Public Workshop
Safety of Hemoglobin-Based Oxygen Carriers (HBOCs)
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH, FDA
THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE, NIH AND
OFFICE OF THE SECRETARY AND OFFICE OF PUBLIC HEALTH AND SCIENCE, DHHS
Natcher Conference Center, Building 45
Main Auditorium, NIH Campus
Bethesda, Maryland
Printable Version (PDF - 426 KB)
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Wednesday, April 30, 2008
LIST OF PARTICIPANTS
HARVEY KLEIN, M.D.
Department of Transfusion Medicine
Clinical Center at NIH
STEPHEN COHN, M.D.
University of Texas Health Science Center at San Antonio
DEMETRIOS DEMETRIADES, M.D., Ph.D.
University of Southern California
MITCHELL P. FINK, M.D.
Logical Therapeutics
DANIEL FREILICH, M.D.,
CDR, MC, USN Naval Medical Research Center
JOHN HOLCOMB, COL, M.D.
University of Texas Health Science Center at San Antonio
CHARLES NATANSON, M.D.
Critical Care Medicine,
National Institutes of Health
EDWARD J. NORRIS, M.D., MBA
The Johns Hopkins University School of Medicine
EDWARD P. SLOAN, M.D., M.P.H.
University of Illinois at Chicago
GUS J. VLAHAKES, M.D.
Harvard Medical School
RICHARD WEISKOPF, M.D.
University of California
ANDREW BAINES, M.D., Ph.D.
University of Toronto
DAVID C. WARLTIER, M.D., Ph.D.
Department of Anesthesiology
Medical College of Wisconsin
RAYMOND REGAN, M.D.
Professor of Emergency Medicine
Thomas Jefferson University
Philadelphia
JOSEPH E. PARRILLO, M.D.
Robert Wood Johnson Medical School
University of Medicine and Dentistry of New Jersey
MARK GLADWIN, M.D.
Pulmonary and Vascular Medicine Branch
National Heart, Lung and Blood Institute
JAY S. EPSTEIN, M.D.
Office of Blood Research and Review
GEORGE P. BIRO, M.D., Ph.D.
Adjunct Professor Department of Physiology,
University of Toronto
JOHN OLSON, Ph.D.
Professor, Department of Biochemistry and Molecular Biology
Rice University
MARCOS INTAGLIETTA
Sangart, Inc.
DOMINIK J. SCHAER, M.D.
University of Zurich,
Switzerland
JOY CAVAGNARO, Ph.D., DABT, RAC
AccessBio
JEFFREY L. CARSON, M.D.
Robert Wood Johnson Medical School
University of Medicine and Dentistry of New Jersey
EZEKIEL EMANUEL, M.D., Ph.D.
Clinical Bioethics Department
National Institutes of Health
THOMAS R. FLEMING, Ph.D.
Department of Biostatistics,
University of Washington
SESSION III: CLINICAL FINDINGS AND MECHANISMS - OPENING REMARKS
FUNCTIONAL ASPECTS OF THE HBOCS AS A CLASS
ORGAN-SPECIFIC ASPECTS OF SAFETY
THE WAY FORWARD: CAN NITRITE MODULATE HBOC TOXICITY?
ROLE OF MICROVASCULAR REACTIONS IN THE DESIGN OF HEMOGLOBIN BASED OXYGEN CARRYING PLASMA EXPANDERS
ENDOGENOUS HB SCAVENGERS AND HBOC TOXICITY
UTILITY OF ANIMAL MODELS IN HBOC EVALUATION
ALTERNATIVE FOCUSED CLINICAL DESIGNS
P R O C E E D I N G S
(08:30 A.M.)
SESSION III: CLINICAL FINDINGS AND MECHANISMS
OPENING REMARKS
MR. KLEIN: Good morning. Welcome back, can everybody hear me? You can't. Can everybody hear me now? Yes, all right, hearing nothing to the contrary, again, welcome, good morning, it's nice to have everybody back.
I'm Harvey Klein. I'm from the Department of Transfusion Medicine here at the clinical center, about 300 yards in that direction. I'm involved in blood transfusion, and have been since the early '70s, and have been interested and involved in substitutes for the red cell and the red cells function from the mid-'70s, along with Dr. Fratantoni, when we were both children, at the Heart, Lung and Blood Institute.
A few housekeeping issues, please turn off all of your cell phones, or least put them on mute, if you have them. In your folder should be all of the disclosures for all of the speakers today, all of the conflict of interest statements. Those people who are speaking or are on panels, I encourage them, if there is an issue that relates to their disclosures, to disclose that orally. Otherwise you can look those up. Please fill out the evaluation forms that are in your packets as well. Those are helpful through to the organizers of the conference and we hope you'll do that.
Just to set the stage a little bit, yesterday we heard a lot about the unmet needs, and there certainly are unmet needs in the area of transfusion in the current clinical status and the way forward. We had an outstanding review of the physiology of oxygen delivery, and the role and the mechanisms of hypoxic vasodilation. We learned about the rational design of its HBOC molecules based on nitric oxide paradigm, and based on the facilitated diffusion paradigm of oxygen delivery.
We learned about hemoglobin oxidation and vasoconstriction, and how oxidation of hemoglobin can result in clinical toxicities. We need to know precisely how structure and function at the molecular level affect the in vivo function, and that we need to know if in vitro oxidative reactions predict in vivo events.
We've heard an awful lot about nitric oxide chemistry, and also about how and why animal models may or may not help us. Their species specificity and safety signals in one model might be difficult to understand in the human model. In the afternoon and late morning, we heard a bewildering amount of clinical data, and we learned that we don't have access to all of the clinical data. Some is proprietary; some is never reported, certainly not in the reviewed literature and not even to the FDA.
We also learned a little bit about the risks of over-analysis of severe adverse events, about the difficulties of adjudication, about the difficulties of analysis per-protocol. We learned that there may also be other explanations, and things that we consider severe adverse events for our molecules. Things like, perhaps, in appropriate dose during trials or fluid overload, or the rate of infusion, total dose administration, or perhaps we're just seeing misuse of these drugs. And maybe there's really very little toxicity. So all this underlines the importance of randomized controlled trials, or ethical trials as we've heard described by our ethicist yesterday and what that means.
Today, we have two panels which are going to focus on the clinical findings and the mechanisms. The format is as follows. We asked each of the panel members to present, if they wish, for no more than 5 minutes and about three slides. And then we will have a panel discussion where there will be questions among the panel members, and I hope everyone will fit out their cards and send them up to the front, so that we can reflect your questions and have the panel members address them
This is the first panel. Dr. Stephen Cohn is professor of Surgery at the University of Texas in San Antonio. Dr. Demetrios Demetriades, professor of Surgery and Critical Care Medicine at the University of Southern California, Dr. Mitchell Fink, who's had a long experience in this area was professor and chair of Surgery at Beth Israel in Boston and at Pittsburgh. He is now with Logical Therapeutics in Waltham, Massachusetts.
Dr. Dan Freilich with the Navy, who is involved in the trials that have been proposed, Dr. John Holcomb from the U.S. Army Institute of Surgical Research at Fort Sam Houston; Dr. Charles Natanson, an anesthesiologist and senior investigator in Critical Care Medicine here at the clinical center; Dr. Ed Norris, who is an associate professor of Anesthesiology at Johns Hopkins and has had experience with, I believe, at least three of these molecules in the clinic.
Dr. Ed Sloan, professor of Emergency Medicine at the University of Illinois, who is the principal investigator on the Sloan et al. slide you saw yesterday for the Baxter trial that was discontinued, and Dr. Gus Vlahakes from Harvard Medical School, professor of surgery, who has also had experience with these drugs. The four overarching questions for this panel are the following.
Can information about the safety and efficacy obtained from clinical trials in one clinical setting; for example, trauma, be used to inform a risk-benefit assessment in a different clinical setting. For example, orthopedic surgery, can you generalize? A second overarching question is given what we know about the biochemistry and pharmacology of the current and the previous HBOCs, can safety information obtained from the study of one HBOC be used to inform safety and risk assessments for a different molecule, a different HBOC?
Third, are there toxicities or harmful interactions between these molecules in a patient's underlying disease -- hypertension, diabetes, or coronary artery disease that are common to all of these molecules, regardless of their structure and regardless of their modifications? And are there lessons for designing the next trial, that is those lessons that we've learned from what we've heard yesterday, rate of infusion, volume, oncotic pressure, et cetera.
So that's the nature of what we hope to address this morning in this first panel. And I believe the first speaker on this panel would be Dr. Demetriades.
FUNCTIONAL ASPECTS OF THE HBOCs AS A CLASS
MR. DEMETRIADES: Thank you, Dr. Klein. Thank you very much for this honor. I am a trauma surgeon and this means I'm going to make comments and recommendations from the trauma surgery point of view. Yesterday, we have heard some beautiful presentations from the NIH scientists, from the industry, from a biostatistician. And from what you have heard and what you have read in the literature, where are we now?
