The dramatic scene that was described at the beginning of the prior chapter — when I was urgently called by Brad to go down to the lab — told the story of the outcome in our first experimental piglet subject.
I shall never forget that moment….
Our team had administered our controlled reperfusion. Despite having just experienced 30 minutes of no blood flow, the piglet was conscious, walking, sniffing around, and looking normal in a natural mobile state.
We could barely contain ourselves.
This immediate recovery of the body and normal neurological function contradicted every traditional belief about ischemia and brain damage. No one in the world had ever done this before! It was simply unbelievable!
I commended our team, “This is so wonderful. Congratulations to all of you. It’s just fabulous.”
Since a picture is worth a thousand words, the reader can type the video link address into their computer’s search engine, or eBook readers can click on the link to see the memorable video that tells an astounding story. (Video 1) Our thrill at this result was enormous, as it may benefit so many deserving people.
Video 1
www.vimeo.com/buckberg/30-minute-recovery
“Houston, We Have a Problem”
Unfortunately, our joy ride of success was not long-lived. An unexpected development occurred.
Our next four test subjects did not have this same terrific recovery. In fact, each of them suffered significant brain damage.
We went from the highest of highs to facing entirely new questions.
Our previously observed return of normal brain activity in the first piglet after 30 minutes of no blood flow was simply unheard of. This singular success could never have been by chance. Nature doesn’t work that way. There was no “miracle.” Instead, our initial triumph demonstrates how science can overturn a conceivably unsolvable problem. What we did made brain recovery happen, and our confidence was unshaken by the four subsequent failures.
We just had to find the mistakes that made us unable to reproduce recovery.
Racing Down the Rabbit Hole
The world of discovery is an electrifying voyage, one accompanied by hurdles that must be conquered.
This consistent challenge of research is not always acknowledged when final results are reported. The real journey is seldom a smooth one, since overcoming roadblocks requires innovation and persistence.
As stated before, my underlying credo is: “If something that you believe should work… does not… then either your idea is wrong or your study was done improperly.” The ischemia/reperfusion concept is valid, so our failures could only mean that we did not do the next four studies correctly.
Our team would work doggedly to overcome the technical errors that had blocked our subsequent recoveries, much the same way a Schnauzer acts after he bites your leg. He never lets go without getting what he wanted.
We would spend the next two years looking for our answers.
Armed with a belief that truth is often hidden but waiting to be revealed, we proceeded to unravel the pitfalls of failure… as we re-entered the unique world of research.
Learn by Doing
A discerning and meaningful motto observes, “Good judgment comes from experience, and experience comes from bad judgment.”
Seasoned researchers have good judgment because they’ve been wrong so often. It teaches them how to avoid future mistakes, while simultaneously giving them the tools to address the ones they cannot evade. They do not quit easily. They become agile by practicing, just as one does for sports or an art.
For this reason, we didn’t give up after encountering negative results. I knew the answer was there, and our first objective was to scour through every piece of our technique to search for it.
It’s (Always) in the Details
The drama of discovery evokes great excitement for the public. But the scientist is not certain of reaching this unique final result when he or she begins. Instead, it evolves along the winding pathway of the pursuit. Clues to the future answer emerge — but they must be identified, appreciated, and carefully followed.
Our reevaluations made us recognize we did not yet know how much blood to deliver during reflow. Could this be the consideration that prevented us from duplicating our initial success? We needed to establish these amounts, especially since they might set crucial guidelines.
Since our overriding goal was to have the brain nourished with sufficient oxygen, we began exploring what volume of blood flow was needed during reflow. This task was initiated by recording oxygen saturation on the brain surface. An electrode was placed on the scalp’s skin that covers the underlying brain. It was a relatively simple technique commonly used in patients, which would tell us the saturation in the brain blood beneath.
Our belief, from previous studies that had been done in patients, was that flow is adequate if there is 55 to 70% saturation. But this was not true in our studies, since we had maintained those levels in all four piglets that developed serious brain injury.
Our next step toward solving this mystery would build upon drawing knowledge from our other prior experiences. In this case, we knew that the heart can have a normal surface appearance — while its inner shell is severely damaged — as we had observed during open-heart surgery or when normal blood reflow was given after a heart attack.
“Could such a discrepancy also occur in the brain?” we wondered. “Might measuring oxygen saturation throughout the brain better reflect what was occurring within it — and be a superior indicator than only monitoring the brain surface?”
That question led us to compare brain surface oxygen measurements against total brain oxygen uptake (which measures surface and deep regions). This could be done as we controlled brain blood flow — as we could readily measure the oxygen level in the blood going to the brain, and then in the venous blood leaving it (after it had extracted oxygen from its blood supply).
So what did we find?
