I held retractors as I watched Dr. Blalock guide his chief resident through each motion of the Blalock-Taussig shunt procedure. I was standing shoulder-to-shoulder with the “giant of heart surgery,” drinking in each thoughtful comment while he tutored the next generation in the procedure that launched the field of cardiac surgery. The pinnacle came when Olive Berger peered at the blue features of the cyanotic child and remarked, just as she had that first time, how pink this child’s appearance became as the shunt was opened and oxygen-rich blood nourished the body.
Though I didn’t realize it then, that historical first surgery would hold additional resonance for me later, as Dr. Blalock’s first assistant in that original operation was William Longmire, who would be my Chief of Surgery at UCLA from 1964–67.
Folklore in Hopkins’ Hallowed Halls
Dr. Blalock’s renown made him a legend at Hopkins, and naturally placed him at the center of many classic stories. These included tales of chief residents being overwhelmed when they first operated with him. In one story, a chief resident had been assisting Dr. Blalock in a procedure that aimed at enlarging the opening of the mitral valve (a structure between the left atrium and ventricle) that had become narrowed because of rheumatic fever.
In performing this operation, Dr. Blalock put a suture (stitch) encircling the top of the appendage of the atrium. He then placed his finger into the appendage to manually widen the thickened mitral valve, while tightly closing this suture around his finger to prevent any bleeding.
But he still noted bleeding after closing the suture. Dr. Blalock was from Georgia and spoke with a southern accent. As he couldn’t use his one hand with its finger in the atrium, he quickly instructed, “Hep me, Hep me, Hep me” to the resident — meaning “Help me, Help me, Help me.” The resident was unsure what to do, until Dr. Blalock stated, “Suck, Suck, Suck” — which meant to place a suction tip at the site of the bleeding. But the flustered resident thrust the sucker past Dr. Blalock’s fingers and pushed it into the left atrium, essentially sucking out all the patient’s blood! Dr. Blalock instantly commanded, “Step on it, Step on it, Step on it” — meaning the resident should immediately stop the suction by stepping on the tubing that ran across the floor. The resident promptly responded and there was a resounding thud as his foot hit the floor. Dr. Blalock winced and stoically declared, “That’s maa foot” — his attention never wavering from the surgery he was performing.
Of course, all was corrected.
This oft-repeated tale revealed the straightforward nature of Dr. Blalock, who was also our leader of cardiac surgery. It made me further appreciate how fortunate I was to have the chance to satisfy my hunger to learn while at Johns Hopkins, a unique institution.
Unexpected Lesson
New ideas face criticism, and resistance to innovative change is not limited just to the world of medicine. Ironically, one of the first times I became aware of this rigidity was at a social event at Hopkins.
As was custom, the Hopkins surgical faculty would periodically invite interns and residents to a gathering at their homes, perhaps to make up for the usual saltines, peanut butter and jelly, and soup that we could afford on our meager salaries. While this was a gracious invitation, I soon discovered that the societal traditionalism at Hopkins was markedly different than its pioneering scientific advances.
One such event occurred at an elegant house with a swimming pool. I’d brought a date, Ingeborg. In 1961, women wore one-piece swimsuits that went from their thighs up to their shoulders. So when Ingeborg walked out looking gorgeous in her usual bikini, it set the conservatives aflutter. Women were aghast. “How can she dare do that?”
Though Ingeborg’s swimwear would eventually become the norm, this showed me early on what happens when people are confronted with something new.
In her own way, Ingeborg was presenting the future, as I would later do with my work.
Naturally, I married her.
Arrival of the Revolutionary Heart-Lung Machine
After Dr. Blalock’s original operation in 1944, the newly created Blalock-Taussig shunts were used universally, their success opening the door toward the future expansion of cardiac surgery. Still, while they improved the amount of oxygen to the body tissues of these blue children, they only provided a temporary solution since the underlying cardiac problem was not corrected by these hookups. As the baby grew, the evolving child needed more and more blood going through this fixed artery. To remedy the problem, we needed to get inside the heart and correct the tetralogy of Fallot defects, or other causes of cyanosis.
This goal would not be possible until 1953, when John Gibbon, a Philadelphia surgeon, invented the heart-lung machine.40 This astounding contribution transformed the field of cardiac surgery by taking over for the heart and lungs. The surgeon could now open the heart and fix the cause of its symptoms. Our legendary Professor Blalock never tried to use the heart-lung machine, yet he dramatically showed the power of his mentorship by passing this torch of leadership to his students, who subsequently became worldwide leaders.
With Great Progress Comes Great Responsibility
How lucky I was to have been at Hopkins near the beginnings of open-heart surgery. I got to be part of a generation of surgeons whose toolbox now included the heart-lung machine, which advanced cardiac surgery in ways previously unimaginable.
Yet here I was, many years later at UCLA in 1992, trying to discover a possible flaw in the usage of this same miraculous development.
While I am an ardent advocate of building on tradition, I also believe it is our absolute responsibility to question if any of what we consistently do is always the correct choice.
