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

• Halothane
• Enflurane
• Isoflurane
• Sevoflurane
• Desflurane

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 –

1. Vessel size/type within that vascular bed.
2. Level of preexisting tone
3. 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.

Baroreceptor reflex

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 -1^st 1-3 hrs.
• 2^nd 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.

MPTP

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.

Opioids

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.