Thesis submitted for the partial fulfillment for the requirement of the degree of DM (Neuroanesthesiology) of SCTIMST. Dr. Gopala Krishna K N

Transcription

1 EFFECT OF DEXMEDETOMIDINE ON PERIOPERATIVE HAEMODYNAMICS, ANESTHETIC REQUIREMENTS AND RECOVERY CHARACTERISTICS IN PATIENTS UNDERGOING TRANSNASAL TRANSSPHENIODAL RESECTION OF PITUITARY TUMOUR Thesis submitted for the partial fulfillment for the requirement of the degree of DM (Neuroanesthesiology) of SCTIMST Dr. Gopala Krishna K N DM NEUROANAESTHESIA RESIDENT DEPARTMENT OF ANESTHESIOLOGY SREE CHITRA TIRUNAL INSTITUTE FOR MEDICAL SCIENCES AND TECHNOLOGY, TRIVANDRUM, KERALA , INDIA

2 DECLARATION I hereby declare that this thesis entitled Effect of Dexmedetomidine on perioperative haemodynamics, anesthetic requirements and recovery characteristics in patients undergoing transnasal transsphenoidal resection of pituitary tumor, has been prepared by me under the guidance of Dr. Prasanta K Dash, Additional Professor, Department of Anesthesiology and the overall supervision of Dr. Manikandan Sethuraman, Additional Professor, Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram. Date: Place: Thiruvananthapuram Dr Gopala Krishna K N, DM Neuroanesthesia Resident, Department of Anesthesiology, SCTIMST, Thiruvananthapuram.

3 CERTIFICATE This is to certify that this thesis entitled Effect of Dexmedetomidine on perioperative haemodynamics, anesthetic requirements and recovery characteristics in patients undergoing transnasal transsphenoidal resection of pituitary tumor, is a bonafide work of Dr. Gopala Krishna KN, DM Neuroanesthesia Resident, and has been done under my guidance and supervision at Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram. He has shown keen interest in preparing this dissertation. Date: Place: Thiruvananthapuram Dr.Prasanta K Dash, Additional Professor Department of Anesthesiology, SCTIMST, Thiruvananthapuram.

4 CERTIFICATE This is to certify that this thesis entitled Effect of Dexmedetomidine on perioperative haemodynamics, anesthetic requirements and recovery characteristics in patients undergoing transnasal transsphenoidal resection of pituitary tumor, has been prepared by Dr. Gopala Krishna K N under the guidance of Dr. Prasanta K Dash, Additional Professor, Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram. He has shown keen interest in preparing this dissertation. Date Place: Thiruvananthapuram Prof. R C Rathod. MD. Professor & Head, Department of Anesthesiology, SCTIMST, Thiruvananthapuram.

5 Acknowledgement Much help came my way in course of the preparation of this dissertation. It is my pleasant duty to recall some of these. At the outset I wish to express my sincere and heartfelt gratitude to my teacher and supervisor Dr. Prasanta K Dash, Additional Professor and Dr.Manikandan Sethuraman, Additional Professor, Department of Anesthesiology, SCTIMST, Trivandrum for his abiding interest and invaluable guidance throughout the course of this work. They have guided me in every step, in every minute, performing the study, and boosted my morale. This work would never been completed without there constant support and encouragement over the course of this study and in writing this thesis. It gives me immense pleasure to express my deep sense of gratitude and sincere thanks to Dr R C Rathod, Professor and Head of Department of Anesthesiology, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, for his constant motivation and invaluable guidance throughout my DM Neuroanesthesia residency. With a profound sense of gratitude I express my thanks to all faculty members of the Department of Anesthesia, and particularly to Dr. Gayatri, Dr.Rupa Sreedhar, Dr.Shrinivas VG, Dr. Koshy Thomas, Dr.Neema PK, Dr Subrata Singha,Dr. Satyajeet Mishra and Dr. Smita V for their morale support and valuable advice and generous help. I am extremely grateful to Dr. K. Radhakrishnan, Director, SCTIMST, Trivandrum for having permitted me to conduct this study and utilize the clinical materials. I am also immensely grateful to Dr. Easwer HV, Dr. Krishnakumar K, Dr. Mathew Abraham (Associate Professors; Neurosurgery) Dr. Girish Menon (Additional Professor, Neurosurgery), Prof. Suresh Nair (Professor and Head, Neurosurgery) and Dr. George CV (Assistant Professor, Neurosurgery) for their advice, inspiration and guidance, kind co-operation and sincere help.

6 I am thankful to all my seniors, friends and colleagues of SCTIMST, Trivandrum, in general and Department of Anesthesiology in particular for their relentless support, love and affection. I will remain ever indebted to Dr.Nilay, Dr. Suparna, Dr. Georgene, Dr. Arimanickam, Dr. Aruvelagan, Dr. Vidhu, Dr. Chattrapal Watti, Dr. Vinay, Dr. Dinesh, Dr. Divya, Dr. Liya, Dr. Arun, Dr. Prakahar and Dr. Savani for their unremitting support, at every step of this study, encouragement and help. I shall fail in my duties if I do not acknowledge my deep gratitude to all those patients who had volunteered themselves as subjects for this study. I am thankful to all OT sisters, and anesthesia technicians of neurosurgery OT complex of SCTIMST for their cooperation and help. Last, but not the least, I am greatly indebted to my family for their constant encouragement and moral support, which has made this work possible. Date: Thiruvanthapuram [Gopala Krishna K N] Senior Resident; DM Neuroanesthesia SCTIMST

7 Contents Sl.No. Topic Page No 1 Introduction Basic sciences Dexmedetomidine pharmacology and Clinical applications. Transnasal transsphenoidal surgery Review of literature Aims & objectives 42 4 Materials & Methods Observations & Results Discussion Conclusions 75 8 Annexures A] Bibliography B] Proforma C] Abbreviations used D] Master chart

8 Introduction INTRODUCTION Dexmedetomidine is a new intravenous drug gaining popularity in neuroanesthesia and neurocritical care practice. This alpha-2 adrenergic receptor agonist offers a unique cooperative sedation, anxiolysis and analgesia with no respiratory depression. Cerebral effects are generally consistent with a desirable neurophysiological profile, including neuroprotective characteristics. In addition, sympatholytic and antinociceptive properties allow for hemodynamic stability at critical moments of neurosurgical stimulation 1. Dexmedetomidine produces dose-dependent sedation, anxiolysis, and analgesia (involving spinal and supraspinal sites) without respiratory depression. 2,3 Alpha-2 agonists are known to reduce anesthetic requirements and because of sympatholytic properties, to afford hemodynamic stability during the intraoperative period 4. These clinical characteristics make this intravenous agent a potentially attractive adjunct for neuroanesthesia and in the neurological intensive care unit (ICU). When a new drug is introduced into neuroanesthesia practice, however, several concerns must be addressed. Principal considerations include the ability of a drug to preserve intracranial homeostasis, to allow a hemodynamically stable perioperative course, to be compatible with neurophysiological monitoring and to ensure rapid emergence to a level of consciousness permitting neurological assessment in the operating room. Additional desirable end points would include cerebral blood volume reduction (helping to minimize operative brain retraction), an 1

9 Introduction optimization of the cerebral oxygen supply and demand relationship, and neuroprotection. Dexmedetomidine decreases plasma epinephrine and norephineprine level perioperatively 5,6. It also attenuates hypertensive responses associated with surgical stimulation 7. Almost 50% 90% of neurosurgical patients require antihypertensive or vasoactive drugs 8,9. Dexmedetomidine remifentanil nitrous oxide anesthesia and propofol remifentanil nitrous oxide anesthesia had comparable perioperative hemodynamic and postanesthesia recovery profiles in patients undergoing intracranial surgery and both avoided requirement for antihypertensive medication 10. Dexmedetomidine significantly attenuated the haemodynamic responses to intubation and the emergence from anaesthesia 11. In addition, it maintained intraoperative cardiovascular stability. Most of the effects were concentration dependent, and the higher dose was more effective than the lower dose. Patients receiving dexmedetomidine had their tracheal tubes removed faster than those in the placebo group, indicating preserved respiratory function. Continuous infusion of dexmedetomidine had been shown to improve hemodynamic stability in patients undergoing intracranial surgery without increasing the incidence of hypotensive episodes or bradycardia. In addition, patients treated with dexmedetomidine were discharged from the post anesthesia care unit earlier 12. The tumours of pitutary fossa can be approached using the transsphenoidal, transethmoidal or transcranial route. The transsphenoidal route is preferred due to 2

10 Introduction the advantage of rapid midline access to the sella with minimal risk of brain trauma or haemorrhage as well as low incidence of postoperative complications. Transnasal transsphenoidal resection of pituitary tumours involves wide fluctuation in haemodynamic parameter like hypertension and tachycardia due to intense noxious stimulus during adrenaline soaked nasal packing, nasal speculum insertion, during sphenoid and sellar dissection. None of routinely used anaesthetic agents effectively blunts the undesirable hemodynamic responses and hence there is a need to use increased doses of anesthetic agents. As the procedure is short, early predictable recovery of consciousness is essential in these patients. In the postoperative period the use of nasal packs, makes these patients obligate mouth breathers and are at risk of airway obstruction. Hence it is imperative that these patients are fully awake before extubation. In BIS-guided anesthetic management of patients undergoing transsphenoidal pituitary surgery, the pressor response after intubation and emergence hypertension was less with use of propofol. But isoflurane, sevoflurane and also propofol did not effectively blunt the undesirable hemodynamic responses during other stages of the surgery 13. Dexmedetomidine as an anesthetic adjuvant in patients undergoing transnasal transsphenoidal pituitary surgery was not studied till date. We decided to proceed with this investigation. The intention of this investigation is to evaluate the usefulness of the sympatholytic and antinociceptive properties of dexmedetomidine, 3

11 Introduction to provide hemodynamic stability at critical moments of surgical stimulation and reduce anaesthetic requirement and the complication associated with it. 4

12 Dexmedetomidine pharmacology Dexmedetomidine Pharmacology General Introduction 14 Dexmedetomidine is a highly selective α-2 adrenoceptor agonist that has sedative, anxiolytic,hypnotic, analgesic and sympatholysis properties. It was first approved by the FDA in 1999 for the provision of sedation in mechanically ventilated adult intensive care patients for up to 24 hours 15. In 2008 it was labelled for use as a sedative in non-intubated adult patients prior to and/or during surgical and other procedures. Dexmedetomidine is not approved for use in any paediatric setting. Despite these licensing restrictions dexmedetomidine use has extended throughout the hospital setting for numerous off-label applications including, 1) Management of postoperative pain, 2) As an adjunct to anaesthesia in adult and paediatric patients, 3) Used in paediatric intensive care and procedural sedative 16. 4) Treatment of cyclic vomiting syndrome, 5) Treatment of shivering after anaesthesia, 6) Withdrawal/Detoxification amelioration in adult and paediatric patients 17. Physicochemical Characteristics Dexmedetomidine Hydrochloride (C 13 H 16 N 2 HCl ) is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl) ethyl ]-1H-imidazole monohydrochloride 18. Dexmedetomidine belongs to the imidazole subclass of α 2 receptor agonists, similar to clonidine, and its structure is illustrated in Figure 1. It is freely soluble in water and has a molecular weight of 5

