Solving the Mysteries of Heart Disease

by Gerald D Buckberg

  The battle plan was clear: we would mimic what occurs in a typical operative procedure. The heart-lung machine delivering typically high oxygen (400 mm Hg) levels was started for our test subjects. Five minutes later, the aorta was clamped and our cardioplegic solution (which we had shown to be safe in neonatal hearts) was used for protection during the cardiac repair.

  The outcomes mirrored what occurred in our prior hyperoxic re-oxygenation studies (those without a cardiac operation), as the same glaring injury reappeared. Remarkably, only five minutes of the 400 mm Hg re-oxygenation were needed again to cause severe oxidant damage and impaired heart function.

  These findings confirmed our expectations of the damaging role that traditional re-oxygenation played in blue baby’s hearts that undergo a technically perfect surgical repair of the reason behind their cyanosis.

  Our next crucial step was to explore if our newly discovered antioxidants could avoid such toxic re-oxygenation damage.

  We had high expectations.

  But they weren’t met.

  Though superb success occurred previously (when we did not stop the heart’s blood supply since we were not recreating an operation), only 50% recovery followed the antioxidant use during cardiac surgery. While we had hoped for a “magic pill,” reality set in, as these drugs fell short.

  Though disappointed, we still had one other arrow in our quiver. We would vary the amount of oxygen delivered.

  It certainly made sense to us. But would it work?

  Indeed it did.

  Nearly complete avoidance of oxidant and functional damage followed our keeping the oxygen level at 100 mm Hg (versus the conventional 400 to 500 mm Hg)! We were on the road toward success. A rewarding outcome was achieved!

  But could we do even better?

  Taking a lead from our studies on “controlled reperfusion,” we now developed a strategy called “controlled re-oxygenation.” In colorful terms, this means “You dance with the same guy who brought ya.” That is, we would begin the procedure by matching the low oxygen level that our cyanotic babies had when they came to us.

  So we started the heart-lung machine at the same hypoxic level (too little oxygen) that had already existed in the cyanotic test animal — about 25 mm Hg — and maintained this hypoxic level for the initial five minutes before clamping the aorta to start the repair.

  The oxygen level was then made normoxic (100 mm Hg) and kept there throughout the period of clamping.

  The outcome?

  Complete recovery of normal heart performance and antioxidant reserve capacity!

  We were elated!

  I felt both gratified and reassured that this sequence of controlled re-oxygenation “paralleled” our earlier victories with controlled reperfusion after acute heart attacks.

  Time to Go Public

  The design, implementation, and completion of this study’s many steps required three years of laboratory research. Yet an astounding and simple conclusion was reached: hyperoxia (O2 at 400–500 mm Hg) should not be used in cyanotic children.

  All of our data on re-oxygenation injury was accumulated before publishing any of it, echoing the previous tactic I used in reporting reperfusion injury. In 1995, this new research was submitted to the Journal of Thoracic and Cardiovascular Surgery, the field’s most prestigious and well-read journal.43 The journal’s editor was John Kirklin, who previously had provided my first career invitation to be a guest speaker at the University of Alabama 20 years earlier, and whose astute observations kindled my controlled reperfusion studies. He had deep interest in re-oxygenation injury because he had helped develop the initial heart-lung machines at the Mayo Clinic, where the earliest operations were performed on cyanotic infants. Kirklin was not a traditionalist. His focus was upon learning, improving, and solving problems related to this device.

  Kirklin graciously helped me organize our report’s contents. He challenged any ambiguities, as a tutor might do with a wayward scholar. I loved it! We shared the same aim: teaching the reader. Each of the 13 articles was evaluated by three reviewers and accepted. These studies were then published as a Supplement to the Journal — only the third time it had issued such an addendum. The second had been our study of reperfusion injury.30, 43

  But Does It Work Where It Really Counts?

  Now it was time for our final step: to apply our experimental findings from the lab to the clinical environment. Ultimately, the only true confirmation of this approach is if it will help our patients.

  A pediatric cardiac surgeon was needed to make this natural progression from lab to patients (bench to bedside), as I did not operate on children. Brad Allen, who was cited earlier in this chapter, took on the role. He was working in Chicago at the time that we did our re-oxygenation studies, but always kept in touch. He was fascinated by our findings and wanted to test this approach in patients.

  Armed with the new ideas we uncovered, he approached Michel Ilbawi, an eminent pediatric surgeon and head of Brad’s department, and asked to implement a new study. It was admittedly pretty gutsy of Brad to suggest that the established master should consider changing his ways. But Ilbawi, like Kirklin, knew existing solutions were not perfect, and his open-minded attitude propelled our discoveries to be applied in his blue baby patients. A true leader, Ilbawi provided Brad with the confidence and support that sows the seeds of growth.

  Brad set the oxygen levels in the heart-lung machine at 120–150 mm Hg, rather than the traditional 400–500 mm Hg levels… and found substantial reduction in oxygen-related damage. Simultaneously, he realized the road to success is often paved not only by the initial answers, but can also benefit from further steps. Brad recognized that another source of injury could be the white blood cell (WBC) component, which can plug capillaries, and invade injured cells to produce dangerous oxygen radicals. His route to counteracting this damage was to use a WBC filter.44

  Brad Allen and Michel Ilbawi’s results in blue babies matched our experimental findings — as improved heart function and greater antioxidant reserve capacity followed their combining lowered oxygen in the heart-lung machine with using a WBC filter.