Firstly, I want to say that I'm very excited. I was very excited. I still remain fairly excited about the products. It's promising, but we are still not there. We are very concerned about the reported complications, complications that increase mortality. We need to encourage the industry to go about and address these issues. We want to see clear statistics. We do not want the statistics to confess under torture, as the statistician said yesterday. We want these speakers to come out freely without any effort.
I believe that with the current status, we're not ready yet for quick trials. We might rush and broaden our inclusion criteria, but I think it will be counterproductive for everybody.
We also heard from a couple of industry speakers that it's not fair to group together all HBOCs. I think this is fair; it is appropriate to judge each product on its own merit. There are significant differences between all of them that you need it into account these differences.
In one area where I firmly believe that we are ready to move in is the compassionate use. We have patients; Jehovah's Witnesses or other groups of patients who are really, practically dying in front of our eyes without being able to do anything.
We know that for acute blood loss, if the hemoglobin goes below 5 -- acute blood loss, not chronic, the patients goes into cardiogenic shock, and you give basal pressors, and you give fluids, and you give whatever you want; they do not respond. This might be an excellent group for compassionate use. We know that for acute blood loss, if the hemoglobin is below 3, it's extremely unlikely that this patients will ever make it; an excellent candidate for the product.
Now, for future, what kind of clinical trials do we need? Well, we need to apply much restrictive criteria. Remember that on the one side we have patients; we have the products with significant complications. We need to use this product in patients who are at extremely high risk of dying. So in other words, the benefits should outweigh any possible disadvantages. I think it's a serious error, and I have seen these in the existing standards. They include all mechanism, blunt trauma -- blunt and penetrating. It's a big mistake, and I'll tell you why. I have seen that one of the inclusion criteria was a blood pressure of 90 or less. I think it's a serious error, and it's unlikely that you're going to see any difference with this kind of criteria. Now, why do I say blunt and penetrating are different? They are very different.
Blunt trauma is extremely unlikely to cause hemorrhagic death within 1 hour -- very unlikely, unless a patient has a rupture of the aorta, a rupture of the heart; in these cases, there is no hope. He will be dead within a few minutes. The typical blunt trauma patient will bleed from the liver, the spleen, the pelvis, the long bones, and will die a few hours later.
The prognosis is very different. If you get patients with blunt trauma and hypertension lower than 90, excluding a trauma, the overall mortality from blood is 20 percent, is 33 percent for penetrating trauma.
And this is the temporal distribution of deaths, the time of deaths in blunt trauma and penetrating trauma. In penetrating trauma, as you can see, the vast majority of deaths will occur within the first 1 hour. And this is the distribution of deaths in blunt trauma, very different. We shouldn't mix them if you really want the best possible scenario.
Now, let's come to the blood pressure of 90 or lower. A model concept in the management of trauma patients is permissive hypotension in penetrating trauma. We now teach and apply -- and this is in the military as well -- but if a patient with penetrating trauma has a systolic blood pressure of 80 or 90, don't give him fluids until you control the bleeding surgically. This applies in an abundant environment.
So it's inappropriate to get the patient of blood pressure of 90 and load him with HBOC or saline or whatever. On the other hand, we know that if the blood pressure is very low, extremely low -- blood pressure is about 40, about 50, there is a risk of cardiac arrest. This is a group which might benefit from aggressive fluids.
So what I would suggest for future trials include penetrating trauma, excluding head with a blood pressure of 80 or lower. And with the control fluids, you might want to consider hypertonic saline, or maybe red cells, but fresh red cells younger than two weeks. And this concludes my presentation. Thank you very much Dr. Klein.
MR. KLEIN: Thank you very much. And we'll bring everybody up on the stage. You'll have an opportunity to send in your questions. Please write them down after each speaker, if you can, and we'll try to get to them.
The next speaker is Dr. Freilich, from the Navy.
MR. FREILICH: Good morning. Can everybody hear me in the back? So I'm not a trauma surgeon, and I'm an Infectious Disease doc, and as many of you know, in a hospital, the characteristic of ID docs is that they're somewhat compulsive, and annoyingly are willing to review all the pages in the record.
And I think one of the issues with HBOCS in general has been broad pressures. And I think that goes to phase 4 activity, trial designs, strategies, and even how to proceed forward. And I think that it can be broad pressures, and I think that's the most important point I want to make.
The Navy has been active since about 2002, with an approach for pre-hospital, where blood is not available, trauma resuscitation and we've been on clinical hold since 2005, and we remain on clinical hold despite a BPAC consensus recommendation that a phase 2 trial should proceed, about 16 months ago.
So we have had had quite a bit of experience thinking about how to potentially design a trial. And we may have made mistakes, and we may still be making mistakes, but at least we've thought about it, and I just wanted to transmit some of that information.
For the sake of disclosure, I should say that the Navy has material transfer agreements and CRADAs with Biopure, and there is a contract to purchase HBOC prototypes for research -- no transfer of funds ever to the Navy.
The final point is that we have no horse in the race. And in fact, I would propose now that any comments that I make right now with exceptions in general, I think, probably applied to most of the second generation HBOCs that are currently in the process of development, and there are certain exceptions to that.
What is the potential benefit? And I think this is an enormous problem in the way trials have been developed over the last 10 years or so, or longer. And this graph, in blue are controls, and red is HBOC 201, and again, I think that other HBOC could be superimposed in many ways in this graph.
On the left are studies with the mortality and controls was really low. And in fact, you can see many of them were 100 percent survival. On the right are high-mortality trials. And you can see, most of the control animals died. This is a summary of the data. What should be clear from the back of the room is that HBOCs don't, in preclinical studies, demonstrate a survival benefit in low mortality scenarios, and this makes sense.
And in clinical medicine potent drugs often are not necessary in low-severity design studies or in low-severity clinical settings. Nevertheless, the design of trials has relied on blood substitution in the hospital, or addition to standard care with the opportunity for benefit is extremely minimal. And if you look at studies or in other indications, for example, add heparin.
Heparin makes very little difference in myocardial infarction when you add it to the whole armamentarium of PTCA and TPA and nitroglycerin, and all the other things. On the other hand, when you have very severe models repeatedly, whether you have associated traumatic brain injury or not, you see significant benefit.
Now, how does this affect your design of studies? I think this is where most of the studies have been done. We have never done a study like this, nor has there ever been a study that's truly against crystalloid or in general a sanguineous controls. All of them have had, including even the coronary European style -- European study with DCLHb have always had some element of competition with blood, or as part of a competition with standard care, which included blood.
Now, this is a very busy slide, but I'm only going to reflect a few things. What I try to do is show that on the left these are studies that had low mortality in controls, and they increase. To get to the highest would be the RESUS trial that the Navy proposed, where we expect a mortality of about 62 percent. It is very difficult to hypothesize that you can extrapolate data where the only potential significant benefit is transfusion avoidance to a study with 62 percent mortality, mostly within 24 hours. And obviously you're expecting a survival benefit.
Secondly, how do you look about -- how do you look at odd HBOCs? You really can't extrapolate one HBOC to another, and you have to be very careful with doing that. For example, if you look at the old DCLHb data, the in-hospital U.S. trial or if you look at the out-of-hospital Kerner trial, which was done in Europe; 95 percent of patients who enrolled in this trial would get excluded by the study, and 85 percent would get excluded in even the European higher-mortality study.
What the Navy tried to do is to exclude that bimodal distribution by using revised trauma score -- and by no means do I suggest that that's the only way to do that. But I don't think that information is static. And I think people learn from mistakes and/or from experience, and there are many ways to try to get that intermediate population. We think we've done it with the RTS of one to four, but there are other ways there to do it.
Finally, again, one learns from experience and some prior mistakes, and one can optimize the trial. And I think that each specific optimization does not necessarily make an enormous difference in terms of the overall benefit ratio. But I think it's very reasonable to hypothesize, and I iterate the word "hypothesize," and therefore a clinical trial should be done to confirm the hypothesis that the totality of the changes are likely to shift way beyond equipoise.
I'm not going to go into all these because I am a little bit past my time. But firstly, I just want to reiterate what's in red. You should target a population with severe hemorrhagic shock and with severe -- with high likelihood of mortality, and you should target a population where blood transfusions are unavailable.
And if you look back at the animal studies, the animal studies have been criticized as potentially not predicting what happens in humans. But they do get vasoactive response, as you just don't see the cardiac side effects. And the reason you probably don't see the cardiac side effects is that they're young animals.
So pick a population that somewhat simulates the studies that you've done in preclinical studies. And I think that young trauma patients probably are similar to that.
I think I'm going to stop here because I have run over time, and thank you for listening.
(Applause)
MR. KLEIN: Thank you very much, Dan. The next speaker is from the Army, John Holcomb. John, you want to give us your thoughts.
MR. HOLCOMB: Okay. Well, I am -- as opposed to the other discussions, I'm not going to talk about HBOCs very much. This first -- the first reference is actually Dr. Demetriades', and he's already showed the slides talking about deaths. Deaths occur very quickly, largely from truncal hemorrhage, they peak at 1 to 6 hours.