13 Dexmedetomidine pharmacology It is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Figure 1 : Chemical structure of Dexmedetomidine. Dexmedetomidine is available in a 2-mL vial of a 100 µg /ml solution. It is generally reconstituted in normal saline to a 4 µg /ml solution, which can be administered via a peripheral or central vein. For Adult patients,dexmedetomidine is generally intiated with a loading infusion of 1 µg/kg over 10 minutes,followed by a maintenance o 0.2 to 0.7 µg/kg/hour. Metabolism and Pharmacokinetics Dexmedetomidine is rapidly distributed, 94% protein bound, and its concentration ratio between whole blood and plasma is It is extensively metabolized in the liver by conjugation (41%), n-methylation (21%), or hydroxylation followed by conjugation and excreted in urine and faeces. Having profound effects on cardiovascular variables it may alter its own pharmacokinetics. With large doses, there is marked vasoconstriction, which probably reduces the volume of distribution. In essence, Dexmedetomidine displays nonlinear pharmacokinetics 19. Dyck and 6

14 Dexmedetomidine pharmacology coworkers 20 found that its pharmacokinetics in volunteers is best described by a threecompartment model. Elimination Elimination Half-Life (hr) Clearance (ml/kg/min) Vd SS (L/kg) Dexmedetomidine These pharmacokinetic parameters apparently are unaltered by age or weight or renal failure, but clearance is a function of height 19,21. The elimination half-life of Dexmedetomidine is 2 to 3 hours, with a context-sensitive half-time ranging from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion. Postoperative patients sedated with Dexmedetomidine display similar pharmacokinetics to the pharmacokinetics seen in volunteers 22. Pharmacology Dexmedetomidine shows a high ratio of specificity for the α 2 receptor (α 2 /α :1) compared with clonidine (α 2 /α 1 200:1), making it a complete α 2 agonist. Another difference between the two agents is that Dexmedetomidine has a short half-life (2-3 hours vs hours with Clonidine). The physiologic actions of Dexmedetomidine are mediated via stimulation of postsynaptic α 2-adrenergic receptors that activate a pertussis toxin-sensitive guanine nucleotide regulatory protein (G protein), resulting in inhibitory feedback and decreased activity of adenylyl cyclase. This results in a reduction of intracellular cyclic adenosine monophosphate (camp) and camp-dependent protein kinase activity, resulting in a dephosphorylation of ion channels 23. This process subsequently 7

15 Dexmedetomidine pharmacology modifies ion translocation and membrane conductance, resulting in decreased neuronal activation and the clinical effects of sedation and anxiolysis 24. Three subtypes of α 2 adrenoreceptors have been described in humans: α 2A, α 2B, and α 2C 25. The α 2A adrenoreceptors are primarily distributed in the periphery, whereas α 2B and α 2C are in the brain and spinal cord Postsynaptic located α 2 adrenoreceptors in peripheral blood vessels produce vasoconstriction, whereas the central action is through activation of presynaptic α2 receptors in the medullary vasomotor center, reducing norepinephrine turnover and decreasing central sympathetic outflow, resulting in decreased heart rate and blood pressure. Additional effects result from stimulation of parasympathetic outflow and inhibition of sympathetic outflow from the locus ceruleus in the brainstem. The latter effect plays a prominent role in the sedation and anxiolysis produced by these agents as decreased noradrenergic output from the locus ceruleus allows for increased firing of inhibitory neurons including the γ -amino butyric acid (GABA) system The activation of α2-adrenergic receptors in the dorsal horn of the spinal cord inhibits the release of substance P, resulting in primary analgesic effects as well as potentiation of opioid-induced analgesia. Effects on the Central Nervous System 1 Sedation Dexmedetomidine seems to exert its sedative and anxiolytic effects through activation of α 2 - adrenoreceptors in the locus ceruleus (LC), a major site of noradrenergic innervation in the CNS. The LC has been implicated as a key 8

16 Dexmedetomidine pharmacology modulator for a variety of critical brain functions, including arousal, sleep, anxiety, and drug withdrawal syndromes associated with CNS depressants, such as opioids 28. The sedation produced by α 2 - adrenoreceptor agonists, unlike that produced by traditional sedatives, such as benzodiazepines and propofol, does not depend primarily on activation of the γ -aminobutyric acid (GABA) system and does not seem to involve the cerebral cortex. Perhaps because of a noncortical site of action, α 2 - agonist seem to engender a different type of sedation compared with GABAmimetic drugs. Dexmedetomidine produces an unusually cooperative form of sedation, in which patients easily transition from sleep to wakefulness and task performance when aroused, and then back to sleep when not stimulated 29,30. The α 2 agonists act through the endogenous sleep-promoting pathways producing a decrease in activity of the projections of the locus caeruleus to the ventrolateral preoptic nucleus. This increases GABAergic and galanin release in the tuberomammillary nucleus, producing a decrease in histamine release in cortical and subcortical projections 27. The similarity between natural sleep (non rapid eye movement) and Dexmedetomidine -induced hypnosis has been speculated to maintain cognitive and immunologic function in the sleep-deprived states (as in the ICU) 31. Similar to other adrenergic receptors, the α 2 agonists also show tolerance after prolonged administration 32. As Dexmedetomidine is approved by the FDA only for short-term sedation (24 hours), tolerance, dependence, or addiction does not seem to be a problem. Dexmedetomidine can be employed for addiction treatment like rapid opioid detoxification, cocaine withdrawal, and iatrogenic induced benzodiazepine and opioid tolerance after prolonged sedation 33. 9

17 Dexmedetomidine pharmacology Analgesia Dexmedetomidine exerts analgesic action at α 2 receptors in the locus caeruleus and spinal cord. The precise mechanisms and pathways by which drugs in this class induce analgesia have not been fully elucidated. Brain, spinal cord, and peripheral mechanisms all seem operant. The most important of these sites may be the spinal cord, where the activation of 2C-receptor subtype seems to accentuate the analgesic actions of opioids in attenuating the transmission of nociceptive signals to brain centers 34. Alpha 2 agonists do have an analgesic effect when injected via the intrathecal or epidural route 35. Clonidine injected in the neural axis helps with shortterm pain, cancer pain, and neuropathic pain 36. Systemic use of Dexmedetomidine also shows narcotic sparing. In the postoperative ICU setting, narcotic requirements were reduced by 50% when patients were receiving a Dexmedetomidine drip compared with placebo 15. In animals, Dexmedetomidine, in contrast to opioids, does not result in hyperalgesia or allodynia after its withdrawal 37. The analgesic effect of Dexmedetomidine has been compared with Remifentanil. In a noxious heat versus pain intensity plot obtained in a group of volunteers, Dexmedetomidine was less effective in reducing pain than Remifentanil. Also, the slope was different, suggesting a different mechanism of action and an effect from sedation 38. In the clinical setting, when pain is likely to occur, if Dexmedetomidine is to be used, the addition of a narcotic seems warranted. 10

18 Dexmedetomidine pharmacology NEUROPHYSIOLOGICAL EFFECTS OF DEXMEDETOMIDINE Cerebral Blood Flow and Metabolism Alpha 2-adrenergic receptors are widely distributed within the cerebral vasculature. Much work on the adrenergic regulation of the cerebral circulation has focused on the extrinsic sympathetic innervation of arteries and pial vessels.α 2 -agonist stimulation of these receptors has demonstrated vasoconstriction in isolated cerebral vessels and in various animal models 39,40,41. Moreover, the inability of locally applied atipamezole (an α 2-antagonist) to substantially inhibit the vasoconstrictor response to systemically administered dexmedetomidine suggests that α 2 agonists might also cause vasoconstriction indirectly through actions at other sites in the CNS 42. Thus, systemic administration of 2-agonists could decrease cerebral blood flow (CBF) via direct α2-mediated vascular smooth muscle constriction and indirectly via effects on the intrinsic neural pathways modulating vascular effects.investigations of the effect of locus caeruleus (LC ) activation (i.e., increases in noradrenergic neural firing) or ablation on local CBF seem discrepant, on the basis of low- to highfrequency activation and species differences, but for in vivo physiological conditions or chemical stimulation, LC-mediated vasoconstriction prevails 43. Lee et al 44 measured middle cerebral artery blood flow velocity by use of transcranial Doppler sonography in healthy volunteers after administration of clonidine and showed a significant decrease in middle cerebral artery blood flow velocity. Using a similar technique, Zornow et al 45 reported dose-dependent decreases 11

19 Dexmedetomidine pharmacology in CBF at four steady-state concentrations of dexmedetomidine. The measurements of regional and global CBF by use of positron emission tomography confirmed reduction in CBF by 30% at clinically relevant concentrations 46. Lam et al 47 similarly demonstrated reductions in middle cerebral artery blood flow velocity in healthy volunteers with dexmedetomidine administration, with preservation of CO2 reactivity and cerebral autoregulation. Cerebrovascular dilation induced by either isoflurane or sevoflurane is less with dexmedetomidine pretreatment 48. Thus, α 2-agonists might be useful adjuncts to inhalational anesthetics (cerebral vasodilators) during neurosurgery in situations in which an increase in CBF should be avoided (i.e., traumatic brain injury, large brain tumors). Sturaitis et al 49 in a study evaluating the effect of dexmedetomidine on brain tissue oxygenation in patients undergoing cerebrovascular surgery, found that even under circumstances of baseline cerebrovascular compromise and hyperventilation, dexmedetomidine seemed to have no detrimental effect on local brain tissue oxygenation. In a study by Drummond et al 50, in a study in six normal volunteers, the administration of dexmedetomidine to achieve serum levels of 0.6 ng/ml and 1.2 ng/ml (with and without hyperventilation) produced the predicted reduction of CBF with a concomitant reduction in CRMO 2. This finding suggests the maintenance of the cerebral oxygen supply-to-demand relationship. However, further work in injured brains needs to be done. 12

