Part XXIII- Episode 6- The Art of Perfusion The Advent of Myocardial Protection Standing on Tall Shoulders- The History of Cardiac Surgery Thomas N Muziani PA-C, CP

“What is to give light must endure burning” Viktor Emil Frankl MD Ph.D. – (1905-1997)

 “Our whole edifice of myocardial protection has been built on serendipity”- Mark Braimbridge MD (1924-2016) Cardiac surgeon at St Thomas’ Hospital, London, UK and crystalloid-cardioplegia pioneer. (Serendipity – the occurrence and development of events by chance in a happy or beneficial way.)

Re-thinking Flawed Dogma:

During the early 1970’s international curiosity in chemical quiescence of the myocardium blossomed, which, by the end of the decade, refined the application of potassium arrest to the point of almost universal acceptance. In the United States, Gay, Sid Levitsky, Roe, Tyers and Gerald Buckberg re-evaluated potassium chloride administration below 40mM for inducing cardiac arrest (Gay and Ebert 1973; Levitsky 1977; Roe et al 1977; Tyers et al 1977).

Initially, Gerald Buckberg et al. at University California Los Angeles (UCLA) advocated utilizing strictly crystalloid solutions (Nelson et al. 1976) for cardioplegia. After extensive research, it became apparent that incorporating the patient’s own blood in the solution facilitated superior results and thus became integrated with their technique of delivery (Follette et al. 1978; Buckberg 1979). During this timeframe, UCLA incorporated utilizing intermittent coronary perfusion with cold blood cardioplegia at a ratio of four parts blood with one part crystalloid. This delivery method was in tandem with systemic core (whole body) hypothermia during the aortic occlusion phase.

While conducting studies on the effects of myocardial temperature, coupled with varying ratios of solutions, another alteration for delivery of cardioplegia was promulgated. There has never been any strong substantiating science to validate using only cold cardioplegia during the induction phase of administration. If logically dissevered- utilizing cold cardioplegia during induction is counter-intuitive and will actually repress global distribution of cardioplegia by hydraulic constriction down to the myocyte…just what you do not want. Cold creates constriction– just fall off a boat into Lake Michigan in December and you will graphically understand the concept. This constriction, coupled with the pathology of coronary occlusions, will insure major diminishment of distribution for cardioplegia down to the myocyte.

For the past thirty years this author has attempted to discover the genesis and rationale for cold induction. All that has been unveiled can be proffered in three statements:

1) Incorporating the studies of Wilfred Bigelow on the benefits of hypothermia on the myocardium, the logical application advocated for delivery of cardioplegia would only be cold.

2) Early bags of cardioplegia were by no means well inscribed that they contained high doses of potassium. Therefore, it was not uncommon to discover that anesthesia or nursing inadvertently would grab a bag of cardioplegia instead of an IV solution. As a result, most institutions intentionally isolated cardioplegia bags into the blood or drug refrigerators- in an effort to thwart inadvertent administration with unintended consequences.

3) Most cardioplegia tubing configurations during the early 70’s involved a rather simple “cooling coil” of PVC tubing encircled in a helical column submerged in an ice water bath. Very efficient natural cooling. However, if your surgeon should request warm induction, the helical coil could not be exposed to cold during induction, which meant you could not place ice into the bucket. This had the potential of becoming a weak link by forgetting to pour ice into the bucket. The warm/cold delivery process turned into a physically taxing juggling act for perfusion; especially because it involved navigating the “surgical side” of the heart-lung machine. Operating the machine and venturing to the “far side”= bad idea.

UCLA and other researchers also agreed with the observation that during induction of cardioplegia in the ischemically damaged, energy and substrate-depleted heart, cold may actually trigger the first phase of reperfusion injury. Experimental and subsequent voluminous clinical data validated that warm induction would “actively resuscitate” the heart and enhance its tolerance to subsequent exposure of cold ischemia imposed due to technical application. Most importantly, warmth is a natural dilator and one of the finest mechanisms to facilitate cardioplegia distribution past coronaries physically occluded with plaque.

There is absolutely no scientific rationale to warrant the application of cold cardioplegia during the induction or reanimation phases of delivery. More importantly, cold during these two phases may actually inhibit global distribution of cardioplegia down to the myocyte to the point where inadequate myocardial protection may manifest itself.