Fred Moore, Jean's brother published a paper in Journal of Trauma this month that actually shows this beautifully in somewhat greater detail, and actually that the mortality from hemorrhagic shock occurs within 1 to 3 hours of admission.
The point there is that anything we are going to do needs to be done very early. It can't be done with individual patient consent or LAR constant. And Rick Dutton showed that in a paper in Journal of Trauma last month as well, along with John Hess's wife that basically LAR consent for hemorrhagic shock studies is a nonstarter, and will doom any study to failure.
Now, Usol (phonetic) and others have recently shown that we can predict massive transfusion within minutes of arrival, with easily available data that's in the emergency center with an ROC curve of 0.8. This is from Germany. There are other papers published from North America on trauma patients. So you have patients from both continents responding the same way physiologically. We can predict who's going to need massive transfusion in the first couple of minutes, and those patients are the ones who are going to die within 1 to 3 hours.
So this is getting at study design actually, so we -- both address the same thing. Rather than talking about HBOCs specifically, the study-designed questions are very important. And clinically, I think we get a lot of information about these kinds of patients in the last 4 to 5 years, previous to some of the designs that we've heard yesterday.
Now, Borgman (phonetic) showed -- this is combat data -- that you can increase plasma by -- by increasing plasma use to red cell use, you can decrease mortality from 65 to around 20 percent. Seven civilian papers will be published this year that show exactly the same thing. Increased plasma platelet to red cell ratios improve survival. Now, why am I going to talk about plasma and red and platelets, instead of hemoglobin? I think that we have been too focused on oxygen consumption and oxygen delivery as a resuscitation endpoint. These are data from 466 massively transfused patients representing almost 40,000 admissions at 16 trauma centers from the last two years ago in the United States.
And as you can see, these patients are critically injured with an ISS of 32. They only have a 40 percent overall mortality. They are a young at age 39, get younger everyday, largely male, blunt injured, they come in moderately hypotensive, tachycardic, acidotic, and with an INR of 1.6; they're all coagulopathic. These are initial data upon arrival, and I point you the hemoglobin of 11. We were all taught that patients coming with hemoglobin of 14 to 15 after losing blood, these were all within 30 minutes of admission. That's not true. Severely injured patients come in with hemoglobin of 11.
Now, that's plenty of red cells floating around to deliver oxygen. That's plenty of red cells, and yet, the focus of this meeting was on giving more oxygen-carrying capability to exactly this group of patients. They don't have an oxygen-carrying deficit, they have a bleeding problem, and they have a profusion problem, and if we fix that, they will do fine.
This is the Kaplan-Meier curves of 466 patients. You can see there's a 24-hour Kaplan-Meier and a 30-day Kaplan-Meier. These patients die very early, this goes right along with more data from the last month of Journal of Trauma, and by giving more platelets and plasma, you shift that curve from a 40 percent mortality up to almost a survival -- to a 90 percent survival.
You're giving same amount of red cells in each group. I think that the data from this is pretty instructive. I think the data coming out, it'll be able to predict massive transfusion, and physiology of what these patients have really going on, pre-hospital and in the ED is pretty instructive and informative for future trials in this area.
That's the end of my slide. I just want to make a couple of comments as well in the last minute. Many lessons have been learned from these studies; both this study and other studies. I think one of the major lessons that we've learned yesterday is that when you have 3,500 medics assigning our patients to a prospective randomized study that they're going to miss a sign about 20 percent of the patients. That is the real world, ladies and gentlemen. We don't have CROs and registered nurses assigning our patients in the emergency department. We have medics are doing a great job, doing as best as they can, and they will miss a sign. We need to track that and make sure that if there are medic units or systems who miss a sign at very high rate, we go educate them and if they don't respond to education, we kick them out of the study, that needs to happen. But it will happen.
Hence we got to figure out what is an acceptable rate of miss a sign. The other thing is that with 5024 and the discussion we've had yesterday about how the process works. The process actually makes us go right from preclinical studies to definitive phase 3 trials because mortality is the endpoint in the current 5024 paradigm of doing research in this area.
You don't get the benefit of phase 1 and phase 2 trials and learn from how best to treat these hemorrhagic shock patients, and what really is an inclusion and exclusion criteria. That I think is a problem. We need to be able to do smaller studies, the phase 1 and phase 2-types or sized studies, if you will, in this group of patients, so we can learn how to do the definitive trials in this group of population who stands to benefit. Thank you very much.
(Applause)
MR. KLEIN: Thank you, John. I hope we'll be asking questions about whether phase 1 and phase 2 trials in other settings would be applicable to trauma because I think that might be an important issue. Next speaker is Dr. Natanson from NIH.
MR. NATANSON: Good morning. I want to thank the organizers for allowing me to speak today. The charge that Harvey has given us, to see if we can find common properties to these hemoglobin-based blood substitutes as a class. They're all derived from red cells -- red blood cells, and then they have different biochemical alterations. But they all interfere with normal nitric oxide functioning.
And therefore, they have a common mechanism of potential toxicity. The question we asked is, as a class, do -- are they associated with an increase in myocardial infarctions and deaths.
We did a meta-analysis; there were three sources for our trials. One was a standard literature search for which we found 13 trials. One was an FDA meeting which had a summary, one set of trials. And we also went through press releases, and we included two trials which had quantitative data from press releases for a total of 16 randomized controlled trials in this meta-analysis.
There are five products listed there in our meta-analysis. And I'm showing you on the left, mortality, on the right; the risk of myocardial infarction. This side favors control that there was an increased risk with the hemoglobin-based blood substitute, this side says there was benefit. Again here's the same for myocardial infarction.
And you can see here that overall, there was a statistically significant 30 percent increase in deaths with these hemoglobin-based blood substitutes, and you can see there is almost a threefold increase in the risk of myocardial infarction with the hemoglobin blood substitutes.
And importantly, this is a test of heterogeneity. As you can see, there is no significant heterogeneity that is treatment effects were quite similar across these products.
This is an "I" square. An I squared of zero means the effects are very, very similar. An "I" squared of 100 per cent means they're very, very different. This says there is the minimum amount of heterogeneity across these studies -- zero.
We also did subgroup analysis in order to -- or sensitivity analysis to see if the effect is consistent across different patient populations. And as you can see here, in all the reported patients studied were -- they described myocardial infarctions, the effect is very consistent, and the mortality effect is very consistent, except in cardiac surgery.
The mortality difference is not statistically different compared to other forms of surgery, but it's interesting (phonetic) to speculate that you do have an increased risk of myocardial infarction during cardiac surgery. But the vascularization -- the revascularization maybe protective to prevent death.
We also looked in studies to see if it made a difference if you had a blood product or a non-blood product as control. And these are the number of patients and these are the number of trials. As you can see here that the mortality in the myocardial infarction data is quite similar, whether you had a blood product control or a non-blood product.
We also sequentially removed each one of these products from the analysis to see if one product alone was responsible for this effect. And this shows you how many patients are left, and how many trials are left after we move the hemocyst. And you can see that no matter which one of these trials we move, or each one of these companies' products we moved, the treatment effect in terms of mortality and myocardial infarction is still on the wrong side. And there is no one trial responsible for this effect.
We did other analyses. We looked at published versus unpublished, detected from your content, the P50, and none of these variables make any difference. Regardless of the product, the patient population study, the control, this was a very consistent and a very robust effect. We conclude, based on analysis of the available data from clinical trials, hemoglobin-based blood substitutes are associated with a significantly increased risk of death and myocardial infarction. Thank you.
MR. KLEIN: Thank you very much, Chuck. I'm sure we'll have a lot of -- a lot of comments about that. It's an important study. I think our next speaker is Dr. Norris, and I don't think -- Ed, I don't think we have slides. So he'll be speaking briefly.
MR. NORRIS: Again, I've no slides, so the lights can stay on, good morning everyone. I'm very glad to be here this morning, and I'm very honored to be able to participate in our panel discussion with such a distinguished group of individuals. My written disclosures did not make it to the printed materials, and therefore I wanted to make a brief oral disclosure.
I'm currently a consultant for Northfield Laboratories and participate as a member of the Data Safety Monitoring Board and the related subcommittees for the phase 3 trauma trial. Since 1997, I've participated as the principal investigator in a number of phase 2 and phase 3 clinical trials with Biopure, Alliance Pharmaceutical, Northfield Laboratories, and most recently, Sangart.
I've also been the principal investigator for both compassionate use and treatment use protocols with the current generation HBOCs. I have received funding from Biopure, Northfield, and Sangart for work related to the interference of HBOCs with common laboratory tests, and lastly I've participated in several scientific advisory board meetings with Sangart over the last several years.
My bio sketch wasn't included in the printed materials either, and I wanted to make just a few quick comments. As mentioned, I am an associate professor in the Department of Anesthesiology and Critical Care Medicine at the Johns Hopkins University School of Medicine and a staff anesthesiologist at the Johns Hopkins Hospital. I'm a member of the Division of Cardiovascular, Thoracic, and Transplant Anesthesia, end I direct the vascular and endovascular anesthesia programs.
