Moderator: Dr G. ParameswaraBy: Dr. Arati Mohan Badgandi

Volatile Agents Acute cardiac effects Delayed effects

IV Induction Agents

Acute Cardiac Effects Vasculature

Neuromuscular blockers

Individual Agents Thiopental Midazolam Etomidate Ketamine Propofol

Opioids In Cardiac Anesthesia

Opioid Receptors Cardiac Effects of

Opioids

Dose-dependent depression of contractile function.

Halothane & enflurane equal & more potent myocardial depression than isoflurane/ desflurane/ sevoflurane (reflex sympathetic activation with latter agents).

Preexisting myocardial depression - greater effect.

Negative inotropic effects by modulating sarcolemmal (SL) L-type Ca2+ channels, SR, & contractile proteins.

All volatile agents cause dose-dependent decreases in SBP.

Halothane & enflurane - predominantly due to attenuation of myocardial contractile function.

Isoflurane, desflurane, & sevoflurane - predominantly due to decrease in SVR.

Volatile agents obtund all components of baroreceptor reflex arc. Effects on myocardial diastolic function not well characterized.

When confounding variables are controlled (e.g., SBP), isoflurane does not cause “coronary steal” by direct effect on coronary vasculature.

Effects of volatile agents on systemic regional vascular beds & on pulmonary vasculature are complex.

Depend on specific anesthetic agent, vascular bed, vessel size, whether endothelial-dependent or endothelial-independent mechanisms are being investigated.

Volatile anesthetic agents lower arrhythmogenic threshold for epinephrine.

Order of sensitization being halothane > enflurane > sevoflurane > isoflurane = desflurane. (mechanisms underlying this effect not understood)

Modulate several determinants of myocardial oxygen supply & demand.

Also directly modulate response of myocytes to ischemia.

Occurs when perfusion pressure for a vasodilated vascular bed (where flow is pressure dependent) is lowered by vasodilation in a parallel vascular bed, both beds usually being distal to a stenosis.

2 kinds of coronary steal: collateral and transmural

Collateral steal - vascular bed (R3), distal to occluded vessel, is dependent on collateral flow from (R2) supplied by stenotic artery. Since collateral resistance is high, R3 arterioles dilated to maintain flow in resting condition (autoregulation).

Dilation of R2 arterioles increases flow across stenosis R1 & decreases pressure P2.

If R3 resistance cannot further decrease sufficiently, flow decreases, producing/worsening ischemia.

Transmural steal - normally, vasodilator reserve less in subendocardium. In presence of stenosis, flow may become pressure dependent in subendocardium while autoregulation maintained in subepicardium.

Reports indicated direct coronary arteriolar vasodilatation in vessels 100 μm or less could cause “coronary steal” in patients with “steal-prone” coronary anatomy (complete occlusion of coronary artery with collateral flow from adjacent vessel with a critical stenosis.)

Studies in which potential confounding variables controlled indicated that isoflurane did not cause coronary steal.

Studies of sevoflurane & desflurane consistent with mild direct coronary vasodilator effect of these agents.

Volatile anaesthetic agents decrease SBP in dose-dependent manner.

Halothane & enflurane - decrease in SBP due to decreases in SV & CO.

Isoflurane, sevoflurane & desflurane decrease overall SVR while maintaining CO.

Baroreceptor Reflex

Volatile agents attenuate baroreceptor reflex.

Inhibition by halothane & enflurane > isoflurane/desflurane/ sevoflurane, each of which has a similar effect.

Each component of the arc (afferent nerve activity, central processing, efferent nerve activity) inhibited by volatile agents.

Delayed Effects Reversible effect on myocardial ischemia.

Prolonged ischemia - irreversible myocardial damage & necrosis.

Nonacute manifestations of myocardial ischemia include hibernating myocardium, stunning & preconditioning.

Volatile agents enhance systolic function recovery in postischemic-reperfused (“stunned”) myocardium if administered before brief periods of ischemia.

Shorter durations of myocardial ischemia can lead to preconditioning/myocardial stunning - reduction in infarct size.

Stunning, 1st described in 1975 - after brief ischemia, characterized by myocardial dysfunction in setting of normal restored BF & absence of myocardial necrosis.

Ischemic preconditioning (IPC) 1st described by Murray & colleagues in 1986.