20 Dexmedetomidine pharmacology Intracranial Pressure Increases in intracranial pressure (ICP) can be detrimental during neurosurgical procedures. A reduction in cerebral perfusion pressure may lead to global or regional ischemia. Internal pressure gradients may be created, producing intracranial brain herniation or external herniation of the brain substance. Surgery under these conditions is particularly difficult, often requiring considerable retraction for adequate operative field exposure. α 2 -Agonists are more potent vasoconstrictors on the venous than on the arteriolar side of the cerebral vasculature 51. Because the venous compartment comprises most of the cerebral blood volume, α 2 -agonists could presumably decrease ICP without greatly increasing arteriolar cerebrovascular resistance. McCormick et al 52 found a significant dose-dependent decrease in ICP after treatment with the α 2-agonist xylazine in a model of intracranial hypertension in dogs. In the human study, Talke et al 53 found that dexmedetomidine administration to patients after transsphenoidal hypophysectomy had no effect on lumbar cerebrospinal fluid pressures. Effect on EEG The anesthetic agents suitable for perioperative monitoring of ischemia and seizures should have minimal effects on the electroencephalogram (EEG). The α 2 - agonists attenuate the α and β fractions and total power of an EEG as well as increased slow-wave activity. This pattern is typically seen with increasing depth of anesthesia. Although the EEG changes produced by α 2-agonists are qualitatively 13

21 Dexmedetomidine pharmacology similar to those produced by other agents, there is an important difference in their mechanisms of action. The preponderance of the lower frequency θ and δ bands, typically seen with increasing depth of inhalational anesthesia, that are observed with most inhalational agents is primarily the result of a direct suppression of the cortical activity. α 2 -Agonists, however, act by interrupting noradrenergic neurotransmission and, subsequently, by disinhibiting the inhibitory interneurons in the LC. As discussed earlier, the LC is the predominant noradrenergic nucleus in the brain, has a number of efferent connections, particularly to the frontal lobes, and is an important modulator of wakefulness. Dexmedetomidine was used successfully in patients with known epilepsy for awake craniotomy 54,55. The adjuvant anesthetic agents, dose administration, and possibly the awake state may modify the EEG and seizure threshold with dexmedetomidine. Effect on Evoked Potentials The anesthetic agent useful in neurosurgery should not interfere with perioperative neurophysiological monitoring. A carefully conducted study in rats confirmed the preservation of the cortical somatosensory evoked potential at clinical and supraclinical concentrations of dexmedetomidine 56. In a study by Sturaitis et al 57, the intraoperative adjuvant administration of dexmedetomidine in patients undergoing craniotomy for tumor or aneurysm had a minimal effect on cortical somatosensory evoked potential amplitudes or latencies. 14

22 Dexmedetomidine pharmacology Hence, dexmedetomidine allows for consistent and reliable neurophysiological monitoring in circumstances in which neural tissue is at risk for injury. Endrit et al 58 in 2008 reported, use of dexmedetomidine as an anesthetic adjunct at target plasma concentrations up to 0.6 ng/ml did not change somatosensory or motor evoked potential responses during complex spine surgery by any clinically significant amount. Neuroprotection Cerebral ischemia is associated with an increase in circulating and extracellular brain catecholamine concentrations. Interventions to reduce sympathetic tone improved neurological outcome. Thus, the treatment with agents that reduce the release of norepinephrine in the brain (e.g., α 2-agonists) may provide protection against the damaging effect of cerebral ischemia. Several studies have shown that dexmedetomidine improves neuronal survival after transient global or focal cerebral ischemia in the rat.the exact mechanism of the neuroprotective effect of the α 2-agonists, however, is unclear. Engelhard et al 69 showed that dexmedetomidine does not suppress the intraischemic increase of cerebral extracellular catecholamines. They suggested that the neuroprotection offered by dexmedetomidine is a result of modulation of the balance between proapoptotic and antiapoptotic proteins 102. Several studies demonstrate that α2-adrenoreceptor agonists reduce excitatory neurotransmitter (e.g., glutamate) release 59. High levels of glutamate depolarize the neuronal membrane and allow calcium to enter into the cell, thus 15

23 Dexmedetomidine pharmacology triggering a number of events that lead to the cellular damage.agents that reduce glutamate release are thus considered neuroprotective. Laudenbach et al 60 found that both clonidine and dexmedetomidine protected against excitotoxic injury to the developing brain. Sanders et al 61,62 showed that dexmedetomidine can reduce isoflurane-induced neuroapoptosis in the developing rat cortex and exerts anti-apoptotic effects in vitro. As dexmedetomidine is the first agent to show neurocognitive protection against isoflurane-induced neuroapoptosis, future studies should compare efficacy against dexmedetomidine for this injury. Effects on the Respiratory System Alpha 2-adrenoreceptor agonists have minimal effects on ventilation.in healthy volunteers, as well as intraoperatively, even very high doses of Dexmedetomidine did not compromise respiratory function. There was no significant difference between placebo and Dexmedetomidine in measures of respiratory function after extubation in the group of ICU patients 63. The lack of respiratory depression, as measured by pulse oximetry and PaCO2, was also demonstrated in patients sedated with Dexmedetomidine, which was administered at infusion rates 10 to 15 times higher than maximally recommended 64. Effects on the Cardiovascular System The hemodynamic effects of Dexmedetomidine result from peripheral and central mechanisms. The α-2 B receptors located on vascular smooth muscle mediate vasoconstriction. In the CNS, activation of α2-adrenoreceptors leads to a reduction in sympathetic outflow and an increase in vagal activity. In addition, Dexmedetomidine 16

24 Dexmedetomidine pharmacology may have some action as a peripheral ganglionic blocker, further enhancing the sympatholytic effect. The net effect of α2-adrenoreceptor action is a significant reduction in circulating catecholamines, modest reduction in blood pressure, and modest reduction in heart rate. The hemodynamic effects of a bolus of Dexmedetomidine in humans have shown a biphasic response. An acute IV injection of 2 µg/kg resulted in an initial increase in blood pressure (22%) and decrease in heart rate (27%) from baseline that occurred at 5 minutes after injection. This initial increase in blood pressure is probably due to the vasoconstrictive effects of Dexmedetomidine when stimulating peripheral α 2 receptors. Heart rate returned to baseline by 15 minutes, and blood pressure gradually declined to approximately 15% below baseline by 1 hour. After an IM injection of the same dose, the initial increase in blood pressure was not seen, and heart rate and blood pressure remained within 10% of baseline 19. Bradycardia has also been described, primarily in younger patients with high levels of vagal tone. Dexmedetomidine is not recommended for patients diagnosed with heart block. The use of β-blockade does not seem to increase the risk of bradycardia. Although hypotension has been described in patients receiving Dexmedetomidine, this exaggerated physiological effect seems to have a frequent temporal relationship to the use of a loading dose and/or preexisting hypovolemia. Omitting the loading dose or not giving more than 0.4 µg/kg reduces the incidence of hypotension, or makes it less pronounced. Giving the loading dose over 20 minutes also minimizes the transient hypertension. 17

25 Dexmedetomidine pharmacology In several studies after IM and IV administration, Dexmedetomidine caused, in a small percentage of patients, profound bradycardia (<40 beats/min) and occasionally sinus arrest/pause. Generally, these episodes resolved spontaneously or were readily treated without adverse outcome by anticholinergics. It would be expected from its profile that Dexmedetomidine would be beneficial to the ischemic myocardium. In animal models, Dexmedetomidine showed some beneficial effects on the ischemic heart through decreased oxygen consumption and redistribution of coronary flow from nonischemic zones to ischemic zones after acute brief occlusion. No rebound effects have been found when discontinuing dexmedetomidine drips, even when it is given for more than 24 hours 14. Endocrine and Renal Effects Alpha 2-adrenoreceptor agonists attenuate responses to stress, including neurohumoral responses. Use of less than 24 hours does not seem to significantly reduce serum cortisol levels. Dexmedetomidine seems to induce diuresis in animal models studied, possibly through an ability to reduce efferent sympathetic outflow 65. In addition, dexmedetomidine has been shown to suppress antidiuretic hormone and increases secretion of atrial natriuretic peptide, resulting in natriuresis. In resting volunteers, dexmedetomidine increased growth hormone secretion in a dose-dependent manner, but it had no effect on other pituitary hormones

26 Dexmedetomidine pharmacology Miscellaneous Effects Gastrointestinal motility Alterations in gastrointestinal (GI) motility and delays in gastric emptying are of particular concern in the perioperative period and in critically ill ICU patients, in whom it may interfere with enteral feeding, lead to bacterial overgrowth, and promote bacterial translocation. Given these concerns, the effects of sedative and analgesic agents on GI motility must be entertained when decisions are made regarding the optimal sedation regimen. In a whole-animal model (rat), Asai et al 67 compared the effects of clonidine, dexmedetomidine, and morphine on GI transit time and gastric emptying using radiolabelled sodium chromate. Clonidine and dexmedetomidine weakly inhibited gastric emptying time and morphine s effect was greater. White blood cell function and inflammatory response. Previous studies have suggested that several anesthetic agents may inhibit various aspects of white blood cell (WBC) function. In an in vitro study, Dexmedetomidine was found to have no effect on WBC chemotaxis, phagocytosis, or superoxide anion production, leading the authors to conclude that there is no concern regarding the use of this agent in patients with acute infectious processes. Study by Venn et al 68 which randomized patients to receive either Propofol or Dexmedetomidine for sedation during mechanical ventilation, there was a decrease in interleukin-6 levels from baseline in patients receiving Dexmedetomidine with no change in patients receiving Propofol. 19

27 Dexmedetomidine clinical applications Uses Given its well-documented beneficial effects of anxiolysis, sedation, analgesia, and sympatholysis with minimal respiratory depression, Dexmedetomidine has been used in various clinical scenarios. Intensive Care Unit Dexmedetomidine has been approved as a short-term sedative for adult intubated patients in the ICU. Dexmedetomidine has advantages over propofol for sedation in mechanically ventilated postoperative patients. When both drugs were titrated to equal sedation as assessed by the BIS (approximately 50) and Ramsay sedation score (5), Dexmedetomidine patients required significantly less narcotics (alfentanil 2.5 mg/hr versus 0.8 mg/hr). Heart rate was slower in the Dexmedetomidine group, whereas MAP was similar. The PaO 2 /FIO 2 ratio was significantly higher in the Dexmedetomidine group. Time to extubation after discontinuation of the infusion was similar at 28 minutes. Patients receiving Dexmedetomidine seemed to have greater recall of their stay in the ICU, but all described this as pleasant overall 30. Several other studies have confirmed the decreased requirement for opioids (>50%) when Dexmedetomidine is used for sedation. Most studies also describe stable hemodynamics during weaning when Dexmedetomidine is used for sedation 70. For sedation in the ICU, loading doses of 0.5 to 1 µg/kg have been used. Omitting the bolus or giving the lower dose has been associated with fewer episodes of severe 20

