Our first step was to freshly evaluate and appreciate the positive role that CPR plays in witnessed arrest… and then to inquire if it could also play a very different role — becoming the culprit that prevents recovery in unwitnessed arrest. This was a critical question, since giving CPR is the first thing done when coming upon someone whose heart has stopped, even if a lapse of time has passed. Our studies had documented that delivery of normal blood was the enemy after extended ischemia (absence of blood flow) — and CPR may start that same process since it will deliver normal blood reflow following the extended ischemia that occurs in unwitnessed arrest patients.
Most importantly, should our theory be true, our conclusion would not be helpful unless we could provide a better alternative. That requirement ignited the second step of our study. We believed that controlled reperfusion could be the answer. So an unprecedented opportunity for a solution was now before us. But it was one that could only be successful if controlled reperfusion successfully protects the brain.
Why Nobody Was Looking
Two opposing issues existed for determining proper medical guidelines for starting recovery after the blood supply is interrupted.
First, conventional belief is that ischemia itself is the lone problem. Speed then becomes the overriding imperative, spurring all efforts to deliver new blood supply as quickly as possible to stop the damage. Thoughts about how the reperfusion process itself can prevent (or cause) tissue damage are never even considered.
Yet our accumulated studies had shown an entirely different reality.
Which brings us to the second issue: the process of reperfusion. My fascination with controlling reperfusion launched from my understanding that normality is “organized” and it becomes disrupted by disease. This concept first captivated me when I observed the frog’s cardiovascular system at Ohio State University, just as it catalyzed my interest in medicine. I subsequently realized that such organization is everywhere, as nature’s orderliness is revealed in countless examples: the intricate design of a leaf as viewed under a microscope, the patterns of a spider’s web, the spirals of the cosmos — such examples never end. This beauty creates the orchestra of life, whose melody is wonderfully smooth and efficient.
Conversely, disorder is created when nourishment to an organ is taken away by a stoppage in blood flow. Beauty is replaced by chaos within the physical components of the cells in the deprived tissue. And as we discovered, these adverse events are not completely reversed when normal blood is delivered to the previously ischemic heart. We observed that such a disorder will create an imbalance of calcium levels that causes muscle rigidity… leads to an acid accumulation that stifles metabolism… promotes loss of amino acids that will impair oxygen uptake… and causes an inability to prevent water from accumulating in the cells. Recognition of these negative outcomes led us to deliver controlled reperfusion to correct these deficiencies. We lowered the calcium, gave a buffer to offset acidity, provided amino acids, and gave a drug (mannitol) to remove the excess water.
Controlled reperfusion became the answer to the problems caused by normal blood reperfusion. Its track record is remarkable, as it returned normal heart function and avoided irreversible changes even after six hours of no blood flow to the heart in both experimental subjects and patients.
This knowledge established the framework for designing how to approach an unwitnessed arrest patient — when the patient is encountered ten to fifteen minutes after experiencing sudden death.
We set aside the conventional belief that all efforts should be totally directed toward delivering new blood supply as quickly as possible, since such an approach yielded complete failure: 99% mortality, with the ultra-rare survivor experiencing terrible neurologic damage. A revolutionary approach was needed to treat what is, in effect, a universally fatal disease.
We found data corroborating the theory that after an absence of blood flow, use of CPR would induce brain damage, since each time the chest was compressed, the brain would receive normal blood. Such awful real-life results were confirmed in experimental studies done by others: survival was unlikely if more than ten minutes of ischemia (no blood flow) had elapsed before CPR was initiated47… and even in those that did survive, severe brain damage occurred if CPR was not started within four to five minutes after sudden death.50
These dire findings only pushed us harder to answer the question: “If delivering normal blood by CPR generates a neurological reperfusion injury — would delivering controlled reperfusion to the brain prevent it?”
A significant question, as we knew a positive answer could have vast implications.
Visions Beyond Unwitnessed Arrest — Strokes!
This last question was the one I brought to my team, which now included Brad Allen, who had been instrumental in our studies of controlled reperfusion after a heart attack as well as in our approaches to re-oxygenate blue babies. He had returned to Los Angeles from Chicago to become a visiting UCLA faculty member, and I was happy to have him aboard.
Interacting with others is one of the great joys of being part of a research team, and new ideas emerge from such interchange. We came upon a major realization as we discussed this project.
I said to Brad, “What we’re really studying here is how to protect and heal the brain after it has been ischemic… regardless of how it got that way.”
Brad recognized where I was going. “Gerry, what I think you’re suggesting is immense. We both know that unwitnessed arrest, while tragic, isn’t nearly as common of an occurrence as…”
“Stroke,” I said emphatically, finishing his sentence. Brad and I were on the same page. “The same extended ischemic period of insufficient blood flow to the brain that exists in unwitnessed arrest happens with stroke as well.”
