Profound, transient hypotension refractory to α₁-agonists and increased bypass flow during cardioplegia administration (intermittent vasoplegia) is a well-recognized yet unexplained phenomenon in cardiac surgery. Retrograde cardioplegia has been shown to cause profound hypotension with greater frequency than antegrade administration despite identical formulations, ischemic intervals, and perfusion parameters. It seems plausible that the link between cardioplegia administration to the arrested heart and the intermittent vasoplegic systemic response may result from a vagally mediated cardiac depressor reflex.

Electrophysiologic and histologic studies have identified multiple vagal receptors within the ventricular myocardium and coronary vasculature that, when stimulated, produce a centrally mediated and prolonged withdrawal of efferent sympathetic activity to the systemic vasculature. During antegrade cardioplegia, hypotension most likely arises from activation of left ventricular chemoreceptors terminating in the inferoposterior wall. These afferents respond to endogenous mediators of ischemia and reperfusion such as bradykinin and prostaglandins.

In contrast, the depressor reflex observed during retrograde cardioplegia likely arises from vagal afferent ventricular mechanoreceptors. In the arrested, decompressed heart, only 20–33% of retrograde cardioplegia traverses the capillaries, while the remainder is shunted through the Thebesian system. The resulting surge in coronary venous pressure causes distension that is easily transmitted to the surrounding interstitial space, creating the mechanical effects of grossly elevated end-diastolic pressure and pathological myocardial stretch despite the absence of true ventricular filling and wall tension.

If the intermittent vasoplegic response to cardioplegia is viewed within the mechanistic framework of a vagally mediated depressor reflex, the optimal intervention to mitigate prolonged hypotension may not be stronger vasopressors (e.g., norepinephrine or vasopressin), but rather the inclusion of lidocaine in the microplegia additive. Lidocaine is known to markedly attenuate reflex vasodepressor responses through the blockade of sodium channels in nerve fibers.