Attenuation Of Haemodynamic Responses To Laryngoscopy And Endotracheal .

PATHOPHYSIOLOGY OF THE HEMODYNAMIC CHANGESThe changes in airway reactivity associated with intubation are:1.Glottis closure reflex, i.e. laryngospasm due to brisk motor response2.Reduction in dead space3.Increase in airway resistance4.Bronchospasm as a reflex response to intubation5.Removal of the glottis barrier and may lower lung volume6.Cough efficiency is reduced.Two academic interpretors of perioperative cardiac morbidity are rise in heartrate and rise in blood pressure.The haemodynamic changes due to intubation resulting from sympatheticnervous stimulation which predispose patients to ischemia comprise of increasein heart rate, blood pressure, pulmonary capillary wedge pressure and reducedejection fraction.An increase in heart rate deleteriously affect myocardial oxygen supply(reduced diastolic filling time) and demand (increased cardiac work load). Bloodpressure has direct relation with cardiac output and systemic vascular resistance.Acute increase in blood pressure affects both myocardial oxygen supply andoxygen demand. During systemic hypertension, peak systolic ventricular walltension occurs, which increases myocardial oxygen consumption.10

Cardiac output and systemic vascular resistance are related to each otherwith variations in one resulting in a compensatory response in the other. Bothheart rate and blood pressure are primary determinants of balance betweenmyocardial oxygen supply and oxygen demand. Heart rate is there on bothoxygen supply and oxygen demand sides of the myocardial equation. Myocardialoxygen supply can increase by a reduction in heart rate and rise in diastolic bloodpressure, both within physiological limits. They act by allowing a prolongeddiastolic filling time and a greater coronary perfusion pressure respectively.Myocardial oxygen demand increases according to rise in heart rate, resulting ina less diastolic filling time and myocardial perfusion time.It has been recognized that there are six determinants of myocardial worki .e. myocardial oxygen consumption. They are:Minor factors (which are more or less fixed):1.Metabolism (20%)2.External work (17%)3.Activation energy (3%)Major factors (can be altered by pharmacological or physical methods):1.Systolic wall tension (30-40%)2.Contractility (10-15%)3.Heart rate11

Systolic wall tension is the most significant determinant of left ventricularwork, accounting for 30 -40% of the energy needs of the beating heart. It isdirectly proportional to the product of arterial blood pressure (afterload) and leftventricular filling pressure (preload). Therefore an increase in either of thesebeyond their normal range will cause an increased myocardial work byincreasing systolic wall tension. This also has a linear relation with themyocardial oxygen consumption. The concept of rate pressure product (heart ratex systemic blood pressure), introduced by Geor ta et al (1957) has been found toeffectively reflect changes in myocardial oxygen consumption.Myocardial contractility accounts for 10 -15% of myocardial oxygenconsumption and cardiac work. Increase in heart rate is associated with a rise inmyocardial contractility. Therefore rise in hear t rate means rise in myocardialwork load i .e. increase in oxygen demand.On the other side of the scale is the myocardial oxygen supply. Supply isregulated by adjusting coronary blood flow, which is dependent on coronaryvascular resistance. As myocardial blood flow occurs in diastole, diastolic bloodpressure gives an estimate of the per fusion pressure. A diastolic blood pressureof 60mm Hg is generally accepted as a lower limit below which the perfusion islikely to be compromised. Duration of diastole is another important factoraffecting myocardial oxygen supply. At a normal heart rate of 75/minute,diastole occupies more than 60 percentage of the cardiac cycle. When the heartrate increases, systolic intervals change little while diastolic intervals decreases12

significantly. At a maximum heart rate of 180/minute, diastole occupies only 40percentage of the cardiac cycle. Here, an increase in rate impairs the myocardialsupply and can lead to ischemia or infarction when the balance between oxygensupply and demand is already compromised. These facts show the importance ofattenuating the stress response.Factors affecting myocardial oxygen supply are:Heart rateMyocardial oxygen supply depends upon diastolic time. Hence, lower theheart rate, more the diastolic time and more the oxygen supply to myocardium.Coronary perfusion pressureIt depends on aortic diastolic pressure and ventricular end diastolicpressure and it increases with a high aortic diastolic pressure and low ventricularend diastolic pressure.Arterial oxygen contentDepends on arterial oxygen tension and hemoglobin concentration.Coronary vessel diameterMyocardial oxygen supply is directly proportional to diameter of coronaryvessel. Hence when the vessel is in stenosis, the supply is reduced13

