Ischemic preconditioning: Inhalational and opiod induced ischemic preconditioning as following
Defn: Ischaemic preconditioning involves – brief period of (1 to 4sec.)occlusion of artery & the same period of reperfusion before performing the anastomosis.
Ischaemic preconditioning can be done,
- By surgeons occluding the artery before starting the actual anastomosis.
- Inhalational anaesthetics are also proved to be having this effect.
- Opioids also produce ischaemic preconditioning
- Handling of heart position changes during surgery also makes myocardium effect of ischaemic preconditioning.
Volatile agents are
Volatile agents and their pharmacological effect on myocardium & vasculature which simulate ischaemic preconditioning & have protective effect during OPCAB or MICAS.
Volatile agents and Myocardial function
- Dose dependant depression of contractile function of heart.
- Halothane & enflurane have more depressing effect than isoflurane, desflurane & sevoflurane.
- Iso, sevo & desflurane have reflex sympathetic activation so the myocardial depression is less .
- Cellular mechanism for myocardial depression by volatile agents→
- Cellular level – negative iontropic effects by modulating sarcolemmal (SL) L-type (ca++ Channels, sacoplasmic reticulum (SR) & contractile proteins .
- L type ca++ currents are decreased & SR ca++ release is depressed.
- Volatiles attnuate the contractile response to lower ca++levels & also
- Decrease sensitivity to calcium.
Effect on Diastolic Function.
Halothane have effect of decreasing compliance & have no effect on myocardial stiffness in general volatile agents prolong isovolumic relaxation phase of cardiac cycle in dose dependant manner .
- Underlying mechanism is again the modulation of ca++ currents including SR ca++ reuptake
- sevoflurane attenuate myoplasmic ca++ overload in reperfusion phase.
Effect on Cardiac Electrophysiology .
- They reduce the arrhythmogenic threshold for epinephrine.
- Order of sensitization being – halothane > enflurane > sevoflurane > isoflurane =desfulrane
Coronary Vaso Regulation.
- Volatiles modulate several determinants of both myocardial O2 supply & demand.
- They modulate myocytes response to ischemia.
- Halothane – minimal or no vasodilatory effect
- Isoflurane – controversial effect, it causes direct coronary vasodilatation in vessels of 100mm or less & cause coronary steal in steal prone coronary anatomy. with significant coronary Stenosis in a vessel supplying a region of ischemic myocardium .presumably vessels more maximally dilated because of local metabolic auto regulation & in whom isoflurane induced vasodilatation in adjacent vessel resulted in diversion of coronary flow away from ischemic region.
Volatile agents have the capacity to modulate mechanisms underlying vascular tone
- Halothave & isoflurane – attenuate endothelial dependant tone by receptor dependant or non receptor dependant mechanisms in coronary micro vessels .
- Several volatile agents cause coronary vasodilatation via K+ ATP channel – dependent mechanisms
- Sevoflurane induced K+ & ca++ channel mediated increases in coronary collateral blood flow.
Systemic regional & pulmonary vascular effects -vascular tone can be modulated by volatile agents other factors which act –
- Vessel size/type within that vascular bed.
- Level of preexisting tone
- Age & indirect effects of agents
Anaesthesia induced hypotension & reflex automatic nervous system activation
- They decrease blood pressure in dose dependant manner.
- Halothane & enflurane decrease in systemic BP is due to decrease in stroke volume & cardiac output.
- Isoflurane sevoflurane, desfurane decrease overall systemic vascular resistance while maintain cardiac output .
- Vascular smooth msusle effects
- Change the ca++ currents thru SR/SL & modulate ca++ sensitivity .
- Halothane enfulrane & isoflurane all increase calcium induced calcium release (CICR).
Volatile agents modulate baseline pulmonary vasculature but also multiple vasocative mechanisms that control pulmonary vascular tone
Sevofutrane & desflurane does not alter hypoxic pulmonary vasoconstriction response.
Attenuate the baroreceptor reflex.