The ramifications truly were gigantic. Even though the lack of brain blood flow causing a stroke is due to a blocked brain artery, our remedy of controlled reperfusion had the same potential with it as with sudden death. Just imagine: there are over 700,000 stroke victims annually in the United States alone.
Our growing anticipation and excitement were palpable.
Daring to Defy the Past
Though eager about ultimately exploring the possibility of addressing strokes, our initial focus remained on unwitnessed arrest. Toward that end, an added hurdle quickly became apparent to one of our new team members, who said, “You realize, even if we can find the answer to treating unwitnessed arrest, our protocol to avoid using CPR will meet great opposition.”
“You mean more opposition than we usually face?” I countered, laughing. He had not yet experienced the entrenched resistance that develops when the status quo of medicine might change.
But I told him he was right. “A dramatic change in thinking would emerge from our approach, since our belief is that restarting normal blood flow by CPR is why unwitnessed sudden death victims do so poorly.”
Indeed, this new concept might change the response by everyone — from the EMTs called to the scene — or a bystander or loved one who makes it to the person. We’d advise them to do nothing, because we’d have a different protocol.
The challenge was enormous, and as another resident chimed in, “It’s going to be a tough sell.”
But an indisputable reality framed my response. “Today’s treatment causes 99% mortality and severe brain damage in the rare survivor. Please explain to me why everyone keeps doing something that they know does not help?”
I reminded them that our approach does not impugn CPR, as it is a vital component of witnessed arrest. It maintains brain blood flow from the outset of cardiac arrest. But CPR may be detrimental — if its start is delayed for more than five minutes after blood flow has stopped.
At this point in my team’s discussion, our approach was only conceptual — a theory. It had still to be tested. The task before us was clear, as we needed to develop a game plan to save both the heart and brain by applying controlled reperfusion after unwitnessed arrest. Equally import
ant, we needed to clearly demonstrate the adverse consequences of applying CPR in unwitnessed arrest.
It was time to begin. We had to build a solid case to stimulate a change in thinking.
Current Approach Recreates Current Results
This was to be a joint project with Friedhelm Beyersdorf, our German research fellow who had made the keen observations that stimulated our clinical (witnessed) sudden death studies. Friedhelm was now Professor of Cardiac Surgery in Freiburg, Germany, and did this collaborative experimental research with us. We would work closely together again, as the 6,000 miles of land and ocean between us did not limit our tight connection.
First, we needed to document experimentally why conventional treatments after unwitnessed arrest caused a very significant problem. At UCLA, we caused unwitnessed arrest in animal test subjects by inducing ventricular fibrillation after passing a wire into the heart through a vein and delivering an electrical current. No treatment was given during the first 15 minutes.
CPR was then started, and the heart-lung machine initiated ten minutes later to provide the body with adequate flow of regular blood. Two of six piglets died, and though the four survivors recovered adequate heart performance, each sustained significant brain injury.59 We had saved the heart, but lost the brain.
In contrast, Friedhelm’s team induced the same 15-minute period of cardiac arrest without CPR.60 But when treatment was started, the heart-lung machine delivered a controlled reperfusion solution to the whole body. A dramatic difference, as the brain and body never received regular blood reflow during initial resuscitation.
Each pig survived with superb heart function. But most importantly, neurological recovery (brain function) was excellent. His team and our group were thrilled because this extraordinary outcome had never been previously achieved. An example of this unheard of recovery is shown in Video 1.
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Video 1
www.vimeo.com/buckberg/15-minute-recovery
Our excitement was tremendous, as these findings substantiated our theory! Simultaneously, they opened the door toward evolving a meaningful and unique treatment of an otherwise devastating disease. This collaborative effort first validated the expected severe neurologic reperfusion damage caused by CPR when it was the primary treatment of unwitnessed arrest — and then dramatically certified that delivering controlled reperfusion is a powerful tool to return superb heart and brain function.
It was a life-preserving finding that had never before been accomplished following an injury that the world thinks is lethal.
However, while these results were captivating, they were also unrealistic. This 15-minute time frame would not account for the amount of time needed for a reperfusion team to be called and then set up and use the heart-lung machine in a sudden death patient.
Yet simultaneously, we had learned from our colleagues in Japan, Korea, and Taiwan that it only took an added 15 minutes of set-up time to start the heart-lung machine — using the simple method of inserting a needle into the artery from the groin (a straightforward approach that made it unnecessary to open the chest to begin the heart-lung machine). This knowledge let us evolve a new game plan to test an extended period of unwitnessed arrest of 30 minutes — to mimic a real-world scenario in which we take advantage of incorporating their proven shortened set-up times for beginning the portable heart-lung machine.
Marching Orders (and Disorder)
Before we launch into the next stage of our study to see if controlled reperfusion can offset brain damage after a longer period of ischemia, I want to provide a simple non-medical parallel to help the reader understand the havoc that ensues in the body when ischemia is “remedied” by normal blood reperfusion — and alternatively when treated by controlled reperfusion — by comparing it to a marching band.
