Limb Ischemia
Some may have seen a movie where a physician — witnessing a patient with a cold, pale-looking leg and feeling no sensation other than pain — then states, “Dead leg. We must amputate immediately.”
That realistic scene would play out in many hospitals, as sudden obstruction of blood supply to the limb causes the classic symptoms of pallor, paralysis, no feeling except for pain — along with contracture of the muscles (a kind of “charley horse” that is profoundly uncomfortable). This occurrence leads to one conclusion: remove the leg.
But is that the only conclusion?
We know that such leg contractures also occur temporarily in many athletes, sometimes from overexertion. Yet there will consistently be complete recovery from this severe and uncomfortable cramp! But when this same condition happens after an artery is blocked — suddenly this symptom is considered the “final negative marker” that has only one solution — amputation.
These situations are not identical, but they do share a commonality that relates to how the cell adjusts its internal calcium concentrations during stress. Knowing this, Friedhelm simply asked — is contracture truly terminal for a leg without blood flow?
It’s What’s on the Inside that Counts
Sudden closure of a leg vessel can happen for any of several reasons. A blood clot could form in its main (femoral) artery due to hardening of the artery and an irregular surface on its inner wall. Or a blood clot might form elsewhere, such as the heart, and travel through blood circulation (called an embolus) and end up in the leg. Or the artery may clot due to irritation by a catheter tube (inserted to help the impaired circulation) that remains in place for several days.
In the case of a clot, logical reasoning would suggest removing the clot, not amputating the leg. But logic doesn’t always win.
That’s because efforts decades earlier to reestablish blood flow by successfully removing a clot — had caused a devastating aftermath in these patients. Resuming a new flow allowed toxic substances that had developed within the dead leg tissue to suddenly wash out into the general circulation. As a result, serious injury to the kidneys, heart, lungs, and brain — and massive leg swelling — would sometimes follow this treatment. In such cases, death rates rose to 20 to 30%, so attempts to restart blood flow were abandoned in favor of amputation. These drastic complications would not occur with leg amputation, as it only had a 1% mortality rate.
Friedhelm recognized the dismal prognosis of traditional treatment — and simultaneously appreciated how controlled reperfusion successfully treated the heart. This disparity (the heart recovering after controlled reflow and the leg dying after normal blood reflow) prompted him to explore using controlled reflow in the “dead” leg.
Could regular blood reflow be the culprit behind this damage after a leg has had no blood flow?
A logical conclusion. But this theory needed to be tested.
Before starting treatment on a patient, Friedhelm needed to confirm in the lab that no irreversible damage would follow six hours of no leg blood flow when controlled reperfusion was used. If successful, this observation would precisely parallel what happened when we studied the effects of six hours of heart ischemia at UCLA — and thus show that just as with the heart muscle, the leg was not dead either.
The team now under Friedhelm’s guidance, first mimicked conventional treatment by returning normal blood in an animal subject. They found sudden and complete damage to a leg that looked normal before reflow. These dire sequences included massive leg swelling… abrupt blood potassium rise (due to toxic washout from the damaged leg) that significantly altered heart rhythm… and kidney failure due to the toxic proteins (myoglobin) released from the leg’s damaged muscle.
Controlled reperfusion would now be used to test his novel concept for the extremity. He established laboratory guidelines for treating the leg by using the already established heart controlled reperfusion protocols.
So what happened?
It worked beautifully every time. No problem developed following its delivery, as the test animal’s leg and the body completely recovered. None of the adverse and sometimes lethal events that followed regular blood reperfusion were observed.66
Friedhelm updated me by phone and I joined him in his elation!
We both knew what would come next.
Bench to Bedside
The role of the lab is to become a bridge to the patient, and Friedhelm would now use this innovative experimental knowledge to test how controlled reperfusion worked in 11 patients with “clinically dead” legs deemed to have “terminal contraction.” Only then would he know if the success in the lab could be transferred to the sick patient.
The results were sensational. These included complete relief of leg contracture as normal function returned to the recovered muscles, while washout injury to other organs was absent!67
With this discovery, a vision emerged for a new landscape of treatment by vascular surgeons, as they (not cardiac surgeons) are the ones who encounter this leg ischemia problem. They could now save jeopardized limbs and restore their function, while avoiding the untimely death or other adverse consequences that result from returning normal blood reflow!
Friedhelm called once more to tell me of these dramatic new findings. I was thrilled because one of my students had beautifully blazed a trail in a new arena of clinical care. Our excitement about the heart now rang equally true for the leg. This clinical confirmation allowed us to ponder an even broader future: could controlled reperfusion help other organs as well?
Friedhelm needed to report these remarkable findings. He sent me his draft for review and I realized that extensive editing was needed. It was my delight to pitch in and then return it to Germany. Friedhelm asked me to be coauthor. I disagreed, advising him that placing my name on this landmark work would be a mistake.
“A hallmark of innovation,” I contended, “is recognition of the innovator. The readers may think this was my work if my name is on it, and it is not.”