I am also director of our Advanced Transfusion Practices Center and director of Perioperative Blood Conservation and Hemodilution Services. My day-to-day clinical activities involve the care of patients undergoing complex procedures that routinely require the transfusion of large amounts, and often massive amounts of donor blood and donor blood products.
And although I practiced just a few yards from one of the busiest transfusion services in the country, we were not able to be all things to all patients regarding the red cell requirements. One of my clinical interests over the last decade has been to develop ways to reduce patient exposure to donor blood and donor blood products. And as a result, we've attracted a large number of patients, often requesting complex and medical surgical without the use of donor blood and donor blood products.
Now, Jehovah Witness patients make up the largest percentage of this group. And I personally participated in the care of over 1000 of Witness patients. This clinical experience combined with HBOC clinical research experience involving nearly 100 patients, receiving nearly 200 units of clinical trial material, I think, prompted the very kind invitation to participate in this panel discussion.
Regarding the topic of our discussion, I personally believe that the current generation HBOCs can indeed serve a critical unmet need in a variety of clinical settings, the common theme of which involves the temporary or permanent unavailability of red blood cells.
Further, I believe that our current understanding of the risk-benefit considerations for these products indeed favors the clinical use in these very select clinical circumstances. And I'm going to stop there and I look forward to a good discussion. Thank you.
(Applause)
MR. KLEIN: Thank you very much, Ed. I think you have as much experience with different HBOCs as perhaps anyone else on the panel. So thank you both for the disclosures and for the information.
Our next speaker is Dr. Ed Sloan from the University of Illinois, and Dr. Sloan, as I said earlier, was the principal investigator for the trial that we heard a great deal about yesterday with the Baxter hemosis product, and he has kindly agreed to come and both speak and be on our panel.
MR. SLOAN: Thank you for the invitation to speak. It has been nice to see people with whom I worked for several years. As a matter of disclosure, the work with Baxter was done through a grant to UIC. I work now looking at this data at the request of the NMRC, through a grant from the Jackson foundation to UIC, and I have served on a data safety monitoring board for Biopure.
We are going to talk a little bit about the DCLHb trials, and share with you data that which you have not yet seen. I'm at the University of Illinois in Chicago. The goal of the development of HBOC is take a difficult clinical setting, and to improve clinical practice, and improve patient outcome. There were two studies, one an in-hospital emergency department study in the U.S. with DCLHb, and a paired pre-hospital study in Europe.
When you combine the information from those two studies, mortality was higher in those treated with DCLHb. Two observations. The first, in a perfect world, your desired mortality risk would be midrange, 40 to 60 percent; this would allow you to study optimally any new methods or therapeutics. In fact, our mortality, or our mortality risk was bimodal at the very low and very high extremes.
One other comment from those two studies; the use of an exception to informed consent was nearly universally accepted. The logistic side was manageable. It appeared appropriate and still does, and I think it remains a vital part of what we do in our emergency and trauma research.
Here are the list of the publications that were made regarding DCLHb, one to be added is the reuse study from the European experience, and the consent-related publications. We're now looking at this data second time at the request of the Naval Medical Research Center, and I'd like to just share with you five aspects of that.
Regarding blood pressure effects -- in summary, blood pressure did not differ with DCLHb use in the clinical trials. Those patients with markedly elevated blood pressures did not differ with the use of DCLHb. In fact, DCLHb with regression analysis only contributed 3 percent to the predictive -- prediction of blood pressures over time. In other words, there was no clinically-consistent pressor effect.
Regarding base deficit and lactate; in the two studies, base deficit did not differ with DCLHb use even though expired patients had a greater base deficit than those who survived. In the U.S. study, where we only had data for lactate in the one study, lactate did not differ basically on DCLHb use, even though expired patients had a greater lactate than that did -- those who survived.
There was no clinically consistent poor perfusion effect as measured in these studies with lactate or base deficit. We also looked at the shock index. The shock index is a simple measure looking at clinically easily obtained markers; heart rate and systolic blood pressure. And in essence, when your heart rate is greater than your systolic blood pressure, it suggested you have uncompensated shock.
Conversely, when your systolic blood pressure is greater than your heart rate, you appear to have compensated adequately, and this is the permissive hypertensive setting in which we now don't over-fluid-resuscitate patients. So this is an easy measure of shock.
And in summary, patients with a shock index greater than one are a clinically uncompensated population of shock patients who might benefit from infusion of an HBOC. And in fact, 120 minutes of shock index greater than one is associated with a two-and-a-half fold increased mortality risk; 40 versus 16 percent as compared to those with a shock index less than one.
Importantly, in these two studies, DCLHb use did not alter the ability of shock index to predict mortality, and the significance of this is in traumatic hemorrhagic shock studies, whether the use of an HBOC is planned, it doesn't appear as though these clinically important markers; systolic blood pressure and heart rate, are modified such that we can rely on our clinical acumen to determine whether patients still need to be resuscitated.
Regarding the study design, we looked at RTS entry criteria, and we found that patients with a low RTS 1 to 3.99 have a very low TRISS survival probability. This might be an optimal patient population for study, if you're looking at optimizing the risk-benefit profile. And we may need to exclude those with a GCS of three, because it is greatly influences mortality and the RTS.
Lastly, we looked at traumatic brain injury. Traumatic brain injury in the U.S. study of DCLHb had a significant influence on 28-day mortality, and in fact, those TBI patients with a GCS of three increased study mortality by 63 percent. As such, I would recommend that the GCS of "three" patients not be included, or be excluded from any future traumatic hemorrhagic shock trials which attempt to look at HBOCs.
So in conclusion, this work continues to be critical. What's important is that the theoretical pressor effects of DCLHb could not be correlated with the most commonly utilized clinical variables that we use to assess patients, such as blood pressure, base deficit, lactate.
And so in order to maximize our studies ongoing, one thing might be to exclude GCS equals three patients, and be very clear as to who our entry criteria is and what the mortality is. So I recommend that we continue to look at these theoretical issues such as pressor effect, and see how they're playing out clinically, so that we can make good decisions as we look at future studies of HBOCs. Thank you.
(Applause)
MR. KLEIN: Thank you very much, that was very helpful. And I think our final speaker is Dr. Vlahakes of Mass General Hospital. He has also had experience with these molecules.
MR. VLAHAKES: Thank you very much. I became initiated in this field when I joined the staff in 1986 because of the enormous pressure we were under from patients to avoid transfusions. This was in the heydays of HIV when the blood supply was in question, and we -- you can sit down with the patients and their family, and spend an hour discussing a complex heart operation, and all they really want to know was whether or not the patient was going to be transfused.
My interest in the field was in the context of these materials as potential blood substitutes, and I had high hopes for the field until the issue of auto-oxidation and rapid clearance came to light, and it's an area that we had worked on in association with Biopure that had provided us with some of the materials that we were working with.
Of note in this study is a potentially interesting hypothesis that awaits testing by someone, and that is that the most rapid clearance and the most rapid rate of auto-oxidation occurs in the early phase, when there are more low-molecular-weight entities present in the circulation. So one issue in the hypothesis for someone to test down the line is whether or not the auto-oxidation phenomenon is reduced by raising the average molecular weight profile of the materials.
We did conduct an interesting phase 2 trial in cardiac surgery, keeping in mind that we had this limited window and time of efficacy. In the first 12 to 24 hours following a heart operation, there is a need to expand the blood volume as patient is warm and dilated, and this results in a nadir in hematocrit, around which transfusion decisions occur.
So the concept was to temporarily support oxygen transport, until the patient was 2 or 3 days after surgery, at which time, they begin to hemoconcentrate by fluid mobilization.
This was a phase 2 study that involved 50 patients in each group. It was a true double-blind study. The blind was tough to organize and maintain, but was successfully done. It involved wrapping the chest drains and the pleurovac with colored cellophane, so the blind would not be broken. It involved removing certain laboratory evaluation and clinical record that might give away the patient's treatment assignment.
And it was powered to determine efficacy with three infusions; two units followed by one unit, followed by another unit, and we used regular clinical transfusion guidelines that are in place at the institutions involved. Now, we also elected to do this in the ICU after the patients had been through their cardiac surgery.
And I think one of the things that you might want to get into the discussion is this is a brand new class of materials for hospitals and hospital personnel to be involved with. And how you introduce something that's brand new, this is not another antihypertensive, it's not a new antifibrinolytic or novel anticoagulant, it's a brand new class of materials that people have never seen before. And how you set up clinical trials has to keep that in mind.
One of the issues we found was that up to four units of material resulted in saving only half a unit of blood, and with some other discussions around potential costs, et cetera. As the safety profile of the blood supply changed in the mid-'90s with donor self-deferral and testing, this took the wind out of this indication to a considerable extent.
Now, the study was not powered to look at safety, but there were a couple of points. There were no myocardial infarctions in the study, and one of the reasons maybe related to the fact that coronary disease was treated surgically before patients were randomized. Parenthetically, the vascular surgery trial which looked at major abdominal aortic reconstruction also did not see any myocardial infarctions, and those patients as a group tend to be very thoroughly screened for the presence of cardiovascular disease before they go through major surgery.