Physicians, and especially surgeons, know that their actions will affect a patient’s health and possibly their life. We meet this enormous obligation by using the best tools at our disposal to remedy an illness. The creation of the heart-lung machine placed a new set of accountabilities upon both the surgeons and the perfusionists (who actually operate them), as this device takes over the patient’s breathing and oxygenation of their blood. But we must make critical choices about how we adjust this device to deliver the proper amounts of oxygen, as well as adjustments to flow, blood pressure, temperature, and other factors.
Nature makes these decisions when the patient’s heart and lungs are functioning normally. But… it is up to us the minute we begin the heart-lung machine. We become “The Ultimate Decision Maker,” and our judgments can powerfully influence surgical outcomes — and impact the patient’s future.
My search to understand the problems we encountered in blue babies led me to ask, “Could the heart-lung machine suddenly shift from a friend to a culprit when we use it in efforts to cure their hypoxia (too little oxygen)?
This new responsibility of controlling the delivery of oxygenated blood to compensate for the baby’s own lack of oxygen… reminded me of our studies with cardioplegia and the development of “controlled reperfusion” following a lack of blood flow to the heart. In those cases, we adjusted the composition and conditions of the first reflow of blood to offset the damage that the return of normal blood supply would cause during open-heart surgery (Chapter 6) or after an acute heart attack (previous two chapters). Now the task was delivering new oxygen after it has been deficient.
This brought up a new question: Could we be causing the surgical problems we were encountering in blue babes?
Airing Out the Issues
Conventional guidelines have been established for how the heart-lung machine is used. The traditional protocol includes administering oxygen at 400 to 500 mm Hg “PaO2” — a term that describes oxygen tension or how much oxygen is dissolved in the blood plasma. These are much higher levels of dissolved oxygen than what we normally have in our blood after breathing room air, where PaO2 is 150. The use of elevated levels is based upon making certain there’s adequate tissue oxygen for body nourishment. No one was looking to alter this globally accepted reasoning because results were good.
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Yet an intriguing dilemma confronts a medical team, who must ask: Should we simply do what we believe is good… or follow what we can test and prove?
We needed to look deeper into the role of oxygen to answer this question.
Oxygen, the Double-Edged Sword
The vital benefits of adequate blood oxygen are widely recognized. But oxygen may also cause damage when delivered in excessive amounts. These lessons about this dual role of oxygen are well known, yet sometimes we hear them without listening.
For example, long before the development of open-heart surgery, it was well-documented that premature infants, when exposed to high concentrations of oxygen therapy, may develop serious damage in the retina of their eye, sometimes becoming blind. This complication would ultimately lead to the lowering of oxygen concentrations in treating immature infants. Yet even this change was not initially embraced. Concerned by the use of these high concentrations, renowned pediatrician Arnold Patz applied for a grant to the NIH (National Institutes for Health, the main U.S. government agency for funding health research) to study the issue.41 But his concerns were rebuffed and cast away with an admonishment by their expert committee that said, “Everyone knows premature babies need high oxygen concentrations.”
It was a classic example by leaders at the NIH of how conventional knowledge is simply accepted even though no one had even considered or tested Patz’s concept. As he found (as have I on many occasions), experts are rarely receptive to having their cherished viewpoints challenged. Fortunately, Patz was not deterred. He found other funding, did his study, and his findings showed a dramatic reduction of baby blindness followed his lowering of oxygen concentrations.
Patz’s conclusions have since been accepted and his guidelines are now used in premature infants in every nursery. But cardiovascular practitioners have not learned, established, or adopted them.
The benefits of oxygen are clear, but adverse consequences of its use in high concentrations have emerged. Increased oxygen can give rise to creating detrimental chemicals called oxygen radicals (also called reactive oxygen species, or ROS) — that destroy tissue by disrupting cellular structure and function, damaging DNA, and by igniting a cascade of other problems.
Fortunately, one of the many marvels of nature is that our “body fortress” contains elements that protect us against different types of stress. Antioxidant substances are produced to offset the damaging effects of increased oxygen tension and combat ROS. Yet this natural defense mechanism does not fully develop in the premature infant. Their body’s antioxidant concentrations are low, which weakens their oxygen protective mechanisms, and accounts for them developing blindness after too much oxygen is delivered.
But here’s the reality: cyanotic children have this same diminished defense against hyperoxia (too much oxygen).42 For this reason, they may suffer enhanced injury when their low blood oxygen levels (only 25 to 30 mm Hg) — are routinely and dramatically enhanced to 400 to 500 mm Hg during an open-heart operation.
Looking Where No One Was Looking
Everything I have described was known at that time, yet no one had tried to examine if the heart-lung machine might play a negative role when used in the treatment of blue babies that undergo the surgical repair to correct the cause of their cyanosis.
In order to see if different guidelines were necessary, I realized we needed to learn more about oxygen. This revealed some information that was pivotal — and fascinating.
First, a normal level of blood oxygen, obtained as we breathe ordinary air, is called normoxia (normal oxygenation). In this circumstance, the oxygen saturation in the blood is about 98% — with nearly all of the oxygen carried in the red blood cells, which transport the bulk of oxygen to tissues.