Important adaptive protective mechanism - provoked by ischemia.

Reduction/abolition in coronary BF usually detrimental to myocardium, instances where brief periods of coronary artery occlusion followed by intermittent periods of reperfusion prior to more prolonged coronary occlusion is beneficial to heart - makes it resistant to stunning /infarction - ischemic preconditioning

Administration of halothane/isoflurane before prolonged coronary artery occlusion & reperfusion reduces myocardial infarct size in vivo.

Beneficial effect persists despite discontinuation of volatile anesthetic before coronary artery occlusion.

Schematic illustration of canine myocardium subjected to 60-min coronary artery occlusion & reperfusion, then stained to identify region of MI (dark red area) within myocardium at risk for infarction (light yellow area). Isoflurane decreased extent of myocardial infarction.

Effect independent of collateral flow.

Requires different time intervals between exposure & maintenance of a subsequent benefit – agent & dose dependent.

Volatile agents that exhibit APC activate mitochondrial K+

ATP channels - effect blocked by specific mitochondrial K+

ATP channel antagonists.

Even though N2O directly depresses myocardial contractility in vitro, ABP, CO & HR essentially unchanged/slightly elevated in vivo due to stimulation of catecholamines.

Myocardial depression unmasked in patients with CAD/severe hypovolemia, resulting drop in ABP may occasionally lead to myocardial ischemia.

Constriction of pulmonary vascular smooth muscle increases pulmonary vascular resistance - results in elevation of right ventricular end-diastolic pressure.

Despite vasoconstriction of cutaneous vessels, SVR not significantly altered.

Increases endogenous catecholamine levels - associated with higher incidence of epinephrine-induced arrhythmias.

Dose-dependent reduction of ABP due to direct myocardial depression. 2.0 MAC of halothane - 50% decrease in BP & CO.

Cardiac depression— interference with Na-Ca exchange & intracellular Ca utilization—causes increase in RAP.

Coronary artery vasodilator, but coronary blood flow decreases, due to drop in SBP.

Adequate myocardial perfusion maintained as oxygen demand also drops.

Hypotension inhibits baroreceptors in aortic arch & carotid bifurcation - decrease in vagal stimulation & compensatory rise in HR. Halothane blunts this reflex.

Slowing of SAN conduction - junctional rhythm/bradycardia.

In infants, decreases CO by combination of decreased HR & depressed myocardial contractility.

Sensitizes heart to arrhythmogenic effects of epinephrine - doses of epinephrine above 1.5 microg/kg should be avoided. (may be due to halothane interfering with slow Ca conductance)

Although organ blood flow is redistributed, SVR unchanged.

Minimal cardiac depression in vivo.

CO maintained by rise in HR due to partial preservation of carotid baroreflexes.

Mild β-adrenergic stimulation increases skeletal muscle BF, decreases SVR & lowers ABP.

Rapid increase in isoflurane concentration leads to transient increases in HR, ABP & plasma levels of norepinephrine.

Dilates coronary arteries - not as potent as nitroglycerin/adenosine.

Does not cause coronary steal phenomenon.

CVS effects similar to isoflurane.

Increasing dose associated with decline in SVR - fall in ABP.

CO relatively unchanged/slightly depressed at 1–2 MAC.

Moderate rise in HR, CVP & PA pressure, often not become apparent at low doses.

Rapid increase in desflurane concentration - transient elevations in HR, BP & catecholamine levels (more pronounced than with isoflurane, esp in patients with cardiovascular disease.)

CVS responses to rapidly increasing desflurane concentration - attenuated by fentanyl/ esmolol/clonidine.

Unlike isoflurane, desflurane does not increase coronary artery blood flow

Mildly depresses myocardial contractility.

SVR & ABP decline slightly less than with isoflurane/desflurane.

Little/no rise in HR - CO not maintained as well as with isoflurane/desflurane.

No coronary steal.

Belong to different classes (barbiturates, benzodiazepines, N-methyl-D-aspartate [NMDA] receptor antagonists & α2-adrenergic receptor agonists).

Effects on CVS are dependent on class to which they belong.

Cumulative effects on vasculature - summation of effects on CNS, vascular smooth muscle & modulating effects on endothelium.

Prototype: Thiopental Induction doses of IV barbiturates - fall in blood

pressure & elevation in heart rate.