Now, although you've heard a lot about the nitric oxide binding and vasoconstriction, virtually all the HBOC preparations that have been studied do change systemic and potentially pulmonary vascular resistance. But despite these concerns, nitric oxide binding and increased vascular resistance has never been shown to override metabolic autoregulation, and there are plenty in the studies -- preclinical studies and the literature to support this.
This could be a benefit in some clinical settings. In particular trauma and cardiac surgery, we are often dealing with low systemic vascular resistance from -- for a number of reasons in the postoperative setting. And one of the points I would make about using blood pressure as an endpoint -- and you might get it into this in some of the discussions -- vasoactive HBOCs may potentially result in under-resuscitation or under-volume repletion of patients.
And one of the reasons why we selected the ICU setting was the fact that the patients were all monitored, (inaudible) catheters and continuous monitoring of blood pressure. And the final issue is the vascular biologic problem. Besides vasoconstriction, do HBOCs do anything to vulnerable plaque? And one of the issues we're going to have to deal with is this potential risk posed by unrecognized coronary artery disease. Thank you.
(Applause)
MR. KLEIN: That was our last set of slides, but I think Dr. Steve Cohn wanted to make a couple of comments before we get the panel up on to the stage.
MR. COHN: Thank you. I'm honored to be on the panel. I have three comments, speaking as a clinician and surgeon, first in regard to the magnitude of the problem, and then a comment about the difficulty with clinical trials in the area of specifically trauma, and finally a lit bit about the risk-benefit considerations.
About recently, I had a patient that came in with a single gunshot wound right below her xiphoid. As she came down the elevator, she was talking to the paramedics and she arrested. Rather than going into the resuscitation room, we took immediately into the operating room, and there we did a thoracatomy and a laparotomy, in a very short period of time, while she was receiving the six units of blood that we kept down in that part of the trauma center, we fixed a hole in her vena cava, and she had -- the porta hepatis was divided.
So we removed her liver, and she stopped bleeding. She was stable, but because we had no more blood available, her heart gradually slowed down. We were asking for more blood, is there more blood -- there was no more blood available. We used up to six units we have here. It will be another 10 minutes before we can get the blood down, and this 20-year-old girl died.
So this problem is the same as it was in 1999; the last time I was here at one of these meetings. We have patients who -- this is not some theoretical concern -- we have patients that are dying because they don't have blood. And this is at one of the busiest level 1 trauma centers in the United States that this occurred. This is not like some place in North Dakota that doesn't have a blood bank.
It turns out that less than 1 percent of trauma patients receiving greater than 75 percent of all the blood transfusions. So it's a fairly small population that gets most of the blood. And there has been a major cultural change since 1999, in that we as trauma surgeons and intensivists don't give blood very much anymore. We looked at our blood transfusion administration history, and we found that we had decreased the number of pack cells given to our trauma patients by 25 percent. Recognizing that trauma uses up about 25 percent of all the blood transfusions in most major tertiary care hospitals, with another quarter being used by transplant, and then the other half is sort of like everybody else.
The other comment I would make is that 40 percent of Americans are greater than 1 hour from any trauma center. So if you're driving on a vacation, in all likelihood, you may well be if you are not in urban center, far away from a trauma center, possibly near hospitals that have no blood available. So if you are unfortunate enough to have a bad injury out in a rural area, you may not have access to a blood bank or the ability to get a massive transfusion. So that's item number one.
The second thing is on clinical trials feasibility. We recently completed a trial at seven of the busiest trauma centers in the United States over 18 months. These were all in severe hemorrhagic shock patients. To get entered into the trial, you had to receive a unit of blood within 6 hours. Okay, so in shock, receiving blood. In those seven centers which had thousands and thousands, and thousands of patients during those 18 months, we only had 382 patients who met entry criteria into the study, and of those, about 90 got the massive transfusion -- that was Fred Moore's data -- but 90-93 got massively transfused to find these 10 units in 24 hours, and only 50 died.
So we're doing mortality studies. The fact is that from a care, the United States, pretty darn good. Not that many people are dying. Even in combat now, with Dr. Holcomb's help, the military has reduced mortality way down. So we're doing mortality studies, we're talking about large trials because not that many people are dying.
The third point is, you know, recently I had a family member who underwent chemotherapy for non-Hodgkin's lymphoma. The chemotherapy led him to have a white count of like zero; he went into septic shock, went to the hospital and almost died. Now, we didn't immediately go out and say, well, gee, we need to stop giving chemotherapeutic agents because we are treating his cancer, he is going to die from his cancer. These patients are going to die from the lack of blood, and we need to start thinking about it in a little different risk-benefit ratio, because this young woman, this 19-year-old -- no question. No question whatsoever. If we had 10 units of a hemoglobin-based oxygen carrier, she would be alive today.
In fact, we had an airplane that was landing in Arkansas picking up a liver right then. Just serendipitously, the liver transplant team was coming in; we were going to put a new liver in this woman. She'd be alive today, 19-years-old, a member of our workforce, maybe she would be working for the FDA, you know -- if in fact we had an HBOC available.
So this is a very clinically relevant thing. It's not going to an easy thing, I realize, to approve, but I really think you need to start thinking about cost-benefit ratio similar to chemotherapeutic agents, rather than similar to a crystalloid or colloid. Thank you.
MR. KLEIN: Thank you very much. Would the speakers please come up to the podium? I thought you were going to say that it wasn't someone without a liver, but without a heart that was going to be working for the FDA.
(Laughter)
MR. KLEIN: And if there are -- if there are cards, someone is going to collect them and bring up there, and while people are getting settled, let me ask the first question. Thank you.
Dr. Natanson, I will start with you since I know you so well. Your recently published meta-analysis showed increased mortality in most every category of trial, with most every HBOC that was available, and showed an increase in cardiac problems with virtually every setting and with virtually every drug. Now, we've just heard about situations where there are very high mortality and trauma in young people.
Is this a setting where one could think of using an HBOC despite the data that you've put together, because of the potential benefit outweighing the risk?
MR. NATANSON: Remember, there has been no meaningfully beneficial effect reported in any clinical trial of HBOCs. Yet, there has been a statistically significant overall increase in mortality, and almost threefold increase in myocardial infarction. So if you're going to study it in humans at this point, I think the only population that a justification could be made is with a 100 percent mortality. And you have to be assured of that.
MR. KLEIN: Would anyone comment on the panel, we have a number of --
MR. DEMETRIADES: If we are ever going to show any difference, any efficacy, you need to select your groups very carefully. It's unlikely to show any benefit if you have a -- if you cast your net too broad. You need to get patients -- young patients with no associated diseases, with -- trauma, and a blood pressure, very low, and then overall mortality of 30 to 40 percent. You're choosing different groups; I think it's unlikely to show any difference.
MR. KLEIN: Any other comments, Mitch?
MR. FINK: So just had a couple of -- two introductory comments. First of all, I chose not to say anything during the formal presentations, because I really had very little to contribute. And secondly, although I've recently joined the dark side, and work in an industry setting, my current company has nothing to do with transfusion or blood products, or resuscitation, and so I'm unconflicted.
I've known Chuck Natanson for almost my entire adult life, and I have enormous respect for him, and I usually disagree with him. But in this case, I must say that I think he makes perfect sense. I think his analysis is spot on, and this is -- he's exactly right. In order to show a difference on the positive side for HBOCs, given the current technology -- I'm not talking about the next generation HBOCs, which might be different and might solve the nitric oxide scavenging problem -- in order to show a benefit, you really have to study patients like the one Steve Cohn was talking about, where the probability of survival in the absence of the resuscitation fluid is exactly zero percent. There, there is a possibility for showing benefit. The problem of course is that finding those patients in meaningful numbers and being able to conduct a study in some kind of reasonable time is a extraordinarily difficult challenge.
Now, the other comment I would make is the following. Hemoglobin does in fact scavenge nitric oxide. There is a lot of controversy here, but there is no controversy about the fact that iron 2 in a heme moiety binds nitric oxide with high affinity. And the class effect is related to the binding of nitric oxide by hemoglobin. That's something that we can't get away from. I'd also point out that people have done a number of trials by modulating the nitric oxide pathway. And when you modulate the nitric oxide-guanylyl cyclase pathway by activating it, you can turn things into useful drugs ranging from nitroglycerin to inhaled nitric oxide, to Viagra.
But when you turn off the nitric oxide-guanylyl cyclase pathway, you run into problems, and it doesn't matter whether it's septic shock, or resuscitation; that seems to be a problem. I think there is a lesson there, and before we would move on to study broad groups of patients, we need to solve the problem of nitric oxide scavenging related to hemoglobin-based oxygen carriers.
MR. KLEIN: Mitch, if I could just follow up on that. Are you suggesting that if you're still in Pittsburgh and I came to you with any of the current generation or the previous generation of HBOCs, for any clinical setting, you'd be reluctant to use any of them knowing what you know now?