ATTENUATION OF HAEMODYNAMIC RESPONSES TO AIRWAYINSTRUMENTATION - LARYNGOSCOPY AND ENDOTRACHEALINTUBATIONDirect laryngoscopy and endotracheal intubation which is beingconsidered the standard measure to secure the airway before induction of generalanaesthesia known to cause a pressor response that leads to undue raise in theblood pressure and the heart rate. Reid and Brace noted the stress response.Various modalities were employed to blunt the stress response to provide safeanaesthesia to the patients with comorbidities. They were1) General Anaesthesia with deeper plane2) Vasodilators3) Narcotics4) Adrenergic blockers5) Calcium channel blockers6) Alpha 2 agonists7) Midazolam8) Magnesium sulphate9) Lignocaine10) Thoracic epidural8General Anaesthesia with deeper planeCardiovascular reactions to the airway instrumentation attenuated whenvolatile anaesthetic agents inhaled and the concentration that is required toproduce the desired effect to obtund the hemodynamic responses to endotracheal14

intubation is referred as MAC- minimal alveolar concentration. The deeper planeobtained by the use of inhalation of volatile anaesthetic gases found to causecardiac depression before airway instrumentation. Volatile anaesthetic agents areHalothane, Isoflurane and Sevoflurane.1Vasodilators:7Vasodilators used to suppress the cardiovascular reactions to noxiousstimuli produced by the airway instrumentation were1) Hydralazine2) Sodium Nitroprusside3) NitroglycerinNarcotics:Narcotics that were used to blunt the hemodynamic response tolaryngoscopy and endotracheal emifentanyl5)Morphine & Pethidine15

Among the narcotics, frequently used to blunt the stress response wasFentanyl. Fentanyl is a synthetic, lipophilic phenylpyperidine derivative opioidagonist with analgesic and sedative properties.MECHANISM OF ACTIONSUPRASPINAL:Fentanyl binds with receptors in rostroventral region of medulla and blocknociceptive stimuli transmission.SPINAL LEVEL:Fentanyl acts in substantia gelatinosa of dorsal horn cells and inhibit therelease of excitatory neurotransmitters.At cellular level opiods bind receptors and stimulate G protein synthesisand increases cAMP which causes hyperpolarisation of membrane and imulationcausedbyairwayinstrumentation.It reduces the in sympathetic tone mediated by centre (Lambie et al 1974)It enhances the vagal tone.16

Antiadrenergic agents:a)α blockers:IV Phentolamineb)β blockers:IV Esmolol25, Metaprolol, Propranolc)α and β blockers:IV LabetololAmong the antiadrenergic drugs, Esmolol is commonly employedconsidering its ultra short lived duration of effect with elimination half life of 9minutes and metabolized by red blood cell esterases. It decreases the restingheart rate along with a decrease in systolic blood pressure therefore causes areduction in heart rate blood pressure product, ejection fraction and finallycardiac index as well. Even though it reduces the heart rate blood pressureproduct followed by decreased ejection fraction, it is able to maintain coronaryperfusion pressure within normal limits.Calcium Channel 4)Verapamil17

Among the calcium channel blockers, Diltiazem was frequentlyadministered even though Nicardipine was considered superior because it maycause reflex tachycardia.α2 adrenergic receptor agonists:Among the alpha 2 adrenergic receptor agonists,1) Clonidine2) DexmedetomidineDexmedetomidine, the α2 adrenergic receptor agonist, a novel drug whichwas extensively studied for its various effects on multiple systems and alsoprovided good pain relief with opioid sparing, sedation, anxiolysis andsympatholysis as its effects. It has aided in reducing Central Nervous Systemsympathetic discharge in a dose-dependent manner. After taking in toconsideration the desired effects it produces with minimal adverse events, it isnow being widely utilized in the anaesthesia armamentarium.Midazolam:It was utilized for sedation and anxiolysisMagnesium Sulphate:11It was utilized for sedation and anxiolysis.18