Depression of medullary vasomotor center vasodilates peripheral capacitance vessels - increases peripheral pooling of blood -decreases venous return to RA.

Tachycardia due to central vagolytic effect. (10%-36%)

CO maintained by rise in HR & increased myocardial contractility from compensatory baroreceptor reflexes.

Sympathetically induced vasoconstriction of resistance vessels increase peripheral vascular resistance.

In absence of adequate baroreceptor response (eg, hypovolemia, CHF, adrenergic blockade), CO & BP falls due to uncompensated peripheral pooling & unmasked direct myocardial depression.

Poorly controlled HTN prone to wide swings in BP during induction.

CVS effects of barbiturates vary, depending on volume, baseline autonomic tone & preexisting CVS disease.

Thiopental decreases cardiac output by:   A direct negative inotropic action  

Decreased ventricular filling, resulting from increased venous capacitance  

Transiently decreasing sympathetic outflow from CNS.

Hence, caution should be used when thiopental is given to patients with LVF/RVF, cardiac tamponade, or hypovolemia.

Dose-related negative inotropic effects - due to decrease in Ca influx into cells with resultant diminished amount of Ca at sarcolemma sites.

Minimal hemodynamic effects in normal patients & heart disease when given slowly/infusion.

Hypovolemic patients - significant reduction in CO (69%) & large decrease in BP - patients without adequate compensatory mechanisms may have serious hemodynamic depression.

Greater changes in BP & HR than midazolam in induction of ASA Class III & IV patients.

Used safely for induction in normal patients & those with compensated cardiac disease.

Due to negative inotropic effects, increase in venous capacitance & dose-related decrease in CO, caution should be used when given to patients with LVH/RVH/cardiac tamponade/hypovolemia.

Tachycardia is a potential problem in patients with ischemic heart disease.

Major CVS effect - decrease in ABP due to drop in SVR (inhibition of sympathetic vasoconstrictor activity), cardiac contractility, & preload.

Hypotension > thiopental, usually reversed by stimulation accompanying laryngoscopy & intubation.

Factors exacerbating hypotension include large doses, rapid injection, & old age.

Markedly impairs normal arterial baroreflex response to hypotension, particularly in conditions of normocarbia or hypocarbia.

Rarely, marked drop in preload may lead to a vagally mediated reflex bradycardia.

Changes in HR & CO - transient & insignificant in healthy patients.

May lead to asystole - extremes of age/ on negative chronotropic medications/ undergoing surgical procedures associated with oculocardiac reflex .

Patients with impaired ventricular function - drop in CO due to decrease in ventricular filling pressures & contractility.

Myocardial oxygen consumption & coronary BF decrease to similar extent, coronary sinus lactate production increases in some patients.

Signifies regional mismatch between myocardial oxygen supply & demand.

Hemodynamic effects investigated in ASA Class I & II patients, elderly, patients with CAD & good left ventricular function, & impaired LVF.

SBP falls 15%-40% after IV induction with 2 mg/kg & maintenance infusion with 100 μg/kg/min. Similar changes in DBP & MAP.

Effect on HR variable. Majority of studies - significant reduction in SVR (9%-30%), CI & SV after propofol - points to dose-dependent decrease in myocardial contractility.

Acute Cardiac Effects

Myocardial Contractility

Propofol - studies controversial as to whether direct effect on myocardial contractile function at clinically relevant concentrations.

Evidence suggests modest negative inotropic effect - mediated by inhibition of L-type Ca2+ channels/modulation of Ca2+ release from SR.

Minimal CVS depressant effects even at induction doses.

ABP, CO & SVR usually decline slightly, while HR sometimes rises.

Tends to reduce BP & SVR more than diazepam.

Changes in heart rate variability during midazolam sedation suggest decreased vagal tone (ie, drug-induced vagolysis).

Small hemodynamic changes after IV midazolam (0.2 mg/kg) in premedicated patients with CAD.

Changes of importance - decrease in MAP of 20% & increase in HR of 15%. CI is maintained.

Filling pressures unchanged/decreased in patients with normal ventricular function, but decreased in patients with elevated PCWP(18 mm Hg +).

As in IHD, induction of anaesthesia in patients with VHD associated with minimal changes in CI, HR & MAP after midazolam.

Intubation following induction with midazolam - significant increase in HR & BP (as not an analgesic).

