure when compared in the two groups of patients was found to be statistically highly significant excepting the baseline values where no significant difference was found. 10 patients in group P received Nitroglycerine infusion (0.5mcg/kg/min) for treatment of intra-operative hypertension. It was not required in group C patient because they remained haemodynamically stable. Sedation was common in group C (33%) while other complications were not observed in group C. They concluded that premedication with 150mcg oral Clonidine has been found to be relatively safe and effective method that provides stable haemodynamics and protection against stress response triggered by pneumoperitoneum in patients undergoing laparoscopic surgeries.

A prospective, comparative randomised study was conducted by Patta S et al23 (2016), 60 adult patients of both genders of ASA Grade I and II were divided randomly into 2 groups of 30 each, Group L and Group C. Group L were given Tab. Labetalol 200mg orally and group C were given Tab. Clonidine 300µg orally 60-90 minutes before induction and vital parameters like heart rate, mean arterial pressure and sedation scores were recorded before premedication and at predetermined times during intra-operative period. There was significant increase in heart rates in group – L throughout the study period when compared to group -

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C. Clonidine on the other hand had better control of heart rate after intubation when compared to Labetalol. The mean arterial pressures recorded at 5min, 10min, 15min, 20 min, 30 min after CO2 insufflation showed statistically significant difference in both the groups with Group –L recorded high mean arterial pressures at all these intervals when compared to group –C. They concluded that oral Clonidine showed better attenuation of haemodynamic changes during laparoscopic surgeries.

Sridhar CB et al27 (2017) conducted a study in which 60 patients undergoing laparoscopic procedures of 90 to 180 minutes were enrolled and were randomly allocated into two groups (test and control). They were given either tablet Clonidine 100mcg (test group) or a multivitamin tablet (control group) 90minutes before the induction of anaesthesia.

Intraoperative heart rate and blood pressure (systolic, diastolic and mean) were recorded prior to intubation, prior to pneumoperitoneum, 15, 30, 60, 90 and 120 minutes of pneumoperitoneum, after carbon-dioxide release and after extubation. The mean heart rate was significantly higher in the placebo group during the entire duration of pneumoperitoneum and after extubation (p<0.05).

The arterial pressures (systolic, diastolic and mean) were significantly lower in the clonidine group (p<0.05) at 15 and 30 minutes of pneumoperitoneum and after extubation. They concluded that patients pre-medicated with low dose clonidine had more stable haemodynamics than those pre-medicated with placebo drug. It provides good perioperative haemodynamic control and lesser requirement of anaesthetic agents. It has an added advantage of lesser postoperative

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complications like shivering, pain, nausea and vomiting. Postoperative analgesic and oxygen requirement also less with clonidine.

Mali A et al19 (2017) conducted a similar study where 60 patients between 18-60 years age group, belonging to ASA 1 and ASA 2 categories scheduled for elective laparoscopic cholecystectomy under general anaesthesia were allocated into 2 groups as Group C and Group P with 30 patients in each group. Patients in Group C received premedication with oral clonidine 150mcg and Group P received Tab. Vitamin C, 90 minutes prior to surgery. The two groups were monitored and compared with respect to haemodynamic parameters (Heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure) and sedation scores. The hemodynamic parameters were observed at Baseline, prior to induction, Immediately after intubation, three minutes after intubation, before pneumoperitoneum, 10 minutes after pneumoperitoneum, 10 minutes after the release of carbon dioxide, 10 minutes after extubation.

Comparing between groups, at all-time points after baseline, the heart rate was significantly lower and closer to baseline levels in clonidine group compared to placebo (P < 0.001 for each comparison). SBP was significantly higher in the placebo group before intubation, after intubation, before and after pneumoperitoneum and after release of CO2 (P < 0.001 for each comparison). But it remained similar in both the groups again after extubation. DBP was significantly higher in the placebo group compared to clonidine group (P < 0.001 for each comparison) before and after intubation, before and after pneumoperitoneum and after extubation. But it remained similar in both groups

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after release of CO2 (P = 0.10). At all-time points after baseline, except after release of CO2, the MAP was significantly lower in clonidine group.

They have concluded that Oral clonidine is a simple and cost-effective form of premedication with ease of administration in patients undergoing laparoscopic cholecystectomy. It effectively attenuates the haemodynamic response to pneumoperitoneum and results in better haemodynamic stability. Oral clonidine also produces dose dependent sedation, it can be considered as an anaesthetic adjuvant as it alleviates perioperative anxiety leading to decreased amount of anaesthetic requirement during perioperative period.

Kotwani DM et al17 (2017) conducted a study in Sixty adult patients between 15-50 years, scheduled for laparoscopic cholecystectomy under general anaesthesia. The patients were randomly assigned to two study groups of 30 patients each, Group CL: received oral clonidine (150 microgram) 90 minutes before induction of anaesthesia and Group C: received placebo. Hemodynamic variables (Heart rate, systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), and EtCO2 were recorded at baseline; 90 minutes following study drug administration, induction of anaesthesia, 5 and 10minutes following intubation, at skin incision, after creation of CO2 pneumoperitoneum and every 15 minutes thereafter till end of surgery; after desufflation; 5 minutes following extubation.