Lignocaine:Lignocaine can be used in various methods to topicalise the airway. Atomisers Nebulisers Spray as u go Lidocaine gargles3 for oropharyngeal anaesthesiaBut adequate drying of airway is necessary for the optimal topicalisationof the airway.Airway nerve blocks:Superior Laryngeal Nerve blockTrantracheal blockGlossopharyngeal Nerve block.Intravenous lignocaine administration was also the preferred methodutilized for blunting the airway reflexes that helped in attenuation of thehemodynamic response to airway instrumentation like laryngoscopy andintubation.19

Figure 4 : Superior Laryngeal Nerve Block2ml of 2% lignocaine given bilaterally on both sideFigure 5 ; Transtracheal InstillationCricothyroid membrane identified and 2 ml of 2% lignocaine given afteraspiration of air.20

NEBULISERNebuliser is a device used to administer medication in the form of a mistinhaled which can be inhaled by the lungs. They are used commonly to deliverdrugs in bronchial asthma. COPD and other respiratory diseases. Nebulisers useoxygen, compressed air or ultrasonic power to breakup solutions and suspensionsinto small aerosol droplets that can be directed inhaled from mouthpiece of thedevice.Figure 6 : Patient Being Nebulized with 4% Lignocaine21

PHARMACOLOGY OF DEXMEDETOMIDINEFigure – 7: Dexmedetomidine ampouleDexmedetomidine has widely been accepted and utilised as an adjunct tothe anaesthetist armamentarium in India very recently. It is a selective α 2agonist developed as an alternative to clonidine. The prototype alpha 2adrenoreceptor agonist is clonidine. Dexmedetomidine is roughly eight timesmore specific for alpha 2 receptors when compared with clonidine because it isshown to have a high ratio of affinity for the alpha 2 receptor (α2/α1 1600 : 1)matched with clonidine (α2/α1 200 : 1) and that makes it a complete α2 agonist.MOLECULAR CHEMISTRY:Dexmedetomidine- a non-selective alpha 2 adrenoreceptor agonist madeup of imidazoline structure. Dexmedetomidine is the chemically active Denantiomer of medetomidine that have been used for sedation and analgesia inveterinary medicine for many years. It was approved for short term sedation ofmechanically ventilated ICU patients by FDA.22

MOLECULAR STRUCTURE OF DEXMEDETOMIDINEFigure – 8: Molecular structure of DexmedetomidineAlpha 2 adrenoreceptor agonists have many beneficial effects likeAnxiolysisAnalgesiaSedation andSympatholysis.ALPHA ADRENERGIC RECEPTORS:30Figure – 9: Alpha 2 adrenergic receptors23

The adrenergic receptors play vital role in our human body. Theendogenous catecholamines namely Epinephrine, Nonepinephrine, Dopamine,etc act on these receptors. They also mediate the clinical effects of many otherdrugs. A sum total of 9 adrenergic receptors have been synthesized that includethree alpha 1 adrenoreceptors, three alpha 2 adrenoreceptors and three betaadrenergic receptors.Alpha 2 receptors have implications in variety of physiological functions.Three subtypes of α2 adrenoreceptors - α2A, α2B, α2C. The α2Aadrenoreceptors are present in the periphery but α2B and α2C adrenoreceptorsare present in the brain and spinal cord. Postsynaptic α2 adrenoreceptorsproduces vasoconstriction but presynaptic α2 adrenoreceptors inhibit the releaseof norephinephrine that produces the desired effect of attenuating thevasoconstriction.The α 2 adrenoreceptor subtype is predominantly present in brain whichmediates functions such as sedation, anxiolysis, analgesia and also behaviouralchanges.The stimulation of α2B adrenoreceptors causes vasoconstriction andsystemic hypertension. Where in α2A receptors stimulation is known to causehypotension24

Hypothermia and behavioral changes are the effects produced by alpha 2csubtype. Hence the effects produced by dexmedetomidine is varied with nospecificity to the particular alpha 2 receptors and it has a wider range of actions.Action of alpha 2 adrenergic receptors26Figure – 10: Actions of Alpha 2 adrenergic receptors25