Another facet of cardioplegia delivery that was studied extensively at UCLA was the “insurance against ischemia” concept employing multi-dose delivery. The hypothesis behind multi-dose blood cardioplegia has its genesis from the occurrence of non-coronary collateral flow that naturally occurs in all in-situ hearts. This non-coronary collateral flow will physiologically rewarm the heart by replacing any diligently formulated cardioplegia solution with systemic (non-cardioplegic) blood at the prevailing temperature in the extracorporeal circuit. This blood enters the heart via open mediastinal connections. This becomes visually apparent as blood fills the coronary arteries or coronary ostia while the aorta is clamped and the heart decompressed.

This natural rewarming can be circumvented with topical ice slush hypothermia…however, this very cumbersome inclusion of topical hypothermia may actually trigger pulmonary complications without any enhancement to cardiac protection. Additionally, for anyone who has inadvertently placed an exposed part of their body into snow or ice for any duration of time will instinctively understand the conundrum of protection vs. intentional frostbite.

Single-dose delivery versus multi-dose delivery of cardioplegia has gained increased attention and popularity again in recent years. Since this article has no intention with engaging in that debate, just a few realities regarding human physiology of an organ when subjected to ischemia should be proffered.

Some of the antagonists that ferment myocardial ischemia are hypotension or shock, occlusive coronary artery disease and aortic cross clamping while on cardiopulmonary bypass. Any of these issues may impart severe damage on the myocardium and/or coronary vascular endothelium. It has been well documented that normothermic global ischemia within a relatively short time frame of forty-five minutes may produce severe contractile dysfunction of the myocardium. It is also well documented that even a short period of regional ischemia of fifteen minutes may produce dysfunction in the absence of infarction (“stunning”).

If global or regional ischemia becomes severe and prolonged enough, frank necrosis of the myocardium will commence. A topic that was much discussed only several years ago and now well validated is the fact that this accrued damage to the myocardium incurred through ischemia is actually compounded post restoration of blood flow…hence the term “reperfusion injury.” Therefore, understanding the full dynamic of cause and effect of complete myocardial protection must focus on amelioration of not only ischemia but include reperfusion injury.

The cardiac myocyte, as pristine an example of Darwinian evolution, is also the most severe casualty to the injury process of ischemic-reperfusion injury. This is because the myocyte is the metabolic and functional center of the heart. It requires the largest oxidative metabolism and ATP turnover rate to support its voluminous energy demands. The myocyte is not the exclusive casualty of surgical ischemic-reperfusion injury. It is now well documented with an extensive history that the coronary vascular endothelium suffers from the effects in a major way. The vascular endothelium is an extremely active tissue. This is primarily due to its ability to release a number of vasoactive factors which in turn regulate organ blood flow along with systemic blood pressure. Coronary vascular endothelium also functions as the interface between blood and the underlying myocardium and myocytes. The endothelium may contribute to a number of disease states such as thrombosis or hypertension…or may be the target of various disease states such as atherosclerosis, ischemic-reperfusion injury. The endothelium most assuredly plays a dual role…as a source of deleterious activators such as platelet activating factor (PAF), endothelium-1 (ET-1), superoxide anion, histamine. Any of these factors may injure the coronary vascular endothelium. But the endothelium is also a source of nitric oxide (NO), adenosine and prostacyclin which protects against endothelial cell injury.

When discussing the advantages of single-dose delivery versus multi-dose delivery of cardioplegia, one last aspect requires further consideration. Science has still not achieved the ability to accurately predict when exactly ischemia will commence its cascade in any given patient. With some humans it will trigger at 6 minutes while some people may tolerate up to 50 minutes of ischemia in the absence of protection. We do know however, that ischemia is analogous to dropping a pebble in a pond. It will start in one spot on the myocardium and branch out globally rather quickly. With single-dose cardioplegia delivery…if the heart is allowed to rewarm during the window of non-delivery, ischemia may be very rapid in the onset. It would serve no benefit to anyone, especially the patient, to have a successful operation just to discover a compromised heart due to lack of replenishment of our own volition.

As a final note for this article; it is with profound sadness that I share the news that Dr. Gerald Buckberg died 20 September 2018 from leiomyosarcoma cancer.

“Optimal Myocardial Preservation: Cooling. Cardioplegia and Conditioning”

Joseph C Cleveland. University of Colorado. 1997