The mean baseline values of all the hemodynamic parameters were comparable (P >0.005). Patients in clonidine group (Group CL) had lower HR, SBP and DBP values as compared to control group (Group C) at all points of time after giving the study drug (P <0.05).

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Percent change from baseline in HR and blood pressure at different points of time was significantly high in control group than in clonidine group. Seven out of 30 patients (23%) in group C required intravenous propofol infusion (dose in the range of 2 - 6 mg/kg/hr) intra-operatively to attenuate severe hypertension (mean arterial pressure of more than 20% above baseline) following pneumo- peritonium, while no patient from Group CL required intra-operative propofol infusion. They concluded that premedication with 150 mcg oral Clonidine has been found to be relatively safe as well as effective method that provides stable haemodynamics and attenuates the stress response triggered by pneumoperitoneum in patients undergoing laparoscopic cholecystectomy.

A randomised, double blind and prospective study by Gautam et al11 (2019) in which Group 1 included patients who received 2 mcg/kg of clonidine diluted in 10 ml normal saline, given slow intravenous infusion over 10 minutes before induction of general anaesthesia. Group 2 patients received 1 mcg/kg of dexmedetomidine diluted in 10 ml of normal saline, given slowly intravenous infusion over 10 minutes before induction of general anaesthesia and found out that both alpha 2 agonists were found to be effective in attenuating the hemodynamic response to pneumoperitoneum during laparoscopic surgeries and also provides reliable postoperative analgesia and sedation when used as a premedication agent.

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MATERIALS AND METHODS

A randomized prospective, double blind study was undertaken in 60 patients undergoing elective laparoscopic surgeries under general anaesthesia. The study was conducted in Department of Anaesthesiology, Govt. Thanjavur Medical College and Hospital.

Study design: Randomised double blinded case control study Sample size: 60 (30 patients in each group)

Sampling method: Randomised sampling

Statistical analysis: SPSS trial version 20.0 software

Method of collection: Patients undergoing elective laparoscopic surgery INCLUSION CRITERIA

1. American Society of Anesthesiologists (ASA) grade I-II of either sex.

2. Age 18-60 years, posted for laparoscopic surgeries.

3. Patients weighing 50-65 kgs.

EXCLUSION CRITERIA 1. Patient refusal 2. Hypertension

3. Ischemic heart disease 4. Rheumatic heart disease 5. Diabetes mellitus

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6. Obesity

7. Anticipated difficult airway

8. Sinus Bradycardia /heart blocks/conduction defects

9. Patients on antipsychotics, digitalis, calcium channel blockers and beta blockers.

10.H/O cerebrovascular disease (accident)

11.Chronic renal disease with increased renal parameters 12.Pre-operative hypotension.

PREOPERATIVE ASSESSMENT OF PATIENT PARAMETERS 1. Blood haemoglobin.

2. Blood glucose level.

3. Serum creatinine and blood urea.

4. Electrocardiography.

5. Chest X-ray.

METHODOLOGY

The institutional ethical committee approval was obtained to conduct the study. Patients who were admitted for laparoscopic surgery in surgery department at Thanjavur medical college hospital were examined and included in the study based on the inclusion criteria, after obtaining informed written consent from the patients. The exclusion criteria listed above was applied, and if necessary, those patients will be excluded from the study.

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Group P (Placebo) were given Vitamin C(500mg) 90 mins before surgery.

Group C (oral Clonidine) were given 5 micrograms per kilogram 90 mins before surgery. Both administrator and receiver were blind to the groups allocated. The sedation score was assessed preoperatively using Ramsay sedation scale.

Ramsay 1 Anxious, agitated, restless Ramsay 2 Cooperative, oriented, tranquil Ramsay 3 Responsive to commands only

Ramsay 4 Brisk response to light glabellar tap or loud auditory stimulus Ramsay 5 Sluggish response to light glabellar tap or loud auditory

stimulus

Ramsay 6 No response to light glabellar tap or loud auditory stimulus

Patients were assessed for level of sedation at 30 min, 60 min, and 90 min after premedication. Patients were shifted to operation theatre with an 18 G IV cannula and maintenance IV fluid. Sedation scoring was done to access the efficacy of premedicant. After shifting into the OT, monitors with non-invasive BP, SPO2, and electrocardiography were connected.

Anti–aspiration prophylaxis such as inj.Ranitidine 1mg/kg and inj.Ondansetron 4mg iv, were given 30 minutes before induction. Premedication

was given with injection Glycopyrrolate 10 mcg/kg iv, injection Midazolam 10 mcg/kg iv and injection Fentanyl 2 mcg/kg iv were given prior to induction.

References

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