28 Dexmedetomidine clinical applications bradycardia and other hemodynamic perturbations. Infusion rates of 0.1 to 1 µg/kg/hr are generally needed to maintain adequate sedation. Delirium in the ICU is a risk factor for increased length of stay and increased mortality. In a double-blind, randomized controlled trial of sedation in ventilated patients with Dexmedetomidine versus lorazepam, it was found that using Dexmedetomidine infusions provided more days alive without delirium or coma and a greater amount of time spent at the appropriate sedation level compared with lorazepam 71. α 2 -adrenoreceptor agonists have been used in the treatment of withdrawal of narcotics, benzodiazepines, alcohol, and recreational drugs. Dexmedetomidine controlled withdrawal behavior and allowed for successful detoxification of young cardiothoracic patients who developed drug withdrawal from prolonged use of benzodiazepines and narcotics in the ICU. Despite sound levels of sedation with Dexmedetomidine, there is limited respiratory depression, providing wide safety margins.this characteristic allows for daily wake up tests to be done in a safe fashion where ICU patients are taken off all sedatives to assess their mental status and titrate sedation in turn shortens their ventilated and ICU length of stay. Siobal and colleagues 72 reported the successful weaning of five ventilated patients who had failed weaning secondary to agitation. Infusions of Dexmedetomidine of 0.5 to 0.7 µg/kg/hr were used (no loading) and permitted the 21

29 Dexmedetomidine clinical applications discontinuation of Propofol in four of five patients. All patients were extubated while still on the Dexmedetomidine infusion. The FDA approved the use of Dexmedetomidine infusions for 24 hours or less. Multiple studies have shown the safety of using this drug for longer periods, however. In data collected from prescribing patterns in 10 institutions, it was shown that Dexmedetomidine was used longer than 24 hours in 33.8% of cases. It also was noted that 33% of patients received a loading dose, 27% of patients received a dose higher than the recommended maximum, and 60% of patients remained on the infusion after extubation 73. Anesthesia As a premedicant, Dexmedetomidine, at IV doses of 0.33 to 0.67 µg/kg given 15 minutes before surgery, seems efficacious, while minimizing the cardiovascular side effects of hypotension and bradycardia 74 Within this dosage range, Dexmedetomidine reduces thiopental requirements (by ±30%) for short procedures 74, reduces the requirements of volatile anesthetics (by ±25%), and more effectively attenuates the hemodynamic response to endotracheal intubation compared with 2 µg/kg of Fentanyl 75. Dexmedetomidine also has been evaluated as an IM injection (2.5 µg/kg) with or without Fentanyl administered 45 to 90 minutes before surgery. This regimen was compared with IM Midazolam plus Fentanyl and was found to provide equal anxiolysis, reduced response to intubation, smaller volatile anesthetic requirements, 22

30 Dexmedetomidine clinical applications and a decreased incidence of postoperative shivering but a higher incidence of bradycardia. Atipamezole, a selective α 2 antagonist, at 50 µg/kg was effective in reversing the sedation of Dexmedetomidine (2 µg/kg intramuscularly), when used to provide sedation for brief operative procedures.this reversal of effects resulted in a more rapid recovery than occurred after equisedative doses of Midazolam. Dexmedetomidine has been used for sedation for monitored anesthesia care. In a study comparing the efficacy of Dexmedetomidine or Propofol as a sedative agent in a group of 40 patients receiving local anaesthesia or regional blocks, Dexmedetomidine (1 µg/kg given over 10 minutes) when used for intraoperative sedation resulted in a slower onset than propofol (75 µg/kg/min for 10 minutes), but similar cardio-respiratory effects when titrated to equal sedation. The average infusion rate of Dexmedetomidine intraoperatively to maintain a BIS value of 70 to 80 was 0.7 µg/kg/min. Sedation was more prolonged after termination of the infusion, as was recovery of blood pressure. Smaller doses of opioid were needed in the first hour 76. Dexmedetomidine sedation has been done successfully in paediatric patients. Two studies, comprising 140 children 1 to 7 years old, reported successful sedation for MRI scans compared with Midazolam or Propofol 77,78. When Dexmedetomidine is used as a premedication 10 minutes before general surgery for cataract removal, intraocular pressure is decreased (33%), catecholamine secretion is reduced, perioperative analgesic requirements are less, and recovery is more rapid 79,80. 23

31 Dexmedetomidine clinical applications For maintenance of anesthesia, Dexmedetomidine has been used in patients undergoing multiple types of surgery. In patients given an infusion regimen to achieve a plasma concentration of slightly less than 1 ng/ml, combined with 70% nitrous oxide, Dexmedetomidine reduced Isoflurane requirements by 90% compared with a control group 81. One retrospective study and two prospective, randomized controlled trials in bariatric surgical patients have found that a balanced anesthetic with Desflurane or Propofol plus Dexmedetomidine (0.5 to 0.8 µg/kg bolus plus 0.4 µg/kg/hr infusion) reduces postoperative pain scores and morphine consumption, and improves hemodynamics compared with Desflurane-Fentanyl or Propofol-Fentanyl anaesthetics 82,83,84. In patients presenting for vascular surgery, three infusion rates of Dexmedetomidine were compared with a placebo infusion starting 1 hour before surgery and administered until 48 hours after surgery. In the groups receiving Dexmedetomidine, more vasoactive agents were required to maintain hemodynamics intraoperatively, but less tachycardia was noted postoperatively. No other significant differences were noted between the groups 85. Grant and colleagues 86 described the use of Dexmedetomidine when securing the airway with a fiberoptic intubation in three patients undergoing cervical spine surgery. The procedure was well tolerated with no hemodynamic compromise or respiratory depression. 24

32 Dexmedetomidine clinical applications Because this drug provides good sedation with minimal respiratory depression, it has been used in patients undergoing awake craniotomies with functional testing and electrocorticography 87 or awake carotid endarterectomies with fewer fluctuations from the desired sedation level and more stable hemodynamics 88. Another use of Dexmedetomidine has been as an anesthetic adjunct or sedative agent for patients who are susceptible to narcotic-induced respiratory depression or sleep apnea. In a morbidly obese patient, the narcotic-sparing effects of Dexmedetomidine were evident intraoperatively and postoperatively after bariatric surgery 89.The addition of Dexmedetomidine infusions to assist on transesophageal echocardiography examination has been described, with better hemodynamic profile and improved patient satisfaction than with benzodiazepine and narcotics alone, with no added respiratory depression. The use of Dexmedetomidine has dramatically increased. This highly selective α 2 agonist has a set of unique effects that include titratable sedation, sympatholysis, and analgesia without significant respiratory depression. Originally approved as a sedative in the ICU, it has found many off-label applications in the ICU, the operating room, and perioperative environment. The off-label use of Dexmedetomidine in infants and children is rapidly increasing. More than 800 reports have been published regarding its use in this population

33 Transnasal Transsphenoidal Pituitary surgery Transnasal Transsphenoidal Pituitary surgery The tumours of Pitutary fossa can be approached using the transsphenoidal, transethmoidal or transcranial route. The transsphenoidal route is preferred due to the advantage of rapid,midline access to the sella with minimal risk of brain trauma or haemorrhage as well as low incidence of postoperative complications. Transnasal transsphenoidal resection of pituitary tumors involves wide fluctuation in haemodynamics parameter like Hypertension,tachycardia due to intense noxious stimulus during adrenaline soaked nasal packing, nasalspeculum insertion,during sellar and sphenoid dissection. Traditionally, microscopic resection of pituitary tumour has been guided by the use of intraoperative fluoroscopy. The endonasal approach can also be performed or assisted by an endoscope. In the postoperative period, these patients are at risk of potential airway difficulties because of nasal packing. Because of presence of the nasal packs, these patients are obligate mouth breathers, and should be fully awake before extubation. In these patients, positive pressure ventilation with a mask has to be avoided, as there is a risk of tension pneumocephalus, venous air embolism, and introduction of bacteria into the subarachnoid space. The main aims of anesthesia for pituitary surgery include maintenance of hemodynamic stability, provision of conditions that facilitate surgical exposure, and a smooth emergence to facilitate a prompt neurologic assessment. 26

34 Review of Literature Review of Literature Alpha 2-adrenergic receptor agonists, as a class of compounds, have been widely used as adjuncts in the perioperative period to exploit their sedative/hypnotic, analgesic, anxiolytic, and sympatholytic properties for the benefit of surgical patients 90,91,92. The initial impetus for the use of α 2 agonist in anesthesia resulted from observations made in patients during anesthesia who were receiving clonidine therapy 90,91. Kaukinen et al 90 in 1979 begun the studies on the perioperative use of alpha-2-adrenergic agonists. This was soon followed by an article by Bloor et al 92, where authors described that clonidine a alpha-2-adrenergic agonist reduces minimum alveolar concentration (MAC) of halothane. Since then hundreds of reports on their anaesthesiological usefulness have been published. Especially in the last 30 years there has been an explosion of research in this area. Dexmedetomidine is a more selective α 2 agonist with a 1600 times greater selectivity for the α 2 receptor compared with the α 1 receptor. It was introduced in clinical practice in the United States in 1999 and approved by the FDA only as a short-term (<24 hours) sedative for mechanically ventilated adult ICU patients 15. Dexmedetomidine is now being used off-label outside of the ICU in various settings 93, including sedation and adjunct analgesia in the operating room, sedation in diagnostic and procedure units, and for other applications such as withdrawal/detoxification amelioration in adult and pediatric patients. Guo et al 94 studied the antinociceptive effect of dexmedetomidine injected in to the locus ceruleus of rat.they concluded that α 2 agonists produce their sedativehypnotic effect by an action on α 2 receptors in the locus caeruleus and an analgesic 27

35 Review of Literature effect by an action on α 2 receptors within the locus caeruleus and within the spinal cord. Given that dexmedetomidine seems to exert its sedative action at the LC, a brain wakefulness and anxiety center, it is possible that cognitive compromise and accompanying disinhibition are less prominent. This theory is consistent with data from studies by Ebert et al 95 and Hall J E et al 96 in healthy volunteers, indicating that cognitive integrity is well preserved in patients receiving dexmedetomidine. Cerebral ischemia is associated with an increase in circulating and extracellular brain catecholamine concentrations.globus et al 97 and kuhmonen et al 98 showed interventions to reduce sympathetic tone improved neurological outcome. Thus, the treatment with agents that reduce the release of norepinephrine in the brain (e.g., α2-agonists) may provide protection against the damaging effect of cerebral ischemia. Several studies had shown that dexmedetomidine improves neuronal survival after transient global or focal cerebral ischemia in the rat 99,100,101. The exact mechanism of the neuroprotective effect of the α 2-agonists, however, is unclear. Engelhard et al 69 showed that dexmedetomidine does not suppress the intraischemic increase of cerebral extracellular catecholamines. They questioned the hypothesis that the neuroprotective effects of dexmedetomidine were related to inhibition of cerebral catecholamines. Engelhard et al 102 in another study suggested that the neuroprotection offered by dexmedetomidine was a result of modulation of the balance between proapoptotic and antiapoptotic proteins. 28