Adjuvant analgesic required to block intubation response.

If given to patients who have received fentanyl, significant hypotension may occur.

Although routinely combined for induction & maintenance of GA during cardiac surgery without adverse hemodynamic sequelae.

Midazolam (0.15 mg/kg) & ketamine (1.5 mg/kg) – safe & useful combination for rapid-sequence induction for emergency surgery.

Combination superior to thiopental alone –

less CVS depression

more amnesia

less postoperative somnolence.

Minimal effects on CVS.

Mild reduction in SVR - responsible for slight decline in ABP.

Myocardial contractility & CO usually unchanged.

Does not release histamine.

In comparison with other anesthetic drugs, etomidate described as drug that changes hemodynamic variables the least.

Studies in noncardiac patients & with heart disease - remarkable hemodynamic stability after administration.

Compared with other anaesthetics, least change in balance of myocardial oxygen demand & supply.

Etomidate (0.3 mg/kg IV), to induce GA in patients with acute MI undergoing percutaneous coronary angioplasty, did not alter HR, MAP & rate-pressure product (RPP), demonstrating its remarkable hemodynamic stability.

Presence of VHD may influence hemodynamic responses to etomidate.

SBP may be decreased 10%-19% in patients with VHD.

While most patients can maintain BP, patients with aortic & mitral VHD - decrease of 17%-19% in SBP & DBP, decreases of 11% -17% in PAP & PCWP.

CI in patients who had VHD & received 0.3 mg/kg remained unchanged/decreased 13%.

No difference in response to etomidate between patients with aortic valve disease & mitral valve disease.

Uses When advantages of etomidate outweigh

disadvantages (with the possible exception of ketamine).

Uses include - when rapid induction is essential, patients with hypovolemia, cardiac tamponade/low CO .

Hypnotic effect is brief - additional analgesic &/or hypnotic drugs must be administered.

Etomidate - no real advantage over most other induction drugs for patients undergoing elective surgical procedures.

Unique feature - stimulation of CVS - increase in HR, CI, SVR, PAP & systemic arterial pressure.

Appropriate increase in coronary blood flow & myocardial work.

Indirect CVS effects due to central stimulation of sympathetic nervous system & inhibition of reuptake of norepinephrine.

For these reasons,should be avoided in CAD, uncontrolled HTN, CHF & arterial aneurysms.

Direct myocardial depressant effects of large doses - due to inhibition of Ca transients, remain unmasked by sympathetic blockade (eg, spinal cord transection) or exhaustion of catecholamine stores (eg, severe end-stage shock).

Indirect stimulatory effects beneficial to patients with acute hypovolemic shock - maintenance of BP & CO.

Combination of diazepam & ketamine rivals high-dose fentanyl technique with regard to hemodynamic stability.

Undesired tachycardia, HTN & emergence delirium attenuated with BZDs.

Similar hemodynamic changes in normal patients & in those with IHD.

In patients with elevated PAP (eg. MVD), causes more pronounced increase in PVR than SVR.

Marked tachycardia after ketamine & pancuronium complicate induction in patients with CAD/VHD.

Uses

In adults, safest & most efficacious drug - decreased BV or cardiac tamponade.

Studies demonstrated safety & efficacy of induction with ketamine in hemodynamically unstable patients requiring emergency operations.

In accumulation of pericardial fluid with/without constrictive pericarditis, induction with ketamine (2 mg/kg) maintains CI & increases BP, SVR & RAP.

HR remains unchanged (cardiac tamponade already produces compensatory tachycardia).

Mild α-adrenergic blocking effects decrease ABP by peripheral vasodilation.

Hypovolemic patients can experience exaggerated declines in BP.

α-adrenergic blocking actions may be responsible for antiarrhythmic effect.

Associated with QT interval prolongation & torsades de pointes.

Prior to administering droperidol, a 12-lead ECG should be recorded.

If QT measures > 440 ms for men/> 450 ms for women, should not be given.

If QT interval is normal & droperidol is given, ECG should be monitored for 2–3 h.

Patients with pheochromocytoma should not receive droperidol as it can induce catecholamine release from adrenal medulla - severe hypertension.

 

With exception of meperidine, opioids do not depress cardiac contractility.