My decision was firm, but we agreed to make me a coauthor on some future report, for the leader here was Friedhelm, not his teacher. My extraordinary pleasure was in watching my student make a monumental accomplishment. Nothing more was needed.68
Further Proof
The next step for Friedhelm was to have colleagues at other centers use his treatment and see if their outcomes upheld his findings. A pair of German cardiac surgery centers joined this first clinical trial by using controlled leg reperfusion on 19 patients with extended limb ischemia, each having an average of 26 hours of no blood flow. This challenge introduced a striking test of our concept.
Only three patients (each having severely damaged hearts — cardiogenic shock) died. Each of the other 16 patients completely regained normal limb function after controlled reperfusion. The corroboration of this concept by others was overwhelmingly positive.69
It was relatively easy for Friedhelm to convince other cardiac surgeons to test out controlled reperfusion in their patients who developed post-operative problems in their extremities. They could simply adjust the reperfusion setups that they routinely used during cardiac surgery.
However, getting vascular surgeons to consider this new approach was much more complicated.
I learned this firsthand when I was a visiting professor at the University of Illinois Hospital in Chicago, where Brad Allen was on their faculty. We were discussing Friedhelm’s work at breakfast when Brad said, “We have a patient with a jeopardized limb where contracture is present. There was complete loss of blood flow to the leg, due to a clot forming around a catheter device in his femoral artery that was used to help his heart perform better.”
I immediately suggested, “Let’s go see him.”
After visiting the patient, I proposed to the cardiac surgeon and the patient’s consulting physician (who was a Professor of Vascular Surgery) that controlled reperfusion might reverse this apparently terminal leg injury.
“It will
never work,” countered the vascular surgeon.
“We have evidence that it can. Try it.”
The vascular surgeon was certain an amputation was needed, but agreed to try the procedure. As the procedure was performed… he was astounded at the immediate and positive role that controlled reperfusion played in this patient’s recovery.70 The vascular surgeon watched the leg muscles that were rigid from contracture become remarkably malleable, along with an absence of the anticipated swelling and other complications.
Unfortunately, the road to acceptance of new knowledge is long and arduous, before the core of thinking changes to allow its general adoption. Toward that end, Friedhelm helped develop a prospective randomized trial by vascular surgeons in Germany and Austria to treat advanced leg ischemia. “Prospective randomized trial” means that some patients would receive normal blood while others would receive controlled reperfusion. The key requirement for validation is to use properly selected patients, and to precisely follow the established methods of controlled reperfusion.
There was great anticipation for validation of Friedhelm’s breakthrough discovery. But the vascular surgeons did not adhere to the controlled reperfusion protocols… and no difference in results was found.
My credo is always, “If it does not work, either the idea is wrong, or the procedure was not done right.” We knew that “the idea was not wrong,” because truly “dead” contracted legs had recovered in previous studies. The failure here was because the surgeons failed to do controlled reperfusion properly. This conclusion is substantiated by the 24 patients who had just been summarized in Friedhelm’s analysis. Their recovery proved the idea was correct.69
Unfortunately for patients, this poorly conducted trial buried any chance to recover doomed extremities. Yet, I know the opportunity will resurface again… because truth always wins.
Lung Transplantation
Finding that the controlled reperfusion approach worked equally well for the heart and leg, supported my fundamental belief that ischemia and reperfusion injury was a biologic process that could be applied to treating other organs.
One such area might be organ transplantation. The donation of healthy organs from an individual to replace diseased ones in another, when successful, can vastly extend the life of the recipient. Still, the process of removing an organ from a body introduces a period where it receives no blood flow, which lasts until the organ has been placed into the recipient. The only safeguards conventionally used to avoid injury are cooling of the donor organ (to lower its energy needs), which is then followed by return of normal blood flow after it is placed in the recipient.
But could this normal blood reperfusion lead to injury?
This became an area of interest for Brad Allen at the University of Illinois. Brad had studied using controlled heart reperfusion following acute heart attacks with us at UCLA from 1984 to 1986. Now in 1997, he noted that in preparation for lung transplantation, a lengthy period of time without blood flow (four to eight hours) was needed to transport the lung from a donor in one city to the recipient at his hospital in Chicago. He wondered if lung reperfusion injury occurred as a result, and if so, could it sometimes hamper success of the lung transplantation procedure? The question that naturally followed was: could controlled reperfusion avoid such a problem?
Of course, before he would try controlled reperfusion in lung transplant patients, Brad would test the effects of transplantation — with both normal and controlled reperfusion — in the lab.
The trauma of normal blood reperfusion was confirmed — by removing the lung of a piglet — exposing it to two hours of warm ischemia (no blood supply and no cooling) — and then replacing it into the same piglet (a procedure called “lung re-implantation”). Reflow of normal blood was given. Severe lung damage resulted, as lung vessels became constricted and thus raised their resistance to blood flow. They also became stiffer, swollen (from added water), and tiny capillaries near the breathing sacs (alveolar) filled with fluid.
Conversely, subsequent tests with using controlled reperfusion for 10 minutes — resulted in normal lung vessel resistance, no lung stiffness or swelling, and normal capillaries.