MR. FINK: Absolutely. If you came to me in Pittsburgh, it's not in the middle of the plains in North Dakota as Steve pointed out, it's at a urban medical center where there is access to pack red blood cells, and if you needed oxygen carrying capacity, which as Dr. Holcomb pointed out is usually not the case. But if you did in fact need additional oxygen carrying capacity, I would use pack red blood cells.
MR. KLEIN: This is for Dr. Vlahakes. Please expound on your statement that vasoconstrictors don't override metabolic autoregulation. And as a second part to that, do you believe that vasoconstriction is not a potentially adverse property of the current HBOCs?
MR. VLAHAKES: The first part, if you look at the studies that -- and again, we're talking about experimental studies -- shock preparations, et cetera, you do not get a deleterious effect on local and organ blood flow, including models of massive blood replacement that started out with -- that started out with preparations in shock.
Secondly, if you look at studies done on the coronary circulation, which is my personal interest, not only did the materials not override metabolic autoregulation, but they had oxygen carrying capacity, while decreasing viscosity. So if you hemodilute with an HBOC -- and this was published in Artificial Cells, Biomaterials, George Hodacasceu (phonetic) is the first author -- you can actually increase maximum potential oxygen delivery in the coronary circulation. We've never seen an override, and this includes materials that contain substantial amounts of tetramer.
Your second question -- the second part of that?
MR. KLEIN: The second part was whether the vasoconstrictive effects of HBOCS are something that you're concerned about in your clinical work?
MR. VLAHAKES: Well, there is two related answers to that. In the cardiac surgery trial, we have complete control over the hemodynamics. We are measuring filling pressures; we are in an intensive care setting where blood pressure can be managed if it became an issue. But many of the patients have the problem of low SVR.
Recovering from a narcotic-based anesthetic, they may have been on vasodilators like ace inhibitors before surgery; there's a relative degree of surgically-induced anemia and its potential consequences on SVR. So in the cardiac surgery trial, any vasoactive effect was more likely to be a benefit rather than a detriment, and we were able to manage it again in the ICU setting.
We picked the ICU setting on purpose in order to have that degree of control and the ability to gather the data. Now, to carry that further, there was a study published -- an animal study that looked at resuscitation, with, I think, the diaspirin cross-linked, the Baxter material. And if you use blood pressure alone as a volume replacement endpoint, this particular study had instrumented the animals that were used, and you wind up with very low filling pressures. You wind up with the wedge pressures down in the low signal digits, if BP alone is used.
So one of the issues with the vasoactivity in clinical setting, where you might not have a lot of monitoring, particularly of preload, you can wind up under-resuscitating your patient, or in a laboratory setting, an animal.
So it is an issue, but it can be overcome with monitoring and patient management, and it's part of learning how to use a new class of -- as I pointed out, this is a new class of materials, and part of learning how to use a new class of materials is how to manage the issues associated with it.
For example, when aminoglycoside antibiotics were introduced to clinical practice, renal failure was potentially an issue with use of aminoglycosides, and what came into the practice to manage it well, the ability to measure peak and trough blood levels, which allowed you to control the risk of nephrotoxicity. Again, this is a new class of material and the vasoactivity, if it's going to persist as an issue with the class; it's something we're going to need to manage.
For those who haven't seen it, I would call your attention to a recent publication in circulation that came out of Warren's Air Force Laboratory, having to do with pretreatment with nitric oxide. It's fascinating, and it's an issue that's going to need some more follow-up in the laboratory. And potentially, if we wind up in further clinical trials with humans and the vasoactivity remains an issue, it's something that might need to be considered.
MR. KLEIN: Let me follow up on that question and ask you then, do you feel that any of the current generation of HBOCs would be usable in a trial of cardiac surgery if you think that that may have a benefit?
MR. VLAHAKES: Well, the only setting -- the issue of course is the blood supply has changed and the safety of the blood supply has changed, and if you look at risk-benefit analysis, if you're able to use blood, if this is not a patient where there is an absolute religious issue -- religious issue for blood transfusion, it's hard to go up against pack red blood cells in patients that are having elective surgery; it's very hard to do.
MR. KLEIN: Dr. Cohn?
MR. COHN: Well, I just wanted to comment, I just had a relative that had an aortic valve put in, didn't require a pint of blood. My impression and that of many others is the use of blood in the hospital is dramatically dropping. We don't use blood hardly ever for general surgery, you know, aortic surgery it's -- basically most of it's gone, and has been replaced by endovascular, where they don't use blood.
The radical prostatectomy is used to be one of our high blood loss areas that's been replaced by robotics and a bunch of others. So there has been a progressive decrease in the use of blood. For sure, the redo, redo, spine and the redo, redo this and that still requires some blood, but overall blood use has really been reduced -- been limited, and I think part of it is because as intensivists, we don't transfuse people in the ICU like we used to; we let people be anemic. And I think that in cardiac surgery, I wonder, Gus, what percentage of your patients get transfused now?
MR. VLAHAKES: Well, it depends on your patient's substrate. So if you're dealing with people of advanced age, and people who have been -- who have had the surgery on the heels of a hospital stay, where they have been catheterized, they will come to surgery with a degree of iatrogenic anemia and the so-called "anemia of chronic investigation," as we call it. And those people will get transfused.
The elective -- the elective aortic valve replacement, such as you've mentioned, particularly with the techniques of autologous priming of cardiopulmonary bypass, now routinely use measures of blood conservation and scavenging all the red cells out of the profusion circuit, you can get by an elective surgery without transfusing people. But that's at least in our practice, that's less than half the patient population.
MR. KLEIN: This one is for Dr. Freilich, and this is would there be a different perception of HBOCs, if the first clinical trial had been the one proposed by the Navy -- and I'm going to ask Dr. Sloan after you comment on that Dan, what he thinks after having seen two trials.
MR. FREILICH: The way I'd like to answer that is first, I'd like to address some of the comments that Dr. Natanson made. And I feel as though I know Dr. Natanson for decades also, since the Friday release of the do-not-distribute JAMA article.
And I just want to say, first of all, I commend the work that was done, and I think it's very important work. And I think the comment that it's an overall class effect, demonstrating potential -- or actually demonstrating statistically significant increased mortality and MIs with HBOCs in general -- and I think the key word is in general -- is really important. But I think it should go no further than the general comment that myelosuppression is a classic manifestation of most chemotherapeutic trials. Now, having made that comment, one could stop developing chemotherapeutic drugs, or one could figure out how to maximize the benefit and to work with the myelosuppression and still try to improve outcome of your patients.
The second comment I'd like to make is that once again, I think we have to be very careful about broad brush strokes. And I think one of them is comparing the blood comparisons and the non-blood comparisons, because in fact, that article makes such a comparison, but there are no non-blood comparisons, there are no trails to date that have been done as such.
I just wanted to make a comment to Dr. Vlahakes about the potential for hyperperfusion due to hyperresuscitation. And I think that's definitely a concern. I must admit, I think in our institution we have now evaluated HBOCs in actually 200, maybe 300 pigs. And for what that's worth, what we have noticed is that if one does pressure-controlled circulation -- pressure controlled resuscitation, as was so often published in the 1990s and '80s before, that is high risk, and you see manifestations potentially including lactic acidosis.
And these have been published and have been noted by FDA numerous times. If you include a simple additional criterion such as heart rate -- and that's not surprising, in the stroke index -- I mean, the shock index that was described by Dr. Sloan, that the addition of heart rate to mean arterial pressure narrows it down to a patient population that's really sick, and it allows you to continue to resuscitate despite the vasoactive effects.
So to answer your question, I think, there would be an enormous difference if one went and first looked at high mortality patients who have a potential for benefit. The potential -- last comment I want to make is that it is -- I find it ironic that in this science, one requires a zero adverse-effect potential.
When the regulations -- and everybody expects that it should be a reasonable risk, and to say that one should study only something where there is 100 percent mortality -- in other words, there is no risk -- I think, flies in contrast with what has been done with all other potent drugs. And I'm in complete agreement with all the comments that studies in 10 percent mortality, 20 percent are undesirable with the current generation of HBOCs, although with risk mitigation studies, such as the addition of nitroglycerin or inhaled nitric oxide or other proteins to get rid of vasoactivity; maybe that would be worthwhile.
But I think that to say that higher mortality studies should not be done unless they're 100 percent, does not seem to fly with current practice.
MR. KLEIN: John.
MR. HOLCOMB: I'd like to echo Dan's comments. It is interesting --
MR. KLEIN: He may be armed, so be very careful.
MR. HOLCOMB: Yeah, that's right. Well I'm going to speak to that. So the two guys in uniform here that are in dogmatic organizations are actually pleading for moderation from our civilian colleagues.
(Laughter)
MR. HOLCOMB: I find that an interesting phase to be in because, Chip, as a trauma critical care surgeon in uniform, it's not a normal place for me to position the whole -- 100 percent, do you really mean that?
MR. NORRIS: I absolutely mean that.