36 Review of Literature Huang et al 103 showed that dexmedetomidine enhances glutamine disposal by oxidative metabolism in astrocytes. This effect occured at pharmacologically relevant concentrations and was large enough to reduce the availability of glutamine as a precursor of neurotoxic glutamate. Laudenbach et al 60 found that both clonidine and dexmedetomidine protected against excitotoxic injury to the developing brain. Ohata et al 48 described cerebrovascular dilation induced by either isoflurane or sevoflurane was less with dexmedetomidine pretreatment in dogs. Thus, 2-agonists might be useful adjuncts to inhalational anesthetics (cerebral vasodilators) during neurosurgery in situations where increase in CBF should be avoided (i.e., traumatic brain injury, large brain tumors). Brede et al 104 studied the neuroprotective effects of α 2 -adrenoceptors in acute ischemic stroke in mice.they could not demonstrate a neuroprotective function of α 2 -adrenoceptors in focal cerebral ischemia. Careful controlling of physiological parameters relevant for stroke outcome is recommended in experimental stroke studies. Two recent studies by Sanders et al 105,106 showed that dexmedetomidine can reduce isoflurane-induced neuroapoptosis in the developing rat cortex and exerts anti-apoptotic effects in vitro. As dexmedetomidine is the first agent to show neurocognitive protection against isoflurane-induced neuroapoptosis, future studies should compare efficacy against dexmedetomidine for this injury. Oak et al 107 performed a study to determine how dexmedetomidine would affect regional cerebral blood flow (rcbf) and microregional O2 29

37 Review of Literature consumption during nonhemorrhagic normovolemia and during severe hemorrhagic hypotension in rats. Dexmedetomidine caused a proportionate decrease of rcbf and O2 consumption in normovolemia. Hemorrhage decreased rcbf more than O2 consumption. Dexmedetomidine prevented rcbf and O2 consumption from decreasing after hemorrhage. The authors suggest that dexmedetomidine might help to provide optimal O2 supply and consumption balance during hemorrhage. Olcay et al 108 studied whether dexmedetomidine could alleviated vasospasm following subarachnoidal haemorrhage (SAH) in an animal model. The histological specimens revealed evidence of arterial narrowing and vascular wall thickening in both SAH-alone and SAH-dexmedetomidine groups. The wall thickness of basilar artery was significantly increased and lumen diameter significantly reduced in SAHalone group in comparison with SAH-dexmedetomidine group. Authors reported that vasospasm is attenuated by dexmedetomidine administered after vasospasm in a rabbit model. Can et al 109 studied effects of dexmedetomidine and methylprednisolone on inflammatory responses in spinal cord injury.tnf-α and IL-6 levels were significantly decreased with methylprednisolone and dexmedetomidine treatment, respectively. Methylprednisolone and dexmedetomidine treatment reduced neutrophils' infiltration in Spinal cord injury.they reported that this study does not clarify the definitive mechanism by which dexmedetomidine decreases inflammatory cytokines but it is the first study to report the anti-inflammatory effect of dexmedetomidine in SCI. Further studies are required to elucidate the effects of dexmedetomidine on the inflammatory response. 30

38 Review of Literature In a study by Drummond et al 50 in a study in six normal volunteers, the administration of dexmedetomidine to achieve serum levels of 0.6 ng/ml and 1.2 ng/ml (with and without hyperventilation) produced the predicted reduction of CBF with a concomitant reduction in CRMO 2. This finding suggests the maintenance of the cerebral oxygen supply-to-demand relationship. However, further work in injured brains needs to be done. Drummond et al 110 in 2010 studied the use of brain tissue oxygenation monitoring during neurovascular surgery and the use of dexmedetomidine as a component of the anesthetic in 5 patients. During general anesthesia with sufentanil and sevoflurane, with or without N2O, a parenchymal brain tissue oxygenation (PbrO2) electrode was placed directly in the territory at risk from the pending neurosurgical intervention., Dexmedetomidine was administered by bolus (1 µg/kg over 10min) and infusion (0.5 to 0.7 µg/kg/ min). Dexmedetomidine administration by bolus and infusion to patients with neurologic injuries related to neurovascular lesions did not result in reductions of tissue PO2 in brain in the vicinity of the lesions.these observations provide no support for a direct cerebral vasoconstrictive effect of dexmedetomidine in human volunteers that is independent of any vasoconstriction that may occur as a consequence of dexmedetomidine induced reduction in CMR. Sturaitis et al 49 in a study evaluating the effect of dexmedetomidine on brain tissue oxygenation in patients undergoing cerebrovascular surgery, found that even under circumstances of baseline cerebrovascular compromise and 31

39 Review of Literature hyperventilation, dexmedetomidine seemed to have no detrimental effect on local brain tissue oxygenation. Hall et al 96 evaluated the effect dexmedetomidine on Electrencephalogram. In humans volunteers, the infusion of dexmedetomidine at a rate of 0.6 µg/kg/h produced EEG changes that correspond to a bispectral index of 60 (moderate to deep sedation). The volunteers, however, were readily awakened simply by talking to them. The results of these studies suggest that processed EEG parameters may be inadequate to assess the depth of anesthesia in the presence of α 2 -agonists. Maksimow et al 111 showed depth of dexmedetomidine-induced sedation can be monitored with EEG-based spectral entropy in 11 healthy, non-smoking men. Spectral entropy was recorded before and during both low (0.5 ng/ml) and high (5 ng/ml) plasma concentrations of dexmedetomidine. At the end of the infusion, subjects were awakened by verbal command and light shaking. Spectral entropy decreased from 84 ± 5 to 66 ± 16 (P= 0.029) during low dexmedetomidine levels and from 84 ± 5 to 20 ± 12 (P < 0.001) during high dexmedetomidine levels. Transitions during loss and regaining of consciousness were analysed separately. Entropy decreased from 76 ± 8 before to 43 ± 10 (P < 0.001) after loss of consciousness, and increased from 14 ± 4 to 63 ± 13 (P < 0.001) on regaining of consciousness. These changes were consistent across all subjects. Bloom et al 112 described minimal effects of dexmedetomidine on somatosensory evoked potentials in 2 patients undergoing cervico-occipital fusion. 32

40 Review of Literature In a study by Sturaitis et al 113 the intraoperative adjuvant administration of dexmedetomidine in patients undergoing craniotomy for tumor or aneurysm had a minimal effect on cortical somatosensory evoked potential amplitudes or latencies. The same investigators looked at the effect of dexmedetomidine on flash electroretinogram and visual evoked potential monitoring during ophthalmic artery aneurysm Guglielmi detachable coiling and clipping and found the recordings to be reliable, with minimal effects on electroretinogram responses and with perhaps a tendency for visual evoked potential responses to be less delayed and less decreased in amplitude 114. Hence, dexmedetomidine allows for consistent and reliable neurophysiological monitoring in circumstances in which neural tissue is at risk for injury. Endrit et al 58 in 2008 reported, use of dexmedetomidine as an anesthetic adjunct at target plasma concentrations up to 0.6 ng/ml did not change somatosensory or motor evoked potential responses during complex spine surgery by any clinically significant amount. Tobias et al 115 studied the effects of dexmedetomidine on intraoperative motor and somatosensory evoked potential monitoring during spinal surgery in adolescents.dexmedetomidine was used as an adjunct to an opioid-propofol total intravenous anesthesia (TIVA) technique during posterior spinal fusion (PSF) surgery without affecting neurophysiological monitoring. 33

41 Review of Literature Anschel et al 116 reported the results of multimodality intraoperative neurophysiological monitoring during 18 cases in which a total intravenous anesthesia regimen incorporating dexmedetomidine was used. Monitoring techniques included sensory (SSEP) and motor evoked potentials (MEP), as well as pedicle screw stimulation. SSEPs were maintained within an acceptable range of baseline amplitude (50%) and latency (10%), and MEPs remained elicitable throughout each case. They found that the anesthetic regimen did not significantly interfere with any of the monitoring modalities used and conclude that intraoperative neurophysiological monitoring in the presence of dexmedetomidine is feasible under appropriate conditions. Zornow et al 117 studied the role of dexmedetomidine on intracranial pressure(icp), In normocapnic rabbits without intracranial pathological conditions, dexmedetomidine at low doses transiently decreases ICP by 30%. In the high-dose dexmedetomidine group, ICP remained unchanged despite a significant increase in arterial blood pressure, and it is likely that systemic hypertension counteracted the decrease in ICP observed with low doses. Dexmedetomidine did not alter ICP in rabbits with cryogenically induced space-occupying lesions. In a human study, Talke et al 53 found that dexmedetomidine administration to patients after transsphenoidal hypophysectomy had no effect on lumbar cerebrospinal fluid pressures. The rationale for this new, off-label use of dexmedetomidine is based on known properties of alpha2-agonists to provide analgesia 118,119,120. While avoiding depression of respiratory function

42 Review of Literature In two different studies by Arain et al and venn et al, dexmedetomidine had been shown to consistently reduce opioid requirements by 30 to 50% in postoperative patients requiring sedation in the ICU 124,125. The analgesic potential of α2-agonists, however, does not approximate the potency of opioids.in a study by Jaakola et al 126 the analgesic efficacy of dexmedetomidine a novel α 2 -adrenoceptor agonist was compared with fentanyl. Single intravenous doses of fentanyl (fentanyl; 2 µg/kg), dexmedetomidine (0.25, 0.50 and 1.0µg/kg) and placebo were administered to 5 healthy male volunteers in a double-blind, crossover study in randomized order. Fentanyl appeared to be more effective than dexmedetomidine; the difference was not, however, statistically significant. Mirski et al 127 and Miyazaki et al 128 in two different study showed dexmedetomidine reduces seizure threshold in various animal models, suggesting facilitation of seizure expression by the inhibition of central noradrenergic transmission. In fact, dexmedetomidine was used successfully in patients with known epilepsy for awake craniotomy for provision of sedation in awake craniotomies 54,55. Mack et al 129 described use of dexmedetomidine infusion as a supplement to general anesthesia in 10 patients undergoing awake craniotomy and neurocognitive testing. They reported successful completion of neurocognitive testing in all patients. Ard et al 130 reported a series of 17 patients who underwent an asleep-awakeasleep technique for awake craniotomy. The dexmedetomidine was continued at 0.1 to 0.4 µg kg/h during neurocognitive testing with satisfactory results.similar reports of the successful use of dexmedetomidine in pediatric patients and in tumor resection 35

43 Review of Literature had also been reported. The optimal dose of dexmedetomidine had been described as around 0.2 mcg kg/ h. Bekker et al 131 reported on the first application of dexmedetomidine for intraoperative language mapping in a patient undergoing left temporal neoplasm resection. The authors used a sleep-awake-sleep technique. Dexmedetomidine was the sole agent for the awake portion of the procedure. The pharmacology of dexmedetomidine allowed the authors to achieve a level of sedation and analgesia sufficient to complete the required neuropsychiatric testing, as well as to perform an awake tumor resection. Souter et al 132 have successfully used dexmedetomidine as a single sedative agent for awake craniotomy with epileptic foci and motor mapping, when coupled with scalp local anesthetic blocks,dexmedetomidine infusion between 0.2 and 0.5 µg kg/h allows successful sedation for craniotomy and basic ECoG. Many published reports documented the advantages, hemodynamic changes, complications associated with the use of dexmedetomidine for awake craniotomy The authors of these case series state that dexmedetomidine infusion at a low rate ( µg/kg/h) may be helpful for intraoperative functional testing in procedures where sedation and mild analgesia are the only anesthetic requirements. Stereotactic implantation of deep brain stimulators for movement disorders represents a challenge for surgeons and anesthesiologists. Most commonly used sedatives may suppress tremor (e.g., propofol) or affect microelectrode recording that is used for precise localization of the surgical target. The use of dexmedetomidine for 36