The remaining oxygen is called dissolved oxygen, which floats in the blood plasma (the fluid in which blood cells and platelets are suspended). Breathing room air provides the 150 mm Hg oxygen level that is normally dissolved in the blood plasma, which actually yields negligible benefit to body function compared to the major contribution of oxygen in red blood cells.
Since normoxia (the oxygen level in room air — 150 mm Hg) causes 98% saturation of red blood cells, one might ask: “If a little bit of oxygen is good, is a lot better?”
Now, one might assume more is better, as had long been believed. But in reality, raising the oxygen level to 400 or 500 mm Hg as is typically done, cannot increase the oxygen saturation level to much more than the 98% level achieved by breathing room air. But it does dissolve more oxygen into the blood plasma. In fact, the heart-lung machine makes this occur very directly because its oxygenator is exceedingly efficient: if the oxygen setting is at 400 mm Hg — then 400 mm Hg of oxygen is dissolved in the blood. Yet the oxygen saturation within blood rises to only 99% — not a significant difference.
Intriguing information. But it remained unresolved about how much oxygen should be administered to blue babies.
Just raising such a question to traditionalists will garner vehement rejection, and stimulate their counterargument about keeping oxygen levels high — a strategy that they believe has “proven” itself over many decades since not all blue babies suffer damage from such operations. They perceive the greater risk is losing the baby because of “insufficient amounts of oxygen” from the heart-lung machine, and so the possibility of hyperoxic damage is not acknowledged. This prevailing attitude precisely matches the thrust of the NIH experts’ comments as they denied the grant application of Patz, thinking his study of lowering oxygen levels to prevent blindness in premature infants was foolhardy.
Yet conclusive answers cannot be gained by adhering to past beliefs — or by assuming that what seems logical is valid. The answer is only revealed through investigation. While the results may be surprising, they are always true. The challenge is to uncover the underlying reasons for them.
Welcome to the job of the researcher.
Initial Investigating Step: Confirm What Is Known
In order to prove if conventional re-oxygenation could harm blue babies, we had to start by showing we could produce this damage in animal test subjects that had been made cyanotic and then treated with sudden hyperoxia (elevated oxygen concentrations).
There was precedent for the preparation of this task, as Vivien Thomas had done the same thing to set the stage for Dr. Blalock’s experimental shunt procedure. Our infant piglets were made cyanotic by either lowering oxygen levels in a ventilator (a device that supplies air for breathing), or with a heart-lung machine.
Once we had created our cyanotic piglets, we first confirmed that these low levels of oxygen did not cause damage (since no injury existed in blue baby heart muscle before re-oxygenation). Our findings showed their hearts had no injury.
That led us to our next step: having the heart-lung machine introduce hyperoxic (excess oxygen) re-oxygenation.
The results were glaringly apparent: oxidant damage consistently developed during the first 5-minute interval in which a traditional 400 mm Hg oxygen level was delivered! Heart performance deteriorated and antioxidant reserves fell.43
This established there was an inherent problem with the use of high re-oxygenation levels in cyanotic infants with lung problems. That is exactly what happened to the blue baby (described at the beginning of this chapter) that surprisingly developed heart failure — the unexpected observation that ignited my search into finding why this tragedy occurred.
While gratified that we had found the reason for this unexpected deterioration, I remained troubled that physicians did not appreciate or understand why this extensive damage may happen. The result is that blue babies continue to receive high-oxygen re-oxygenation protocols in major centers around the world.
Our goal became clear. We needed to uncover solutions.
Closing In!
We knew that cyanotic babies don’t have a strong reserve capacity of antioxidants (those natural substances that combat toxic oxygen) and have limited ability to produce them. Consequently,
these babies are unable to neutralize the damaging agents that surplus oxygen will produce. So we thought to first see if a treatment that added antioxidants might offset this damage.
We tried various types of antioxidants, using different amounts of each. Though met with failure many times, we were tenacious in our pursuit.
We finally found the adverse oxygen-related changes could nearly be avoided by adding any one of four specific types of antioxidants — provided they were given before hyperoxia was caused by the heart-lung machine.
Then we took a different step. Instead of finding a way to counter administering high levels of oxygen, we confronted our suspected culprit head on and lowered the amounts of oxygen administered.
The result was both elegantly simple and profound:
Re-oxygenation injury did not happen if normal oxygen levels (100–150 mm Hg) was used, and hyperoxic levels (400 mm Hg) were avoided. This assumption was what we had hoped to be true — the proof is always in the pudding — and now we had proven it. Everyone on the team was delighted that we had found a solution to this terrible global problem.
But we were not done yet. The most critical and challenging part needed to be solved.
Re-oxygenation and Heart Surgery
So far, we had only done trials on animal subjects that did not experience the open-heart surgery that would be needed to help these cyanotic babies. Our next step involved confirming whether re-oxygenation damage will develop as the congenital defect causing cyanosis was corrected.
Solving the Mysteries of Heart Disease Page 17