Brad took it a further step. In prior lung transplantation studies, Brad had found that adding a white blood cell filter would counteract toxic byproducts caused by white blood cells (WBC). So he added a WBC filter during controlled reperfusion, which produced even better results.44
Brad realized the next important step in the experiment would be to mimic the lung being kept cold, as it is transported to the recipient before transplantation. He simulated this process by again providing controlled reperfusion into the transplanted lung — after it had experienced 24 hours of cold storage (in an icebox). Amazingly, the positive results following 24 hours of ischemia precisely mirrored the findings when controlled reperfusion was delivered after two hours of ischemia at normal temperature conditions!71
These excellent findings were critical to protecting the lung during its transplantation… yet they also protected the other (normal) lung in the recipient’s body. That’s important because normal blood reperfusion of a transplanted lung can cause a washout of toxic substances that circulate to injure the non-transplanted lung — similar to what happened following normal blood reflow when treating a dead leg, as was described in Friedhelm Beyersdorf’s studies.
Protecting the normal lung is vital, since the patient must rely on it if the transplanted lung does not properly function. While its injury from conventional reperfusion would be on a lesser scale than that of the transplanted lung… this normal “back-up” lung would experience diminished reserve function as there would be heightened resistance to blood flow, increased stiffness and swelling, and small capillary damage.72
It was hoped that all of this could be prevented with controlled reperfusion — and indeed it was. Healthy lung function was normal after 24 hours of storage when controlled reperfusion was used.
Human Trials
These experiments established the findings necessary to allow controlled pulmonary reperfusion to begin to be used with patients undergoing lung transplantation.
That next critical step was done on patients at the University of Texas — and results were excellent.73 Medical teams there were elated by the positive outcomes. Brad and I were particularly delighted and encouraged because everything that we had hoped for was proven true.
This approach has now subsequently been used at UCLA in over 100 patients.74 Unfortunately, at UCLA, the recommended ten-minute duration of controlled reperfusion (using both the solution and white blood cell filter) was arbitrarily reduced by the transplant team, even though there had been no supplementary studies to support such a change. The results were still good overall, but further investigations are needed to evaluate the effectiveness of this shortened protocol, compared to what was originally recommended from the experimental studies.
This could be an important consideration, as the long-term effects of lung transplantations introduce another concern. We had always found that reperfusion damage is worse in the organ’s inner shell, as was quite evident in the heart and brain. It is similarly true with the lung, as its inner cell lining of small breathing tubes may suffer long-term damage and cause a non-reversible condition called bronchiolitis obliterans. That results in inflammation and closure of the small breathing tubes. A tragedy unfolds in which lung transplantations that seem initially successful, may later lead to patients dying prematurely because of this lethal complication.
While the UCLA results thus far show a reduction in the development of bronchiolitis, it is too soon to fully tell the long-range consequences. There needs to be long-term testing of those patients that received normal blood — and those who received properly delivered controlled reperfusate — to determine if this lethal complication is also avoided by the new approach.
The Liver
This path toward proving the universal benefit of controlled reperfusion to various organs is an
ongoing journey.
Though explorations with transplantation had so far only focused on the lungs, the trauma of ischemia (absent blood flow) is prominent in patients undergoing any kind of organ replacement. As with the lungs, the only conventional protection against this comes from cooling the removed organ… which is then followed by normal blood reperfusion after it is placed in the recipient’s body.
As I’ve mentioned before, one of the thrills of working in a university is the interchange between practitioners of different disciplines. This was certainly true for organ transplantation, as UCLA has the largest liver transplant program in the United States. Its leader, Ron Busuttil, fully understood the enemy: the problems associated with ischemic reperfusion injury. Such injury led to awful consequences. The transplanted liver becomes congested, swells, and toxic enzymes wash out into the body. Extensive care is required, yet the liver may still fail completely and the patient succumbs.
Our ears were always open to hearing of new problems to solve in this area, since we believed our answer to the ischemic reperfusion process can benefit any organ. With this in mind, Brad Allen suggested we do a pilot study of controlled reperfusion after liver transplantation.
We first needed to determine if extensive injury indeed followed two hours of warm ischemia and normal blood reflow. This finding would become the yardstick by which we could measure the effectiveness of our approach. As it turned out, the challenge of such injury was a severe one. Both pigs undergoing warm ischemia and normal blood reperfusion died. Each exhibited the symptoms of severe liver damage before their death.
Now it came time to test our methods. Our experiences with the heart and leg and lungs rang true again. The two pigs receiving controlled reperfusion had complete recovery. And every indicator that might have pointed toward damage returned to normal within 24 hours.
Just as there is great significance to having others confirm positive results with patients (as Brad’s success with patient lung transplants was duplicated by the Texas researchers), the same was true for documenting this extraordinary lab recovery. These positive experimental results were verified by one of Ron Busuttil’s associates, who repeated our study in his lab. Our team had no part in that research, yet again — there was no reperfusion injury. A pattern became evident, as their liver findings mirrored the same return to normality that we had encountered in our studies of the heart, brain, limb, and lung, and in Brad’s two pilot studies of the liver.75
Solving the Mysteries of Heart Disease Page 24