  Their approach was then used in 72 patients with severe cyanosis. Recovery of heart function was excellent, without lung swelling or body swelling from water accumulation. There was no need to leave a baby’s chest open after surgery due to a swollen heart.45, 46

  A dramatic change from their prior experience with conventional high-oxygen approaches.

  Further Corroboration

  Another UCLA alum played a significant role in confirming our initial findings. While a postdoctoral fellow with us at UCLA, Kiyozo Morita had conducted many of our experimental studies on re-oxygenation injury, along with Kai Ihnken from Germany. Kiyozo became a respected pediatric surgeon in Japan, and applied our protocols with great success on his patients.

  In 2012, he was invited to write an overview about re-oxygenation injury in the World Journal for Pediatric and Congenital Heart Surgery.47 Aside from recounting his prior experimental work at UCLA, and citing findings from his own practice, he summarized internationally published papers about cyanotic children that were successfully treated with controlled re-oxygenation. These reports came from the United States, England, Turkey, Germany, Japan, and China. Each verified that use of normal levels of oxygen in heart-lung machines had offset impairment of heart function and oxidative reserve capacity. Moreover, since re-oxygenation affects the whole body (it is not limited only to the heart and lungs), Kiyozo showed that reduction in brain damage also occurred in cardiac surgical patients.

  I was elated by Kiyozo’s achievement, and filled with pride as I watched how those whom I’d mentored in the laboratory evolve into leaders in their fields.

  Now, we naturally expected there would be widespread changes in the re-oxygenation treatment of blue babies following this worldwide confirmation of our 1995 experimental findings.

  This did not happen.

  How could that be?

&n
bsp; I do not have the answer, but know that many pediatric surgeons think our worldwide analysis of the role of oxygen injury is simply unimportant. They don’t believe that the problems they see are related to re-oxygenation injury. Instead, they blame these unforeseen complications on other reasons. After all, they followed long-accepted traditions, so how could those actions create such a problem? Surprisingly, they adhere to this unyielding conclusion despite their need to sometimes keep a recovering baby’s chest open for several days because the damaged heart swells after its injury… or need to use a temporary mini heart-lung machine because the baby’s heart cannot support life.

  As Frank Lloyd Wright, the renowned architectural genius, said, “An expert is a man who has stopped thinking because ‘he knows.’”

  CHAPTER 11

  Back from the Dead:

  Sudden Death and

  the Lazarus Syndrome

  The Bible tells the tale of Lazarus, who is returned to life from the dead. Though an ancient story, it still resonates today.

  Nearly 400,000 times a year in the U.S., someone suffers an abrupt, unexpected death involving their heart. Called “sudden death” in medical reports, it is characterized by the immediate loss of consciousness that follows the loss of an “effective” heartbeat. This means the heart either stops completely or continues beating in such a way that it is ineffective at delivering blood to the brain. This is critical, as failure to pump sufficient blood to the brain will result in brain death after only four to five minutes.

  Understanding this is important in order to differentiate between what’s simply described as a “heart attack” from what is called “sudden death.” In both cases, the heart may malfunction due to its receiving an inadequate supply of blood, most commonly the result of narrowing of its nourishing arteries, since about 70% of these sudden death patients have disease in their coronary arteries. The difference is while there is damage to the heart with a heart attack, it continues beating and supplying blood to the brain.

  With sudden death (also known as “cardiac arrest”), the heart will either stop beating, or more commonly, develop an abnormal heart rhythm called ventricular fibrillation. This chaotic heartbeat prevents any meaningful contraction from the now quivering heart muscle. There is no blood pressure and this triggers sudden death.

  This process is devastating, and has nearly always been fatal.

  Beginning of Change

  Things began to shift in 1961, when knowledge that sudden death led to 100% mortality without treatment spawned the emergence of two remarkable discoveries.

  First, a defibrillator had been developed to electrically shock the heart and restore a normal rhythm. This is the type of device commonly seen on medical shows where paddles are placed on the patient’s chest as “Clear!” is shouted to be sure no one is touching the patient. A precise electrical shock is administered to the body in the hopes of restarting the normal heartbeat.

  Still, the problem remained as how to keep the heart pumping blood — especially to the brain — until a defibrillator could be brought to the patient and then applied (hopefully successfully), so that further treatment might then be used.

  This led to the second discovery, a technique that would eventually be taught not only to doctors and nurses, but also to emergency medical technicians (EMTs), lifeguards, and eventually people in all walks of life: cardiopulmonary resuscitation, or CPR. This is accomplished by manual compression of the sternum by pressing down on the chest with two hands at a certain rate per minute. This external treatment physically compresses the heart to make it eject and pump blood through the body to deliver oxygen to the brain and other organs. CPR is always combined with artificial respiration to bring oxygen-containing air into the lungs.