Meperidine increases HR (structurally similar to atropine), while high doses of morphine, fentanyl, sufentanil, remifentanil & alfentanil associated with a vagus-mediated bradycardia.

ABP falls due to bradycardia, venodilation & decreased sympathetic reflexes – due to histamine release, reduced by slow administration (<10 mg/min).

Meperidine & morphine - histamine release in some individuals - profound drop in SVR & ABP.

Can be minimized slow opioid infusion/adequate intravascular volume/ pretreatment with H1 & H2 histamine antagonists.

Combination of opioids with other anaesthetic drugs (eg, nitrous oxide, BZDs, barbiturates, volatile agents) can result in significant myocardial depression.

Major CVS effect of exogenous opioids - attenuate central sympathetic outflow

Endogenous opioids & opioid receptors, esp ∆ receptor important in effecting early & delayed preconditioning.

Plasma drug concentrations altered by CPB due to hemodilution, altered plasma protein binding, hypothermia, exclusion of lungs from circulation & altered hemodynamics that modulate hepatic & renal blood flow. (specific effects drug dependent)

Opioid receptors regulating CVS – centrally at CVS & RS centers of hypothalamus & brainstem, peripherally at cardiac myocytes, BVs, nerve terminals & adrenal medulla.

Opioid receptors differentially distributed between atria & ventricles.

Highest receptor density for binding of κ-agonists in RA & least in LV. Similarly, distribution of δ-opioid receptor favors atrial tissue Rt heart > lft.

Mechanism of opioid-induced bradycardia is central vagal stimulation.

Premedication with atropine can minimize bradycardia, especially in patients taking β-adrenoceptor antagonists.

Moderate slowing of HR beneficial in CAD-decreases myocardial oxygen consumption.

Degree of myocardial impairment influences response.

Critically ill patients/with significant myocardial dysfunction - lower doses of opioid – altered kinetics.

Decrease in liver BF due to decreased CO & CHF reduces plasma clearance - patients with poor LVF develop higher plasma & brain concentrations for given loading dose/ infusion rate than patients with good LVF.

Infarct-reducing effect of morphine shown in hearts in situ, isolated hearts & cardiomyocytes.

Morphine improves postischaemic contractility & provides protection against ischemia-reperfusion injury.

Fentanyl gp proved to be most reliable & effective for producing anesthesia for patients with valvular disorders & CABG.

Major advantage of fentanyl & analogs for patients undergoing cardiac surgery is lack of cardiovascular depression.

Succinylcholine stimulates nicotinic cholinergic receptors at NMJ - & all ACh receptors.

CVS actions very complex.

Stimulation of nicotinic receptors in parasympathetic & sympathetic ganglia & muscarinic receptors in SAN can increase/decrease BP & HR.

Low doses can produce negative chronotropic & inotropic effects, but higher doses usually increase HR & contractility & elevate circulating catecholamine levels.

Children susceptible to profound bradycardia.

Bradycardia occurs in adults only if 2nd bolus of succinylcholine is administered approximately 3–8 min after 1st dose.

IV atropine (0.02 mg/kg in children, 0.4 mg in adults) normally given prophylactically to children, prior to 1st dose & always before 2nd dose.

Nodal bradycardia & ventricular ectopy reported.

Atracurium causes hypotension & tachycardia.

CVS side effects unusual unless doses > 0.5 mg/kg administered.

Transient drop in SVR & increase in CI independent of histamine release - slow rate of injection minimizes these effects.

Cisatracurium, Doxacurium, Vecuronuim does not affect HR or BP, nor does it produce autonomic effects.

Mivacurium releases histamine about same degree as atracurium.

CVS side effects can be minimized by slow injection over 1 min.

Patients with cardiac disease rarely experience drop in ABP after doses > 0.15 mg/kg, despite slow injection rate.

Pancuronium – HTN & tachycardia - vagal blockade & sympathetic stimulation.

Latter - combination of ganglionic stimulation, catecholamine release from adrenergic nerve endings & decreased catecholamine reuptake.

Caution in patients where increased HR would be detrimental (eg, CAD, idiopathic hypertrophic subaortic stenosis).

Increased AV conduction & catecholamine release - Ventricular dysrhythmias in predisposed individuals.

Principal advantage of pipecuronium over pancuronium - lack of CVS side effects due to decreased binding to cardiac muscarinic receptors.