The total brain oxygen uptake differed from what we expected from the surface measurements. The surface could receive abundant oxygen — while the inner portions remained undernourished. In fact, we observed an inverse relationship, meaning that if the surface level was less, the whole was better. (We would later learn the reasons behind this discrepancy.)
Before doing more studies… we first tested piglets that did not have any limitations to their circulation, and determined that delivering 750 ml/minute of brain blood flow was necessary to maintain normal healthy brain function.61 This baseline flow became our gauge to ensure that the brain would receive an adequate reperfusion blood flow in our further experiments.
The fruits of this new knowledge led us to do six more controlled reperfusion studies, with fresh optimism that we’d solved the flow and oxygen nourishment problem.
But we did not fulfill these positive expectations.
Only two of six pigs recovered, despite receiving the normal brain blood flow rate. Again, we were stumped. This should have worked, especially since the controlled reperfusion avoided brain damage in two subjects. Apparently, normal flow wasn’t the answer — at least not the only answer.
Again, we needed to pore over our protocols to find the flaw. We restudied the data, and indeed found that it spoke back to us.
We discovered that recovery only happened when average blood pressure was above 60 mm Hg. The four subjects that did not improve, had a lower pressure and developed severe injury, despite our providing the normal brain blood flow rate. We now understood a proper blood pressure was another part of the answer.
So defining how to achieve the desired pressure became the next impediment we needed to overcome — especially as several intertwining factors made this task difficult.
We already knew that stopping a brain’s blood supply is always accompanied by a response in the body that generates a very high blood pressure — as adrenaline concentrations rise abruptly in the blood to excite the vascular system. But this could awa
ken the subject. To prevent that from happening, we had increased the inhaled anesthesia dose (from 1% to 3%). This lowered the blood pressure by relaxing blood vessels — and ensured the subject stayed unconscious.
But while we found that these higher doses did produce the desired reduction of blood pressure — they also lowered the total brain oxygen uptake — while simultaneously raising surface oxygen saturation! This taught us an unexpected, but important lesson: whole brain nourishment had been diverted away from the inner part of the brain and sent toward its surface, thereby creating the higher surface measurements that were so misleading in our prior trials.
We had inadvertently caused poor brain flow distribution by our decisions about the anesthesia drugs, leading us now to realize that lowering the anesthesia dose was essential. Yet we still needed to keep the subject unconscious.62
So we sought a new answer — and found one in an available alternative drug. Adding Nembutal (a brain anesthetic) would induce brain coma (ensuring the pig did not awaken) — but did not lower blood pressure.
Another piece of the puzzle had been successfully added!
But we weren’t done yet.
One Final Element
Brain swelling is a major problem following brain injury, as the brain resides within a rigid skull casing. It simply cannot expand, so that any water gain worsens damage. Dangerous brain swelling (from water) becomes accelerated if blood pressure is high during early reperfusion. Because of this, using a higher blood pressure can be dangerous. This introduced another challenging dilemma.
As I seek out research guidelines, nature is always my primary source. This stems from my recognition that problems arise whenever we make decisions that deviate from its rules. Conversely, following nature’s proven patterns yields wonderful scientific remedies.
This principle holds true in designing medical care, as physicians often learn that “what they think is right” may be incorrect, because it differs from “what nature knows is right.” That rule resurfaced as I reviewed the guidelines that have long been used to deliver blood flow to the brain. Conventionally, brain nourishment is delivered by a pump that provides a smooth flow without pulsations. This method is used universally, as nearly every heart-lung machine and blood delivery pump in the world will consistently deliver a smooth flow that is without waves.
Yet nature does not follow this rule. Instead, the body has pulsatile perfusion (as can be felt in our body’s pulse), mirroring the pattern of the pulsations of ocean waves. Using this stimulus of mirroring nature, we developed an apparatus that furnished pulsatile blood flow. It worked. The pulsatile flow improved brain blood flow distribution, despite its delivering a lower average blood pressure! This is not a new concept. Its “ebb and flow” was elegantly described by ancient scholars like Galen in AD 180.
Time to Test
This step-by-step process to uncover what went wrong in our last studies set the stage for a new series of controlled reperfusion trials that would follow 30 minutes of no brain blood flow.
All our efforts were rewarded.
Excellent recovery of body and brain function was observed following our delivery of controlled reperfusion — and these findings were repeatedly achieved in other subjects!63
We had done it.
The impossible became possible. The unsolvable was solved.
A feeling of fulfillment and glee came over everyone. We knew that this unique outcome might have enormous impact. Our excitement was overwhelming. We saw that so many patients could be helped. I believe we tapped into the infinite reward of research: envisioning its clinical application that will help the sick and buoy their families!
Our journey reminded me of a Winston Churchill quote: “Success is going from failure to failure without losing enthusiasm.” A pathway we precisely followed.