  The combination of these two new treatments allowed us to stimulate and maintain a heartbeat without opening the chest. They made a huge impact.

  Now we could bring someone back from the dead. Lives would be saved.

  Indeed, the development of CPR created a sea change in cardiology — which I know firsthand as I was fortunate enough to start my internship at Johns Hopkins Hospital in 1961 when these new protocols were introduced.48 I felt very lucky to be part of this thrilling new advance.

  Not only did I have the chance to meet two of the authors of this report (William Kouwenhoven, an electrical engineer, and James Jude, a cardiac surgeon), most importantly, I also had the opportunity to use these innovative methods when sudden death developed after cardiac surgery.

  I recall my first experience. A post-surgical patient died from sudden death as he unexpectedly lost his heartbeat, stopped breathing, and sank into his bed unconscious. With no other physicians around, I called out to a nurse to alert the staff. I immediately checked for a heartbeat by feeling the patient’s pulse: it was absent. I started chest compressions while another intern forced air into the patient’s lungs by performing mouth-to-mouth breathing. This was done until a breathing tube could be placed, which allowed the ventilator to fill the lungs with oxygen and then empty them of carbon dioxide.

  This was a very tense time for me — an intern — as I suddenly had full responsibility. My patient’s life was at stake! It was no longer a training exercise.

  I heard others wheeling in the defibrillator as we kept giving CPR. This was momentarily stopped so we could place the paddles on the patient’s chest. After making sure everyone was clear of the patient, the button was pressed — creating the telltale zap as the device discharged an electrical current onto the chest that then reached the surface of the quivering heart.

  The defibrillation worked on the first try! The heartbeat rhythm resumed, and a strong pulse could be felt. The drama was intense, but the patient revived. Even though colleagues congratulated me and the other intern for our actions, I was mostly relieved, and awed that this miraculous combination worked.

  Those minutes were breathtaking. We witnessed a dead person magically recover to become a living one. How wonderful that these researchers could create such a treatment! Soon, I would be just one of many physicians worldwide whose ability to save lives became amplified by utilizing a novel treatment with a profound impact.

  Experiencing this incredible contribution firsthand made me think about how wondrous it would be if I could someday come up with such a powerful new idea that others could use.

  While I realized that CPR was still a small step forward since only 10% of patients receiving it at that time survived, the door seemed open toward learning why sudden death events occurred… and the important second step of designing new treatments to vastly improve success in resuscitating patients.

  Surprisingly, that did not happen.

  Today the Same as Yesterday

  CPR is still used today, much as it was back then.

  When other people are nearby to witness a person’s sudden death after the heart stops beating — whether out in the world at large, or nestled within the hospital setting — we call this event a “witnessed arrest,” and immediately starting CPR has become the international standard.

  Yet despite what you may have been told or seen on television medical shows that glorify the heroic efforts of teams that use CPR to save a life… the sobering truth is that 90% of these patients succumb. Remarkably, this 10% survival mirrors the same rate that existed in 1961 when CPR was discovered.49, 50

  This tragedy becomes compounded, as among the rare 10% of patient survivors, half of them (50%) suffer permanent brain damage because blood supply to the brain was inadequate.

  This sad dilemma begs the question: Why hasn’t there been more progress?

  The Main Problem

  The unfortunate reality is conventional medical wisdom considers that once sudden death occurs, there is little more we can do than what we already do. Yet this “established” belief is the nemesis to progress. It hinders the evolution of new approaches, and contradicts Einstein’s fundamental concept of “nothing changes until something moves.” What must move fir
st is our thinking.

  The plot thickens, as misleading statistical analyses compound the problem by providing illusions of “progress.” In this case, subsequent improvement in survival from 10% to 15% was now considered a “50% enhancement of outcomes.” Self-congratulatory praise is shared among the medical community, but this reaction departs from reality — as actual survival only rose by 5%.

  To uncover elusive answers, investigators must frame their fundamental focus differently. The question must be, “Why do 85% of patients still die from an event that suddenly snatches life away from someone seemingly completely normal only moments before?”50

  Minimal Movement

  As described, minimal advancement between 1961 and 2018 has allowed the 85% mortality to continue. This 5% improvement was marginal as it resulted from only minor enhancements: how often to shock the heart to reverse ventricular fibrillation, and using body cooling to lower oxygen needs and reduce the inflammation from impaired circulation. This latter cooling technique came from clues gained through patients who revived better when they were found in cold water (for example, a driver losing consciousness after plummeting his car into a frozen lake), compared to patients suffering sudden death at normal temperature.

  The absence of significant treatment improvements is due to the medical community’s view of sudden death as a disease. Therefore, it aims its efforts at restoring an effective heartbeat. This total focus on how to administer the fewest shocks from the defibrillator, or learning if body organs should be colder or warmer, has resulted in the minimal 5% survival improvement over 50 years. The ongoing failure to reduce brain damage in the rare survivor has clearly exposed the profound limitations of adhering to traditional treatment.

  An innovative approach is needed.

  The first step requires recognition that traditional methods have failed. This appreciation must be coupled with a willingness to consider new approaches to counter these awful outcomes.

  New View: Sudden Death as a Symptom, Not a Disease