44 Review of Literature deep brain stimulator placement improved patient satisfaction without compromising target localization. In a series of pubished reports(2 reports by Rozet Iet al 136,137 and Elias et al 138 ) on use of dexmedetomidine for deep brain stimulator placement, dexmedetomidine in low-dose infusion rates (0.3µg/kg/h to 0.6 µg/kg/h) was shown to be a better choice because of its non-gaba-mediated mechanism of action allowing for microelectrode recording, hemodynamic stability, and analgesic properties Optimal conditions for Microelectrode recording or stimulation testing can be obtained with the use of conscious sedation as long as short-acting drugs are used and stopped before the recordings and testing. Bekker et al 139 reported that dexmedetomidine had been used successfully for sedating patients undergoing awake carotid endarterectomy, permitting intraoperative neurological examination.this prospective, randomized, double-blind study demonstrated that the use of dexmedetomidine resulted in less fluctuation from the desired sedation level intraoperatively compared with the control group (midazolam/fentanyl/propofol management). Furthermore, patients sedated with dexmedetomidine were comfortable and cooperative and had a lower incidence of postoperative hypertension than patients in the control group. Uyar et al 140, In a randomized, double-blinded, placebo-controlled study, 40 patients undergoing craniotomy with attachment of a pin head-holder were randomly assigned to one of 2 equal groups. The placebo group received saline, whereas the treatment group (Dexmedetomidine group) received a single bolus dose of dexmedetomidine (1 µg/kg) intravenously over 10 minutes before induction of anesthesia. Single bolus dose of dexmedetomidine before induction of anesthesia attenuated the hemodynamic 37

45 Review of Literature and neuroendocrinal responses to skull-pin insertion in patients undergoing craniotomy. Changani et al 141 studied the use of dexmedetomidine for sedation in patients with traumatic brain injury (21). Dexmedetomidine infusion was used safely and uneventfully in three traumatic brain injury patients with high levels of anxiety and agitation. Pandharipande et al 142 compared the dexmedetomidine and lorazepam for sedating patients with acute brain dysfuntion during mechanical ventilation. Clinical outcome showed no significant differences in ventilator free days, length of stay in the ICU and rate of mortality after 28 days. Previous studies had shown that dexmedetomidine could dramatically reduce end-tidal concentrations of volatile anesthetics. A study by Fragen et al 143 indicated that dexmedetomidine reduced the amount of sevoflurane necessary to effectively and safely anesthetise humans by 17%. Gunes et al 10 evaluated the role of dexmedetomidine in patients undergoing intracranial surgery. They compared perioperative hemodynamic and postanesthesia recovery profiles in patients anesthetized with dexmedetomidine remifentanil nitrous oxide versus propofol remifentanil nitrous oxide anesthesia. Acute arterial blood pressure elevations were treated with increasing doses of propofol and dexmedetomidine. No patient (in either group) required antihypertensive medication. Lawrence et al 144 in a double-blinded, placebo-controlled study investigated the effect of a single pre-induction intravenous dose of dexmedetomidine 2 µg.kg 1 on anaesthetic requirements and peri-operative haemodynamic stability in 38

46 Review of Literature 50 patients undergoing minor orthopaedic and general surgery. Patients were anaesthetised with nitrous oxide/oxygen/fentanyl, supplemented if necessary with isoflurane. The mean (SD) intra-operative isoflurane concentration was lower in the dexmedetomidine-treated patients than controls (0.01 (0.03)% compared to 0.1 (0.1)%; p = 0.001). Although six of the 25 treated patients required isoflurane at some stage. The haemodynamic response to tracheal intubation and extubation was reduced in the dexmedetomidine group as was intra-operative heart rate variability. Postoperative analgesic and anti-emetic requirements and peri-operative serum catecholamine concentrations were lower in the dexmedetomidine group. Hypotension and bradycardia occurred more frequently after dexmedetomidine. Yieliz et al 145 studied the effect of dexmedetomidine on haemodynamic responses to laryngoscopy and intubation and Perioperative haemodynamics and anaesthetic requirements. Fifty patients scheduled for elective minor surgery were randomised into two groups (dexmedetomidine group and placebo group, n = 25 in each group). Preoperative administration of a single dose of dexmedetomidine resulted in progressive increases in sedation, blunted the haemodynamic responses during laryngoscopy, and reduced opioid and anaesthetic requirements. Furthermore, dexmedetomidine decreased blood pressure and heart rate as well as the recovery time after the operation. Alex Bekker et al 12 randomly assigned patients scheduled for elective craniotomy to receive either sevoflurane opioid or sevoflurane opioid dexmedetomidine anesthesia. A significantly smaller proportion of patients in the dexmedetomidine group required treatment with antihypertensive medications (12 of 28, 42% vs 24 of 28, 86%, P=0.0008). The dexmedetomidine group required fewer 39

47 Review of Literature opioids in the period, but there were no differences in the use of sevoflurane. In the postanesthesia care unit, patients in the dexmedetomidine group had fewer hypertensive episodes (1.25 ± 1.55 vs 2.50 ± 2.00, P = ) and were discharged earlier (91 ±17 vs 130 ± 27 min, P = ). There were no differences in the requirement for postoperative opioids or antiemetics. In conclusion, a continuous infusion of dexmedetomidine improved hemodynamic stability in patients undergoing intracranial surgery without increasing the incidence of hypotensive episodes or bradycardia. In addition, patients treated with dexmedetomidine were discharged from the PACU earlier than patients in the placebo group. Tanskanen et al 11 reported the effect of dexmedetomidine infusion on perioperative hemodynamics in patients maintained with nitrous oxide, isoflurane, and fentanyl. Fifty-four patients with supratentorial brain tumour scheduled for elective surgery were randomized to receive in a double-blind manner a continuous dexmedetomidine infusion (plasma target concentration 0.2 or 0.4 ng /ml) or placebo. The patients received fentanyl 2 µg/kg and 4 µg/kg at the induction of anaesthesia and before the start of operation in dexmedetomidine group and placebo group respectively. Anaesthesia was maintained with nitrous oxide in oxygen and isoflurane. The median times from the termination of N2O to extubation were 6 (3 27), 3 (0 20) and 4 (0 13) min in placebo, dexmedetomidine -0.2 and dexmedetomidine -0.4 groups, respectively (P<0.05 ANOVA all-over effect). The median percentage of time points when systolic blood pressure was within more or less than 20% of the intraoperative mean was 72, 77 and 85, respectively (P<0.01), dexmedetomidine -0.4 group differed significantly from the other groups. Dexmedetomidine blunted the tachycardic response to intubation (P<0.01) and the hypertensive response to 40

48 Review of Literature extubation (P<0.01). Dexmedetomidine -0.4 group differed in the heart rate variability from placebo (93 vs 82%, P<0.01). The study concluded that with dexmedetomidine, there was a decreased response to noxious stimuli, intubation, and extubation, thus yielding greater hemodynamic stability compared with placebo. Compared with fentanyl, the trachea was extubated faster without respiratory depression. Gunes et al 146 in patients undergoing supratentorial craniotomy studied the infusion of dexmedetomidine as an adjuvant for a comparison of sevoflurane, desflurane or isoflurane anesthesia. The concentrations were lower throughout the study period than during concentrations of initial anesthetic agents. In the sevoflurane-dexmedetomidine group, the sevoflurane concentration was reduced by a mean of 50% from the induction of anesthesia to dural closure. Similarly, desflurane concentration decreased by approximately 36%, isoflurane concentration reduced by 40%.In addition dexmedetomidine provided better brain relaxation and good surgical field exposure. 41

49 Aims and Objectives AIMS AND OBJECTIVES 1) To assess the effect of dexmedetomidine on the maintenance of hemodynamic stability in patients undergoing transnasal transsphenoidal resection of pituitary tumors. 2) To assess if the use of dexmedetomidine reduces intraoperative opioid and inhalational anesthetic requirement. 3) To evaluate the provision of condition that facilitates surgical exposure. 4) To evaluate recovery characteristics when dexmedetomidine is used as anesthetic adjuvant. 42

50 Materials and Methods MATERIALS AND METHODS Study design was prospective randomized blinded placebo controlled trial. After obtaining approval from institutional ethics committee and written informed consent, 44 consecutive neurosurgical patients undergoing transnasal transsphenoidal resection of pituitary tumour were enrolled in the study. Patients were randomized to one of the two arms based on computer generated random numbers. Group D to receive dexmedetomidine infusion (n =22) Group C to receive 0.9% sodium chloride as placebo (n =22) Inclusion criteria: Patients categorized as American society of Anesthesiology (ASA) class 1or 2 Age years Elective Transnasal Transsphenoidal resection of pituitary tumor surgery Preoperative Glasgow coma scale (GCS) 15 Exclusion criteria: American society of Anesthesiology (ASA) class 3 and above Age less than 18 years and more than 65 years Preoperative Glasgow coma scale (GCS) <15 Anticipated difficult airway Preoperative heart rate <50 beats per minute First or second or third degree heart block 43

51 Materials and Methods Known allergy to dexmedetomidine Patient on beta blockers, coronary artery disease, left ventricular dysfunction Pregnant or nursing woman Antihypertensive medication with alpha-methyldopa, clonidine or other a2- adrenergic agonist Participation in another drug study during the preceding 1 month period Patient refusal MATERIAL Dexem TM, 2 ml ampoule (Manufactured by Themis Medicare Limited ) Each ml contains Dexmedetomidine hydrochloride injection equivalent to Dexmedetomidine..100µg. METHODOLOGY Upon arrival in the operating room, patients were connected to standard monitors such as electrocardiogram, invasive arterial blood pressure monitoring, and pulse oximetry probe. Entropy monitor was used for titrating anaesthetic drugs according to the observed depth of anaesthesia. The baseline heart rate, blood pressure and oxygen saturation were recorded. Patients in the Group D received intravenous infusion of dexmedetomidine diluted in 50 ml saline (200µg in 50 ml saline) 15 minutes before induction of anesthesia and patients in Group C received 0.9% normal saline (50ml). 44