Imagine the participants all marching in unison. A marvelous sight. The beauty of the body’s natural order in metabolic, cellular, and structural forms — within an organ and between all the organs as they work in harmony.
But this majesty disintegrates when the band is ordered to halt and is dismissed. Now all the marchers move in different directions — forward, backward, sideways. The prior coherent march disintegrates into disunity, a dysfunction that mirrors what happens when blood flow stops to the organs during ischemia.
This uncoordinated action is accentuated if the band members are then abruptly ordered to begin marching again. This sudden attempt to return order is comparable to restoring normal blood flow after unwitnessed arrest. Each marcher tries futilely to restart from a different place, but chaos reigns. It is impossible to synchronize their motions with those of the other band members.
A “reshuffling period” is needed to transition the marchers from chaos to regaining alignment. This regrouping period parallels delivering controlled reperfusion after ischemia. By supplying the selected ingredients to reverse the chaos within the organs, their “starting position” changes in a way that realigns the metabolic, cellular, and physiologic processes toward normal. Synchronization recovers and a “re-unified band” can now perform well again.
Diving into the Unknown — 30 Minutes of No Brain Blood!
Before we began the next stage of our study, I reviewed what we had already learned.
We knew the accepted perception that irreversible damage in the body follows periods of no blood flow… reflects a finding that is based upon the awful recovery that always follows reperfusion with normal blood. This nemesis has resulted in the time-honored belief that an irrevocable damage follows only four to five minutes of brain ischemia.
Yet this was powerfully contradicted by our findings that controlled reperfusion will successfully treat the brain after 15 minutes of sudden death. These revelations could open the door to developing new treatments to avoid the (previously believed) “inescapable” dilemma of permanent brain damage after unwitnessed arrest.
Further, the scope of our study on unwitnessed sudden death may be far reaching, since it might expand into an application for treating strokes — the third leading cause of death in the U.S. These high stakes inspired everyone, me most of all.
This compelled us to explore our next challenge: could the brain recover from even longer periods with no blood flow?
How privileged we were to launch the next phase of this “impossible dream” — as will be revealed in the following chapter.
CHAPTER 13
Unwitnessed Arrest
Part II: Expansion, Rejection, and Future Realities
The foundation for the next stage in our search had already been laid by Friedhelm’s study, which showed that brain damage could be completely avoided after 15 minutes of unwitnessed cardiac arrest. We would now aim for 30 minutes as we expanded to evaluate longer ischemic time periods. This interval was lengthy enough to allow scrambling a resuscitation team to initiate the use of a heart-lung machine following unwitnessed arrest.
Our next stage would create an opportunity to study this for both unwitnessed arrest and potentially, for stroke treatment. Brad raised the question, “What if there was a way to treat the brain of a stroke victim by giving controlled reperfusion directly into the obstructed artery?”
A fascinating notion. With a stroke, the heart is working fine, so there is no inherent need for a heart-lung machine to take over the circulation.
I pointed out, “And if what you’re suggesting were possible, it would provide a much quicker path to administering the controlled reperfusion. The question is, how can you do this?”
Brad considered that. “Let me think about it.”
He first had to confront the dilemma of having no way to mimic a stroke, other than stopping all of the brain’s blood supply — by sudden death. A big obstacle to overcome — if we were also going to study how to treat stroke victims without cardiac
arrest.
Brad returned to my office a few days later.
“I’ve got it.”
His innovative thinking led to an ingenious method to obstruct all of the brain’s blood flow by blocking its blood vessels as they came from the aorta — by accessing them through a small incision into the breast bone. He would then use small simple neck incisions to access the carotid arteries that lead to the brain. While brain blood supply was interrupted for 30 minutes, catheters would be placed in them for delivering either normal blood or controlled reperfusion into the brain for our testing.
I had one word to describe Brad’s plan: “Phenomenal.” But my next words were: “Now prove it!”
We began our experiments.
Blood flow to the brain was stopped for 30 minutes in animal subjects, mimicking what happens after prolonged sudden death or in the early stages of a stroke. This was followed by delivery of normal blood reperfusion — to match how a typical brain injury is conventionally treated.
Immediate and irreversible brain damage was apparent, and vastly exceeded what we saw after 15-minute periods of brain ischemia (no blood flow to the brain). This reflected the real-world outcomes of patients that survive a stroke. They may develop paralysis on one side of the body, speech and language impairment, memory loss, vision issues, behavior changes, and have their lives shortened.
The next step was the most critical — as we now delivered controlled brain reperfusion after the same 30 minutes of brain ischemia. We knew that if this didn’t work, we would have to rethink our approach, start over, or perhaps even abandon the pursuit.
Solving the Mysteries of Heart Disease Page 21