EFFECTS IN THE CENTRAL NERVOUS SYSTEMSEDATION15“The alpha 2 agonists acts through the endogenous sleep endorsingpathways and produces their sedative effect. The subjects remain sedated untilthey are stimulated and when they are stimulated they become arousable, alertand respond without being uncomfortable.They also quickly return to their sleep-like state therefore allowing the"daily wake up" tests to be conducted safely and efficiently. There is minimalrisk for respiratory depression and considered safe.ANALGESIA:The analgesic effects of dexmedetomidine are multifaceted. The principlesite of analgesic effects of dexmedetomidine is in the spinal cord. The analgesiceffects of dexmedetomidine are present, even when the drug is given viaintrathecally or through epidural route. Dexmedetomidine produces- no desiredactions on opioid receptors but when dexmedetomidine is known to decrease gthereforeagent.Dexmedetomidine causes only moderate reduction in pain when systemicallyadministered and it needs addition of opioids or NSAIDS for good pain relief.26

EFFECTS ON THE RESPIRATORY SYSTEMThe desired sedation effects of dexmedetomidine reduces minuteventilation eventhough the ventilatory response to hypercapnia20 is wellpreserved and maintained which ultimately reflects the similarity with thephysiology of normal sleep pattern. The major difference when compared withopioids areit causesminimal respiratory depression. Soultimatelydexmedetomidine is one of the options for awake fibre optic intubation.EFFECTS ON THE CARDIOVASCULAR SYSTEMAlpha2 agonists known to produce a decrease in HR, systemic vascularresistance and indirectly it can decrease the myocardial contractility, strokevolume and mean arterial pressure.It is known to cause a bi-phasic response in cardiovascular system whenthe bolus dosage of dexmedetomidine is given. Initially there is a increase inmean arterial pressure and decrease in the heart rate when compared with thebaseline after 5 minutes of bolus administration. Initial phase is due to its actionon alpha 2 receptors in the periphery. Peripherally located alpha 2 receptors arepresent in the blood vessel wall that leads to vasoconstriction. This initial phasecan be significantly avoided by slow infusion over 10 min. In our study, it wasavoided by infusion of the dexmedetomidine over ten minutes.27

During late phase the heart rate returns to its baseline by 15 minutes andblood pressure drops by 15% below baseline by 1 hour. The incidence ofhypotension and bradycardia is been related to the administration of a loadingdose. Therefore giving the loading dose over 10 minutes as slow infusion alsominimizes transient hypertension.27MECHANISM OF ACTION:Alpha 2 receptors belongs to the G protein coupled receptors. It made upof 7 transmembrane helices. By coupling uncoupling mechanisms thephysiological response and effect is produced. The proposed mechanisms includedecrease of adenylyl cyclase that inhibits the opening of the voltage gatedcalcium channels causing hyperpolarization.DOSE:Dexmedetomidine is usually available in 1ml and 2 ml ampoulescontaining 100 mcg/ml. It is usually given as loading dose of 0.5 mcg/kg 1mcg/kg over 10 min which is followed by maintenance of 0.2-0.7 mcg/kg. Theinfusion is prepared by adding 48 ml of 0.9% sodium chloride with 2 ml ofdexmedetomidine thus making 50 ml, so that each ml contains 2mcg ofdexmedetomidine.28

DISTRIBUTION, METABOLISM AND ELIMINATION:Dexmedetomidine is 95 % protein bound but it neither displaces any drugnor does it get displaced by any other drug. It gets metabolized in the liver byglucuronidation and cytochrome P-450 enzymes. Hence dose adjustment will beneeded to be made in patients with liver dysfunction andimpairment thatproduces deranged liver functions .It gets eliminated by the kidney but no dose change needs to be made inpatients with renal dysfunction.DRUG INTERACTIONS:Drug interactions of dexmedetomidine are of clinical significance as it hasmany interactions. The serum concentration of dexmedetomidine is usuallyincreased by CYP2A6 inhibitors such as isoniazid, methosxsalen andmicaonazole thereby increasing the effects of dexmedetomidine. On the otherhand it tends to increase the level of CYP2D6 substrates such as tc.Adverseeffectsofdexmedetomidine like bradycardia and hypotension may get be increased by theuse vasodilators and beta blockers along with it

chart no. title page no. 1 age distribution 55 2 sex distribution 56 3 weight distribution 57 4 comparison of asa 58 5 comparison of mpc 59 6 comparison of trends of heart rate 61 7 comparison of trends of systolic blood pressure 64 8 comparison of trends of diastolic blood pressure 68 9 comparison of trends of mean arterial pressure