52 Materials and Methods The dose of dexmedetomidine given was 1 µ/kg over 10 minutes as intravenous loading dose followed by 0.7 µ /kg /hour till 10 minutes before the end of surgical procedure. Both the groups received fentanyl 3 microgram/kg body weight before induction. Anesthesia was induced with propofol (up to 2mg/kg) titrated with the loss of eye lash reflex. Neuromuscular blockade was achieved by vecuronium 0.15 mg/kg intravenous. After adequate neuromuscular blockade was achieved, direct laryngoscopy and intubation of trachea with appropriate size endotracheal tube was performed. Endotracheal tube placement was confirmed with auscultation and end-tidal carbon-dioxide monitoring. The hemodynamic variables like heart rate, blood pressure, end tidal carbondioxide and inhalation agent concentration, entropy values were noted at the various stages of the surgery as described below. Anesthesia was maintained with air in oxygen (50%:50%) and isoflurane (gradually increased to 0.7% end-tidal concentration) and 1.0 microgram per kg increments of fentanyl. Intermittent positive pressure ventilation with tidal volume of 7 to 8ml/kg body weight was done to maintain end tidal carbondioxide between 32 to 35mm Hg. Total fresh gas flow rate was kept constant at 2 L/min. Posterior pharynx was packed with moist cotton gauze under direct laryngoscopy. 45

53 Materials and Methods Entropy was used to guide the administration of isoflurane. The entropy range during maintenance was 40 to 60. Neuromuscular monitoring was used to titrate administration of vecuronium. Further doses of fentanyl and inhalational agent were decided according to the haemodynamic changes and clinical signs of anesthetic depth. Any rise in the heart rate or mean blood pressure, more than 20% of baseline and clinical signs of light anaesthesia (bucking, lacrimation, sweating, flushing and movement) was treated by fentanyl 2.0 µg /kg. If that was not sufficient within 4 minutes, isoflurane end-tidal concentration was increased by 0.2% every 4 minutes up to a maximum of 1.1%. Once hemodynamically stable, isoflurane end-tidal concentration was decreased by 0.2% every 4 minutes as long as the values remained in the predetermined limits. If end-tidal concentration of 1.1% was not sufficient to decrease arterial pressure and heart rate within acceptable values, fentanyl was given in 1.0 µg / kg increment every 4 minutes until the objective was achieved. If hypertension continued to persist appropriate antihypertensive agents like beta blockers, combined α β blockers were used. If hypotension (SBP<90 mm Hg) occurred, mephentermine 5 mg or phenylephrine 50 to 100 microgram intravenously was used. Bradycardia (HR<40 beats per minutes) was treated with 0.6 mg bolus of atropine. The number of interventions required when haemodynamic variables were outside the predetermined window was recorded. 46

54 Materials and Methods Termination of anaesthesia: The study drug infusion was discontinued at approximately 10 min before the estimated end of surgery. At the end of surgery, defined as the time when the neurosurgeon removed the nasal speculum. Isoflurane was discontinued and the lungs were ventilated with 100% oxygen. The doses of fentanyl, end-tidal Isoflurane and MAC of Isoflurane administered during maintenance were recorded. Ondansetron 4mg as antiemetic agent was prophylactically administered in all patients. At the end of surgery, neuromuscular blockade was antagonized with neostigmine 50 microgram/kg and glycopyrrolate 10 microgram /kg, when the train-of-four response was 2 or above. The patient s trachea was extubated when respiration was deemed sufficient and patients were able to open the eyes spontaneously or obey simple commands. All patients received intramuscular diclofenac sodium 75mg.The time to emergence, extubation and time space orientation (stating name and date of birth) was noted. Emergence time was measured as the time interval between Isoflurane discontinuation and the time to open eyes spontaneously or on verbal commands. Extubation time was measured as the time interval between Isoflurane discontinuation and extubation (performed when the patient obeyed verbal commands, demonstrated purposeful movement, and had adequate spontaneous breathing). Recovery characteristics were assessed with a modified Aldrete score (0 to 10) at 10 minutes after tracheal extubation, depending on respiration pattern, 47

55 Materials and Methods oxygen saturation, Blood pressure, level of consciousness and movements of all our limbs. An observer who was blinded to the group allocation of the patients carried out the assessments of all early recovery end-points. All patients were then moved to the neurosurgery ICU, where observation was continued by an investigator and an ICU nurse, neither of whom was aware of the anaesthetic regimen. Data collection: The hemodynamic variables (HR,SBP,DBP,MAP), Etco2, End-tidal inhalational agent concentration, Entropy values were noted during the various stages of the surgery: 1. Base line 2. Before and after intubation (preintubation and postintubation maximal rise within 3 min of tracheal intubation) 3. Before and after nasal packing of saline swabs soaked in adrenaline (prenasal packing and postnasal packing maximal rise within 3 min) 4. Insertion of Hardy s self-retaining nasal speculum (prespeculum and postspeculum maximal rise within 3 min) 5. At the time of sphenoid bone and sellar ridge dissection (maximal rise) 6. Pre extubation and post extubation maximal rise within 3 min of post extubation) Intraoperative total fentanyl and antihypertensive use was noted. Intraoperative fluid intake, urine output and blood loss was noted. 48

56 Materials and Methods The quality of the surgical field in terms of blood loss and dryness was rated at the same predetermined times by the neurosurgeon, who was unaware of the pharmacological treatments, using a four-point scale: 0 point : excellent surgical conditions; 1 point : moderate bleeding; 2 points : abundant bleeding with reduced view of surgical field; 3 points : impossible to perform surgical maneuvers. The time to emergence, extubation and time space orientation (stating name and date of birth) was noted. Recovery characteristics were assessed using modified Aldrete score (0 to 10) at 10 minutes after tracheal extubation. Modified Aldrete Scoring System Category Score = 2 Score = 1 Score = 0 Respirations Breathes,coughs freely Dyspnea Apnea O2 Saturation SpO2 > 92% on Supplemental O2 SpO2 < 92% on O2 room air Circulation BP ± 20 mmhg preop value BP ± mmhg pre-op value BP ± 50 mmhg pre-op value LOC Awake and oriented Wakens with stimulation Non-responsive Movement Moves 4 limbs Moves 2 limbs Moves 0 limbs spontaneously spontaneously spontaneously 49

57 Materials and Methods The level of postoperative pain was assessed by patient questioning, using a four-point scale (0-none; 1-mild; 2-moderate; 3-severe). The incidence of nausea or vomiting on a scale 0 3 (0-none, 1-mild, 2- moderate and 3-severe) and other adverse events were also recorded. Pain and postoperative nausea or vomiting (PONV) were assessed at ICU arrival and then every 15 minutes for initial 2 hours in ICU. Arterial blood gas was done in all patients after 90min of arrival in the ICU. STATISTICAL ANALYSIS Results obtained from the study were expressed in mean +/- SD, for non parametric data Chi square test was applied and for numeric data with continuous variables ANOVA for repeated measures followed by post hoc analysis with least significance difference (LSD) was performed. A p value less than 0.05 was considered as statistically significant and less than 0.01 as highly significant. The software SPSS 17.0 was used for analysis. 50

58 Observations and Results OBSERVATIONS AND RESULTS Results obtained from the study were expressed in tabular form in the following section. Numeric data has been expressed as mean ± SD. Chi square test was applied for non parametric data. ANOVA for repeated measures followed by post hoc analysis with Least Significance Difference (LSD) was performed for comparing continuous variables within the groups at different time points. For intragroup comparison (at the same time point, between the groups), students t test was applied. A p value <0.05 was considered as statistically significant and <0.01 as highly significant. The software SPSS (version 17.0) has been used for analysis. Forty four patients were randomly allocated to the 2 groups, comprising of 22 patients each. Group D (Dexmedetomidine) and Group C (Control). Table 1: Demographic data and prevalence of hypertension in the Dexmedetomidine and in Control Groups. Table 2: Nature of Pituitary adenoma and duration of surgery in the Dexmedetomidine and in Control Groups. Table 3a, 3b : Changes of hemodynamic parameters; Heart Rate (HR), Mean Arterial Pressure (MAP), Systolic Blood Pressure (SBP), and Diastolic Blood Pressure (DBP) with respect to different time points between the Dexmedetomidine and in Control Groups. [* denotes the level denotes the level of significance when Dexmedetomidine group has been compared with Control group at each time points. p<0.05 is considered to be significant (*), p<0.01 is highly significant (**) 51

59 Observations and Results, indicates the level of significance when baseline has been compared with the values at other time points within the same group, ( ) indicates p<0.05 i.e Significant; ( ) indicates p<0.05 i.e highly significant] Baseline Heart Rate (HR), Mean Arterial Pressure (MAP), Systolic Blood Pressure (SBP), and Diastolic Blood Pressure (DBP) were comparable between the groups. HR was higher in Control group when compared with Dexmedetomidine group during postintubation, postnasal pack, postspeculum, sphenoid dissection and at postextubation stages. When HR was compared with baseline at different time points within the group, it was found that in Dexmedetomidine group HR was low compared to the baseline at prenasal pack, prespeculum, stoppage of agent, and at postextubation stages. In Control group no significant changes in HR was observed at different time points when compared to the baseline. Mean Arterial Pressure (MAP), Systolic Blood Pressure (SBP), and Diastolic Blood Pressure (DBP) were significantly higher (p<0.01) in the Control group when compared with Dexmedetomidine group at the following time points: postintubation, post nasal packing, prespeculum, postspeculum, sphenoid dissection, sellar dissection, stoppage of agent and at postextubation stages. MAP, SBP, and DBP were significantly lower in Dexmedetomidine group (p<0.01) when compared with their respective baseline values during prenasal packing, prespeculum, sellar dissection, stoppage of agent and at postextubation stages, while in Control group they were significantly higher when compared with the baseline values during postintubation, postnasal packing, postspeculum and at postextubation stages 52

60 Observations and Results Table1: Demographic profile of the Dexmedetomidine and Control Groups (mean ± SD) Parameter Dexmedetomidine Control Group Group Age (years) 41.9 ± ± 12.3 # Weight (Kg) 63.5 ± ± 10.1 # Sex(male: female) 10:12 15:07 # ASA I/ASA II 12:10 09:13 # History of hypertension(n) 3 4 # # Statistically Non significant Table.2: Pituitary pathology, Duration of surgery and total fentanyl requirements in the Dexmedetomidine and Control Groups Dexmedetomidine Group Control Group Non-funtioning pituitary adenoma GH secreating pituitary adenoma 3 3 ACTH secreating pituitary adenoma 0 1 Prolactin secreating pituitary 0 1 adenoma Duration of surgery (minutes) 187 ± ± 38.2 # (mean ± SD) Total fentanyl (microgram/kg) (mean ± SD) 4.7 ± ± 1.5** p > 0.05 Non-significant, **; p < highly significant 53