MR. HOLCOMB: That's really unfortunate. I would agree with Dan. Nothing is 100 percent. Standing in the emergency department, trying to figure out what cavity to operate in, what fluid to give, how much, when to start, when to stop; Sir, that is not a 100 percent place to live, that's not reality. Your comments remind me of the statistician from yesterday. They don't live in reality. And so let's --
(Applause)
MR. HOLCOMB: Now, the flip side is, your article is fascinating, and I don't disagree with many other things you said. It causes us to pause, and have questions and to do further study. So my plea is actually, to do a series of iterative emergency research studies in this area. That's what we need, so we can have more data within which we make good decisions.
When you read the "shock" chapter in ATLS, I know all of you have taken ATLS because you're all are trauma experts -- when you read the ATLS chapter and go to the references, the guide for massive transfusion used in 2008 was a paper written in 1985 that has no control group, and has 11 patient centers. That's when we do massive transfusion today, in 2008. It was in a really poor paper from 1985.
The second paper is actually much better, it's from 1976, and recommended whole blood. That's the state-of-the-art in massive transfusion in the United States, and around the world because ATLS guides early trauma care around the world.
And ladies and gentlemen, we need to do iterative studies. Nothing is 100 percent to get better than that. Thank you.
(Applause)
MR. KLEIN: I don't want to let Ed Sloan off the hook. Ed, you were the PI for the Baxter study, and I know that has been analyzed and re-analyzed, and re-re-analyzed. And we heard Tim Estep tell us that there may be lots of reasons aside from toxicity of the drug why the trial was stopped for excess mortality. We know about the trial that was stopped in Europe, even though there wasn't excess mortality.
You've looked at that so long, would you today be able to design a trial using one of the generation of current HBOCs, whether it was the now discontinued hemocyst or some other -- in a similar trial, knowing what you know?
MR. SLOAN: Yes, in reanalyzing this for 10 years, there are two things to consider. One, you need to have control over knowing what patients are being entered to make sure that they are not call violations that sabotage the ability to study the effect of any therapeutic. The second would -- I would avoid inclusion of any patients with a GCS of three.
So with regard to the comments that have already been made, I would suggest the following. You cannot study a patient population in whom the mortality is likely to be 100 percent. You're pointing us in the direction of studying the most critically ill patients that we can study.
I would therefore look at patients with an extremely low RTS, who are physiologically ill, who likely have a great deal of injury as measured by the injury severity score. I would exclude the use of the GCS equals three patients, and then you might approach mortalities of 70, 80, 90 percent, which will allow you to study a very sick population of patients, and still understand whether or not there maybe benefit -- therapeutics.
Regarding Dr. Natanson's data, I'd like to just make two comments if I could. Much as we when doing any study, if the study ends up not putting as where we need to be, we try to look for subsets, in whom there might be benefit in order to -- hypothesis generate for the next study. I would also take data and say, let's look at the patient populations for whom these class of drugs appear to impart the greatest harm.
In other words, if much of the mortality imbalance is related to a stroke study, and you don't include it -- include stroke patients in your future studies, you may have overcome some of the problem or some other hurdle that we now face, based on the aggregate meta-analysis.
The second comment I would make is we need to be very careful in looking at myocardial infarction -- because if many of the patients who are claimed to have myocardial infarction, it was on the basis of elevated cardiac enzymes. But ultimately, there was no left ventricular dysfunction and/or long-term mortality related to it.
I think most of us, if we believe that the therapeutic would improve outcomes in other ways, would settle for some elevations -- which may occur incidentally, just with the use of pressors or other agents, I state parenthetically. So there are some -- I think that the work is important. I just think now what forces us to look closely at -- to find out how we can identify a patient population who is least likely to be harmed, given this aggregate meta-analysis look, and to consider things such as enzyme elevations, which may not be clinically relevant, if you have a gunshot wound and you no longer have a liver, and you're just in need of blood or some oxygen-carrying solution, or any type of therapeutic to get you over the hurdle.
MR. KLEIN: Thank you. I think I'm going to leave the definition of MI to the next panel, which is going to specifically look at organ toxicities, but that's an important point. I think Dr. Fink wanted to make a comment, and then Dr. Cohn. Mitch?
MR. FINK: So, just a couple of three quick responses. First of all, comparison has been made several times this morning, and I think even yesterday, to cytotoxic chemotherapy for cancer. As far as I'm aware, currently -- I'm not an oncologist, but as far as I'm aware, currently there is no alternative to cytotoxic chemotherapy for cancer.
But there is an alternative to HBOCs for resuscitation, for the vast majority of patients who need additional oxygen-carrying capacity, and that's pack red blood cells. Although pack red blood cells carry their own risks, trolley (phonetic) being the biggest as far as I am aware, they do have a remarkable safety record.
So if you're going to study an HBOC in a high-risk population, it has to be in a population where the alternative, that is pack red blood cells is unavailable, I think, in order to conduct a study ethically. That is a reasonable study to do. It's just -- from a logistical standpoint, extraordinarily difficult one to do.
It's just an extraordinarily difficult study to do. The second point is I think there was a comment made this morning that because the blood-lactate concentrations in some of these subjects who received HBOCs were not significantly different than the control group, that there is no evidence of tissue ischemia. The problem with that assessment is that blood lactate concentration in trauma victims has nothing to do with blood flow to the tissues. It has to do with the circulating catecholamine levels in the patients. If you beta-block the patient, the blood lactate concentration drops.
It's a biochemical mechanism at the level of the skeletal muscle; it is not a reflection of local tissue perfusion. So it's not a useful measure of whether you are causing vasoconstriction in key vascular deaths.
MR. KLEIN: Dr. Cohn, and then Dr. Natanson.
MR. COHN: Okay. We are conducting a resuscitation trial and taking patients in profound shock including patients with severe brain injuries with Glasgow Coma Scale of 3, the highest we can get our mortality is about 40 percent. That's the people that come in that are herniated. And so, 100 percent population, probably not viable, unless they're actually in complete arrest, and now, you are talking about reanimation, it's completely different kind of bargain, that's number one. Okay, the Lazarus effect.
The second thing is in regards to Dr. Finks' comment. One of the problems with doing clinical trials is that the trauma patients were in urban centers, and as you've heard from the PolyHeme trial, they attempted to compare a blood substitute or an oxygen carrier with -- in a setting where there was not blood available, in the pre-hospital setting. But the pre-hospital time in both groups is only 26 minutes. And it's hard to know how much you could get in 26 minutes, and also what kind of benefit there might be, which leads you to say, well, what about 3-hour transports.
Earlier in my time, and in my current position, I was on call in -- I got a MedCom Call that the helicopter was heading out to pick up someone 2 hours away -- 2-1/2 hours away in a place called Uvalde, who had been shot in the groin who had been shot in the groin and was hypotensive. And the hospital crew brought some blood with them to the small hospital, and en route back, he got four units of blood, and when he arrived he had no blood pressure and a barely palpable carotid pulse. He survived because they had brought their oxygen carrier out with them.
Doing the trial in that population, long transports, I think would be extremely logistically difficult to do. And one of the issues that Dr. Holcomb and I were talking about yesterday is that the crews typically break -- they go -- they're becoming noncompliant. They know that blood or a blood substitute is better than nothing in this person who is in shock and dying. They're going to go head and break the code and give it if it's onboard.
They're just not going to comply with this. No one's going to let a patient die. The crew thinks that it's going to resuscitate him; they're going to give it. So it's very difficult to do this kind of trial, even though I agree that might be a good opportunity.
MR. KLEIN: Dr. Natanson?
MR. NATANSON: I want to state my case a little bit more clearly. I am fully supportive of HBOCs. I think this is a great idea in the area of research that needs to be fully, fully supported and -- move forward. It's a product that we desperately need. It's just at this point, if you compare the data that I provide and the data that Dr. Silverman provides, myocardial infarctions mortality are not the limit of toxicity.
The toxicity involves renal failure, stroke, pulmonary injury, liver function abnormalities, pancreatitis. If you look at these data sets, these are diffusely toxic. We need to return to the animal models. We need to get a new formulation, and in order to move this field forward -- which we need to do -- we need to come to that understanding. And that is only way I believe, we are going to advance the field.
MR. KLEIN: Let me just follow up on that because I had a number of questions for you, some fairly inflammatory. But let me just ask this one, which is less so. Meta-analysis usually looks at outcomes from studies using identical drugs. How can you lump together so many different studies using different HBOC products?
MR. NATANSON: Are you asking me?
MR. KLEIN: Yes, Chuck, could you address that one?
MR. NATANSON: Say it again, I'm sorry. Say it again.
MR. KLEIN: Usually, when you're doing a meta-analysis, you're looking at a single drug. How can you lump together so many different studies using different HBOC products?
MR. NATANSON: There is no (inaudible) what you do in terms of meta-analysis. Meta-analysis begins with a question -- a scientific question. The scientific question we asked was is, these are all hemoglobin-based products, and they are all blocked -- or inhibit normal function of nitric oxide. But once you do a meta-analysis, you then are required to not compare apples and oranges, you can only compare like effects. And so then, what you do is you do a test of heterogeneity. And the test of heterogeneity is the Breslow-day test we did, and we found that the treatment effect was very consistent across all of these clinical trials, regardless of the clinic indication that was used, regardless of the manufacturer, regardless of whether it was a published study or an unpublished study, and regardless of the chemical alteration.