Reversible myocardial ischemia
- Shorter duration of myocardial ischemia can lead to ischemic preconditioning or myocardial stunning [myocardial dysfunction inspite of normal blood flow & by absence of myocardial necrosis] .
- Volatiles attenuate ST segment deviations in setting of short duration ischemia & limites infarct size & lactate production after prolonged ischemia.
Ischemic preconditioning has following character
- Results in two periods of protection -1st 1-3 hrs.
- 2nd period – late or delayed 24to 96 hrs after preconditioning stimulus.
- Occurs also in noncordiac tissues- brain and kidney.
- Ubiquitous across species.
- Most pronounced in longer species in lower metabolism & slower heart rate .
- Seems to be important clinically because angina within the 24 hr period preceding an AMI is associated with improved outcome .
- Mediated by multiple endogenous signalling pathway.
Preconditioning can be triggered by events other than ischemia
- Cellular stress of various form .
- Pharmacologic agonists.
- Anaesthetic drugs.
Volatile agents & ischemic preconditioning
- Elicit both early & delayed preconditioning .
- Mitochondrial K+ ATP channels play a critical role in this process .
- Activation of channels.
- Volatile agents can trigger preconditioning without concurrent ischemia during triggering period.
- Volatiles they potentiate the effects of direct mitochondrial K+ ATP channel openers.
- Other multiple pathways activated dung APC/IPC
- Adenosine A-1delta , opioid or protein coupled receptors can trigger IPC.
- Protein kinase with & the nuclear signalling pathway, mitogen activated protein kinase (MAPK) are all imp signally pathway in preconditioning .
- volatiles agents have been shown to modulate at least PKC translocation
- Oxidant stress load may trigger preconditioning on the one hand or mediate reperfusion injury on the other hand .
Volatile agents can the increase oxidant stress to level that trigger preconditioning.
Mitochondrial permeability transition pore[MPTP]& inhibit na+_H+ exchange attenuating ca+2 overload & cell edema. Inhibition of mito condrial permeability by APC has been suggested to decrease myocytc death & PKC also has role in IPC – induced delay in MPTP opening eNos – prevent MPTP opening.
Volatile agents attenuate cell death & apoptic mechanism by mitochondrial activation, modulate mitochondrial energetics decrease cytochrome C release . into cytoplasm & attenuate mitochondrial & cytoplasm Ca++ overload.
Mitochrome C release – attenuate apoptic mechanism.
Many studies demastroted useful & protective effects of volatile agents in cardiac surgery in respect to reduced mortality, ↓ cavdiac troponin release, ionotrope requirement, time to extubation, intensive care unit stay, hospital stay & survival .
Effects of ischemic preconditioning:-
- Reduce the size of an infarct results from prolonged ischemia.
- Reduction in damage to myocardial intracellular structure.
- ↓ in dysfunction of cardiac contractile machinery.
- Direct reduction in arrhythmias with IPC.
Opiods and IPC
Opioid receptors & early IPC
Many studies demonstrated opiods involvement in IPC .
- ↑ survival time.
- Tissue preservation before surgical transplantation .
- Enhancing cellular tolerance to hypoxia .
- Opioid receptors are responsible to mediate effect of endogenans opioids to elicit IPC
- Metenkephalin, leuenkephalin & met enkephalin .
- Aug-phe produce reduction in cell death .
- Enkephalins are most likely serve as trigger & distal effectors of IPC .
- Delta opioid receptors have important role in IPC.
Fig – A – inducing ischemic duration followed by reperfusion for same duration before anstomosis.
Fig – B – shows brief periods of ischaemia periods of ischemia provide early& late phase protection.
Activation of G-protein compared with delta opioid receptor involved in protective phases.
Morphine has demonstrated significant reduction in infarct size & have myocardial protective effect .
This effect is mediated by glycogen synthase kinase β & phosphatidylinositol – 3 kinase pathway .
Remifentanyl , also have protective effect .
fentanly studied in limited & has had mixed results.