61 Observations and Results Table 3a :Comparison of Heart rate and Mean arterial Blood pressure in 2 study groups(mean ± SD) Heart Rate (beats/min) Mean Arterial Blood pressure(mmhg) Stages Group D Group C p value Group D Group C p value (n=30) (n=30) (n=30) (n=30) Baseline 76.3 ± ± ± ± preintubation 71.4 ± ± ± ± postintubation 68.2 ± ± * 95.1 ± ± ** prenasal pack 65.6 ± ± ± ± ** postnasal pack 66.8 ± ± ** 91.0 ± ** prespeculum 65.6 ± ± ± ± ** postspeculum 66.9 ± ± ** 92.5 ± ± ** sphenoid dissection 68.0 ± ± * 87.6 ± ± ** sellar dissection 65.5 ± ± * 82.3 ± ± ** stoppage of agent 66.0 ± ± ± ± ** post extubation- 0 min 66.7 ± ± ** 84.9 ± ± ** post extubation- 15 min 65.0 ± ± ** 81.2± ± ** post extubation- 30 min 64.0 ± ± ** 83.1 ± ± ** post extubation- 45min 63.1 ± ± ** 84.4± ± ** post extubation-6 0 min 62.5 ± ± ** 85.1± ± ** * denotes the level of significance when Dex group has been compared with Control group at each time points p<0.05 is considered to be significant (*), p<0.01 is highly significant (**), indicates the level of significance when baseline has been compared with the values at other time points within the same group, ( ) indicates p<0.05 i.e Significant ; ( ) indicates p<0.05 i.e highly significant. 54

62 Observations and Results Table 3b: Comparison of Systolic Blood pressure and Diastolic Blood pressure in 2 study groups(mean ± SD) Stages Group D (n=30) Systolic Blood pressure (mmhg) Group C (n=30) p value Diastolic Blood pressure (mmhg) Group D (n=30) Group C (n=30) p value Baseline 131 ± ± ± ± preintubation ± ± ** 75.6 ± ± postintubation ± ± ** 75.5 ± ± ** prenasal pack 114.3± ± ± ± * postnasal pack ± ± ** 72.1 ± ± ** prespeculum 113.4± ± * 67.5 ± ± ** postspeculum ± ± ** 74.2 ± ± ** sphenoid dissection 117.5± ± ** 69.8 ± ± ** sellar dissection ± ± ** 65.9 ± ± ** stoppage of agent ± ± ** 62.1 ± ± ** post extubation- 0 min 117 ± ± ** 68.9 ± ± ** post extubation- 15 min 113 ± ± ** 65.3 ± ± ** post extubation- 30 min ± ± ** 65.9 ± ± ** post extubation- 45min ± ± ** 67.8 ± ± ** post extubation-60 min ± ± ** 68.0 ± ± ** * denotes the level of significance when Dex group has been compared with Control group at each time points <0.05 is considered to be significant (*), p<0.01 is highly significant (**), indicates the level of significance when baseline has been compared with the values at other time points within the same group ( ) indicates p<0.05 i.e Significant ; ( ) indicates p<0.05 i.e highly significant Table 4: Isoflurane inhalational End Tidal (ET) and Minimum Alveolar Concentration (MAC) requirements in Dexmedetomidine and in Control Groups. ET(Isoflurane) MAC Stages Group D Group C p value Group D Group C p value preintubation 0.8 ± ± ** 0.7 ± ± ** postintubation 0.8 ± ± ** 0.7 ± ± ** prenasal pack 0.8 ± ± ** 0.7 ± ± ** sphenoid dissection 117.5± ± ** 69.8 ± ± ** sellar dissection ± ± ** 65.9 ± ± ** stoppage of agent ± ± ** 62.1 ± ± ** post extubation- 0 min 117 ± ± ** 68.9 ± ± ** post extubation- 15 min 113 ± ± ** 65.3 ± ± ** post extubation- 30 min ± ± ** 65.9 ± ± ** post extubation- 45min ± ± ** 67.8 ± ± ** post extubation-60 min ± ± ** 68.0 ± ± ** ** denotes the level of significance when Dexmedetomidie (D) group has been compared with Control (C) group at each time points p<0.01 is highly significant (**) 55

63 Observations and Results Table 5: Response Entropy (RE) and Static Entropy (SE) in Dexmedetomidine Group and in Control Group at different time points Response Entropy Static Entropy Stages Group D Group C p value Group D Group C p value (n=30) (n=30) (n=30) (n=30) Baseline 97.3 ± ± ± ± preintubation 48.3 ± ± ± ± postintubation 43.1 ± ± ** 39.7 ± ± ** prenasal pack 41.0 ± ± ** 39.3 ± ± ** postnasal pack 40.5 ± ± ** 39.0 ± ± ** prespeculum 40.6 ± ± ** 38.7 ± ± ** postspeculum 39.0 ± ± ** 47.6 ± ± ** sphenoid dissection 40.1 ± ± ** 38.3 ± ± ** sellar dissection 40.1 ± ± ** 38.2 ± ± ** stoppage of agent 47.9 ± ± ** 45.6 ± ± ** post extubation- 0 min 97.9 ± ± ± ± ** denotes the level of significance when Dexmedetomidine(D) group has been compared with Control(C) group at each time points. (**) - p<0.01 is highly significant. Table 6: Dexmedetomidine induced Hypertension, Bradycardia ad Hypotension in Dexmedetomidine Group. Dexmedetomidine bolus induced Hypertension 2/22 (9.1%) Dexmedetomidine bolus induced Bradycardia 3/22(13.6%) Dexmedetomidine infusion induced Hypotension 2/22(9.1 % ) 56

64 Observations and Results Table 7: Comparison of fluid intake, urine output & blood loss (mean±sd) Group D (n=22) Group C (n=22) P value Fluid intake 1291 ± ± # Urine output 561 ± ± # Blood loss 135 ± ± * SD-standard deviation,d-dexmedetomidine,c-control # P > 0.05 Nonsignificant, *p < statistically significant Table 7: fluid intake and urine out between 2 groups were statistically not significant. Blood loss was significantly lower in dexmedetomidine group compared to control (p< 0.05). Table 8 : Intraoperative use of Antihypertensive in 2 groups Group D (n=22) Group C (n=22) Intraoperative Antihypertensive used 0 7 D-Dexmedetomidine, C-control, n-number of patients Table 8: Intraoperative antihypertensive was used in 31.8 % of control group.but none of the dexmedetomidine group required antihypertensive. Table 9 :Recovery characteristics in 2 study groups (mean ± SD) Group D(n=22) Group C(n=22) Emergence time(min) 6.95 ± ± 2.19** Extubation time(min) 8.05 ± ± 2.27** Orientation time(min) ± ± 3.11** Modified Aldrete score 10 ± ± 0.55** SD-standard deviation,d-dexmedetomidine,c-control, n-number of patients. ** P<0.01-Statistically highly significant 57

65 Observations and Results Table 9: Emergence time,extubation time and time to orientation were significantly shorter in dexmedetomidine group when compared to control group (p<0.01). Table 10: Bleeding Score in the 2 study groups Bleeding score(0-3) Group D(n=22) Group C(n=22) o Modified Aldrete score at 10 minutes of extubation was significantly better with dexmedetomidine group when compared to control group (p<0.01). Bleeding score: 0-Excellent surgical condition,1-moderate bleeding,2-abundant bleeding with Reduced view of surgical field,3-impossible to perform surgical manoeuvres. D-Dexmedetomidine,C-control Table 11 :Comparison of Bleeding score between 2 groups : Group D(n=22) Group C(n=22) P value Excellent surgical condition # Moderate to abundant bleeding 5 13 SD-standard deviation,d-dexmedetomidine,c-control # P > 0.05 Nonsignificant, Table 10,11 : Bleeding score (0-3) was compared between 2 groups.none of the group had score 3. Though more number of patients in the dexmedetomidine group had excellent surgical condition compared to control group, but statistically not significant.moderate to abundant bleeding was more in control group compared to dexmedetomidine group,, but statistically not significant. 58

66 Observations and Results Table 12 : PONV and Postoperative pain score in 2 study groups : Group D (n=22) Group C (n=22) PONV score (0-3) Pain score (0-3) PONV- Postoperative Nausea vomiting, D-Dexmedetomidine,C-control Table 12,13: PONV were more in control group compared to dexmedetomidine group.statistically highly significant(p<0.01). Table 13 :PONV comparison between 2 study groups Group D Group C (n=22) P value (n=22) No postoperative nausea vomiting 17 (77.3%) 13 (59.1%) 0.005** Postoperative nausea vomiting 5 (22.7%) 9 (40.9%) SD-standard deviation,d-dexmedetomidine,c-control, n-number of patients. ** P<0.01-Statistically highly significant Fisher exact test was used. 59

67 Observations and Results Table 14 : Postoperative pain comparison between 2 study groups Group D (n=22) Group C (n=22) P value No Pain 17 (77.3%) 13 (59.1%) 0.005** Mild to moderate pain 5 (22.7%) 9 (40.9%) SD-standard deviation,d-dexmedetomidine,c-control, n-number of patients. ** P<0.01-Statistically highly significant Fisher exact test was used. Table 14: pain score were more in control group compared to dexmedetomidine group.statistically highly significant(p<0.01). Table15 :Comparison of Pao 2 and Pco 2 after extubation in 2 groups Group D (n=22) Group C (n=22) P value Pao ± ± # Pco ± ± # D-Dexmedetomidine, C-control, n-number of patients, # Statistically Non significant Pao 2 - partial pressure of oxygen.pco 2 -partial pressure carbodioxide Table 15: comparison of partial pressure of oxygen and partial pressure of carbondioxide after 2 hours of extubation between 2 groups were statistically not significant (p > 0.05). 60

68 Graphs and illustrations Graph1: Changes in Heart Rate between the groups. * indicates p<0.05; ** indicates p< = Baseline, 2= pre intubation, 3= post intubation, 4= pre nasal pack, 5= post nasal pack, 6= pre speculum, 7= post speculum, 8= sphenoid dissection, 9= sellar dissection, 10= stoppage of agent, 11= post extubation- 0 min, 12= post extubation- 15 min, 13= post extubation- 30 min, 14= post extubation- 45 min, 15= post extubation- 60 min 61

69 Graphs and illustrations Graph 2 (above): Changes in Mean Arterial Pressure between the groups. Graph 3 (below): Changes in Systolic Blood Pressure between the groups. * indicates p<0.05; ** indicates p< = Baseline, 2= pre intubation, 3= post intubation, 4= pre nasal pack, 5= post nasal pack, 6= pre speculum, 7= post speculum, 8= sphenoid dissection, 9= sellar dissection, 10= stoppage of agent, 11= post extubation 0 min, 12= post extubation 15 min, 13= post extubation 30 min, 14= post extubation 45 min, 15= post extubation 60 min 62

70 Graphs and illustrations Graph 4 (above): Changes in Endtidal isoflurane between the groups. Graph 5 (below): Changes in minimum alveolar concentration between the groups. * indicates p<0.05; ** indicates p< = pre intubation, 2= post intubation, 3= pre nasal pack, 4= post nasal pack, 5= pre speculum, 6= post speculum, 7= sphenoid dissection, 8= sellar dissection, 9= stoppage of agent, 63