Reflections on Success
This was a formidable experience of another type for us, because we, as cardiovascular surgeons, now entered a new arena: the untapped world of recovering the brain, rather than the heart. Our results pointed toward a potential sea change in the treatment of unwitnessed arrest and stroke victims worldwide.
Taking a moment to reflect on what we had done, I said to Brad, “You know, we couldn’t have solved this 15 years ago. We didn’t have the vast background of information, nor enough experience, to face such challenges.” Brad agreed.
I wondered how many beginning researchers could have taken those steps, and could have used the data to work out the details? Our experience, coupled with unrelenting curiosity, made us better researchers. This knowledge fuels my dedication to the residents and research fellows who work with me for two-year periods. I am passing the torch, much as Julien Hoffman did with me from 1969 to 1970.
Yet, I couldn’t help but wonder: if we didn’t have that initial success with the first test subject to spur us on, would we have continued?
The answer is yes. We never embarked on a research project on which we gave up. An answer was always found, because the logic was sound. Some might suggest it was luck, but that is something I neither believe in nor rely upon. Instead, the “data is the data” and contains information that tells a story… though oftentimes one that needs to be uncovered. It is the world of science, requiring the sequential pursuit from observer to experimenter to observer, as mentor Claude Bernard taught us.
Please remember that our continued success in different aspects of research is not because “I am a man for all seasons.” I never spread myself over multiple projects at once. Instead, for several years at a time, I devote enormous energies to a single project. The unwavering drive to find the solution of each study grew out of knowing an answer was attainable.
The Exciting New Future
I was particularly eager to continue exploring how our novel treatment might also transform the treatment of strokes — an enormous global issue.
I focused on this during one of my morning swims at 5:45 AM. Since 1997, I have been part of a UCLA club called the Bruin Masters. Early every morning, master swimmers meet and our coach runs us through different strokes, distances, and times. Besides being wonderful exercise, it is a place where I can also generate new ideas.
While swimming laps, I pondered how our results could lead toward a new protocol for strokes. I envisioned how cardiologists could immediately access a patient’s blocked artery, then push a catheter beyond the obstruction to promptly deliver controlled reperfusion past the blockage — and protect the brain. Then the artery could be opened by angioplasty to restore normal circulation. The catheterization lab could function as “The Fast Response Treatment Wing.”
All the necessary tools exist for this to occur, and hopefully the appreciation of our findings and their application might catalyze its development. But that can only happen if we safely extend the time frame even further without brain blood flow and get consistent recovery using controlled reperfusion.
Our next step!
Funding the Evolution of New Ideas
Friedhelm’s report of his unique results, as well as our successful work at UCLA with Brad Allen, was published in major United States and European Journals.60–64 But this did not alter the strong resistance from cardiologists to having their catheterization labs used as a threshold for conducting such revolutionary approaches.
We were not deterred. We felt that as more studies were completed, there would be more and more compelling evidence of this lifesaving treatment’s feasibility. As we had done many times in the past, we sent a grant request to NIH (National Institutes of Health) for financial support to continue the studies.
Novel ideas never find recognition because they sound good. Rather, they emerge into the spotlight after being tested. That might seem a natural progression to the public, but how does this really happen? As you have read in these pages, it is not as if some faucet opens so that truth flows freely from it. Instead, there must be sprouting of the seeds into ideas that create a new way of thinking, which must be transform
ed into innovative actions and results.
Such a venture needs a mechanism that permits the investigator to explore and overcome a broad number of unanticipated obstacles. This is where we enter the world of the laboratory research study. Yet there is an inherent dilemma to this approach: no funding entity wants to unquestioningly provide backing to unknown research.
Monies come from outside independent sources (they are virtually never supplied by the native institution, as none of my studies were funded by UCLA). The eternal challenge for the investigator is to convince others to financially support their research. This takes the form of a grant proposal.
The method behind this process is seldom discussed, as there’s a Catch-22 to the procedure. This means to secure funding, you must first present a preliminary (pilot) study that verifies your capacity to achieve the stated goal.
The riddle is to figure out how one finances this vital exploratory study.
The usual practice is to use part of the funds from a prior grant to do the next pilot study. This does not abuse present available funds. There is no cheating, because the goals of the prior funded study were fully accomplished (as its pilot study was funded by the study that preceded it). This leap-frog approach to financing the groundwork for each subsequent study is simply a way of life in the world of research.
Again and again, I followed this route in my investigative work and its success paved the way for the evolution of each new idea during this 50-plus year career. It has allowed me success in a string of innovative pursuits thought unsolvable by traditional methods. This chapter on unwitnessed arrest falls into this category.
Startling Turn of Events
NIH was our primary funder, and we looked forward to using their support to pursue our next stage of discovery. Brad was made principal investigator and it was my thrill to help my former student succeed!
I was not prepared for the NIH response.
Solving the Mysteries of Heart Disease Page 22