MR. KLEIN: Dr. Demetriades?
MR. DEMETRIADES: In this panel, we've heard some real, hard, scientific facts, which unfortunately, we do not like. And then on the other hand, we've heard some one-liners and clever things, which we like. At the end of the day, there is a message for the industry. There is a major need for these products; we are still not there. You need to go about and improve these problems.
And I want to urge the FDA, at least, for compassionate use, to look into this again an allow us to go ahead with that. Thank you.
MR. KLEIN: Thank you. Dr Vlahakes?
MR. VLAHAKES: A lot of the questions that have been posed are only going to be answered by through clinical research. And you're not going to be able to -- there is only so much you can do with animal models, et cetera. And one of the decisions that's going to have to be made by the agency is whether or not it's going to be back to the laboratory and to the dreaded R. word "reformulate," in order to get us some clinical trials.
Secondly, I would emphasize the importance of piloting clinical studies in phase 2. And the agency has occasionally even suggested that -- to vendors that they should pilot their planned phase 3 clinical trails in phase 2. And on one occasion, that advice was not heeded to the detriment of the ultimate phase 3 trials.
So there is a lot -- there are a lot of bugs to be worked out, when you're using this in the clinical setting. And I'm not speaking now, so much of the kind of the fast-pace, fast-breaking trauma setting, but the setting in other surgical areas with inpatients.
The second thing is hospital care has changed a lot, and if you have a brand-new entity being put into clinical trial at an institution that has never used it before, you really have to assess your clinical sites, and to find out about issues such as clinical areas that are covered versus not covered, other hospital list, how consistent is the postoperative care and the ability to get very good observations made, and potential problems, either evaluated properly and aborted.
The change in -- for example, how staff hours and the increasing number of services that may not be completely covered or cross covered in the off-hours can have a potential adverse impact on the conduct of a clinical trial. And some of that, you're going to find out through a well-analyzed phase 2 trial, before you get into phase 3.
MR. KLEIN: Thank you. We've reached the end of the hour. And I have a whole packet of questions. So I would just ask those who wrote them, attack our panelists in the dry coffee hour. I want to thank our panelists for taking the time to come here, for keeping to their time and for their opinions. Thank you very much.
(Recess)
ORGAN SPECIFIC ASPECTS OF SAFETY
MR. WEISKOPF: Please everybody take your seats so we can begin.
In the past day-and-a-half or day-and-a-quarter, we have heard much about toxicities and mechanisms and the planning group has put together and organized a group of experts regarding subject of organ toxicity and they will be examining the HBOCs in that light, in light of specific organ toxicity, trying to draw on various sources of information.
The names are as you see them before you and they are all professors at their home institutions, of course, with the exception of Mark Gladwin who is here at the NIH and that’s not to say, he isn’t as accomplished as the others, it is just it doesn’t offer that level of title.
In addition to professorships that you heard Mr. Mitch Fink point out, he is also the CEO of a bio-tech company and I also consult through a bio -- a pharmaceutical -- a company as well.
And these are the topics that these people will be making some presentations, followed by a panel discussion. And here, I’m not going to read all this, this is just too much. I’ll summarize it though. These are the conflicts of interests that go back much further than the government generally requires. Many of these are Paleolithic information, and the only thing that really is truly current is Mark Gladwin’s disclosure that he has both a patent and a patent application regarding nitrites.
The format of this session is very similar to the one that we just finished, and that is, we will have very brief presentations by the panelists of five minutes each, followed by a question and again, questions from the audience are in the same written format.
But before getting to that, I’d like to make a few comments about the limitations of our discussion here. And I want to give you a little bit of my perspective before I even say -- talk about the limitations. That following a nearly 30-year academic career, which included not only consulting for industry, doing my own trials, doing trial designs, doing phase I trial in HBOCs, consulting for the FDA at times.
I then went to industry, a different industry unrelated to HBOCs, but worked with executive management in a moderate-sized pharmaceutical company for two years, so -- and I understand industries’ concerns very well, I think.
So I’ve come at this from a variety of perspectives and we have all heard those perspectives here in the past day-and-a-half. With that in mind though, I feel it necessary to point out the limitations that not only this panel will be discussing, but the limitations as we have heard other people discuss and perhaps even as we read the literature that the -- we are dealing with a limited amount of clinical information in the public domain.
The FDA of course has a database, which is much larger than the information we have been discussing and that is because much of that information is proprietary. Not all completed trial data even are available to the FDA, as we all know, some trials have been finished and data never submitted to the regulatory authority.
This raises issues not only of efficacy and safety that we have been talking about. But I think it also raises issues of ethics that I would hope that in the next panel will be addressed as well. In addition to that, not all the public information we have been discussing or will discuss is peer-reviewed. Some of it, as you have heard, come from corporate announcements, some perhaps from abstracts that are not necessarily peer-reviewed.
In addition to that even the data -- all the data, whether it be public domain or not, peer-reviewed or not, much of it depends upon site-reported information as opposed to independently reviewed AEs and SAAs. Both of these types of data have their own problems, and make it difficult for us to have a full clear discussion.
And for those in the audience and elsewhere who believe that their data are not correctly interpreted by some, the only answer I can propose to them is that if you believe that, the answer is to be more transparent with a great deal of clarity.
In addition, what we have been talking -- a lot of what we’ve been talking about, have lumped things together with resulting heterogeneity, which has the potential disadvantage of diluting signals from individual study trials.
With those brief comments, I think, we’ll move on to the first speaker, and the first speaker is Professor Baines from the University of Toronto who will talk to us about renal issues.
MR. BAINES: Thank you very much. It’s a pleasure to be here and very entertaining at times. My question is, why is acute renal failure so uncommon in these HBOC trials. If we look at Dr. Silverman’s review of the available literature, it is only about one percent of the controlled patients and not significantly different proportion of the test subjects that have what is reported as acute renal failure.
There has been a recent review of careful analysis of renal injury, acute kidney injury, in various intensive care situations, the ones which are most relevant to, I think, our situations are those after elective cardiac and abdominal aortic surgery and what is found there is that the, the incidence of acute kidney injury and the word is different, is about 15 to 22 percent. That’s without any use of HBOC. One wonders then, have we got a problem of definition here as to what is acute kidney injury and what is acute renal failure.
There has been a recent consensus conference, which has modified the riffle criteria. The riffle criteria we developed about 2004, for evaluating kidney injury and classified it into risk, injury, failure, loss, and end-stage disease.
We now have stage 1, 2, 3, and they are classified on the basis of the serum creatinine changes and urine output changes. And if you use those criteria, and the data that’s provided by Dr. Silverman, it seems that in the trials that we had information to go on that the prevalence or incidence, sorry, of stage 1 and stage 2, acute kidney injury in the HBOC trials was greater than 25 percent decrease in GFR in both the Hemosol and Baxter trials.
And interestingly, an apparent increase in GFR, in the Biopure and Somatogen trials, and there is only one trial where the goal standard was used for measuring glomerular filtration rate, and that was the Sangart trial which used iohexol clearance.
And one wonders whether, rare or uncommon predisposing factors account for the low incidence of acute kidney injury, which is still low by comparison with some of the reported ICU incidents, which can get up as high as 70 or 80 percent of the patients in ICU having acute kidney injury by these new criteria.
There have been studies which suggest that polymorphisms and a variety of factors involved with processing reactive oxygen species and inflammatory reactions may account for the susceptibility of some patients to acute kidney injury where others will escape. It may be differences in drug therapy with ACE inhibitors and NSAIDS, and so forth, age, and diabetes.
There are limitations in picking up kidney injury by using just serum creatinine, because of the delayed response in the rise, the nonlinear relationship to glomerular filtration rate, and very often, almost always, I would think, the unknown initial glomerular filtration and serum creatinine.
This leads to an ascertainment bias, for example, you take the 0.38 milligram per deciliter increase that was reported in the Hemosol trials, and you put that increase on a base of 0 6 milligrams per deciliter, the lower reference range for a woman; that would be equivalent to a 40 percent decrease in GFR.
If you put it on top of the upper reference range, 1.1, it’s only a 26 percent decrease in GFR, but it takes it out of the reference range, and that would lead to that individual being classified as having perhaps, acute renal failure, when in fact they had a modest decrease in GFR, and the other person would be classified as being within normal reference range and not abnormal.
What we need are better markers, sort of a troponin for the kidney and these are being now revived again in the Sangart trial NAG was used, N-acetylglucosamine, indices of inflammation and NGAL, IL, interleukins, and KIM-I which is a marker of proximal tubular changes.
Lastly, the one problem that we faced is that animal models don’t correlate well with human disease. It is very hard to reproduce acute renal injury that mimics the human disease.
That having been said, when you do look at what happens with acute kidney injury, it is primarily an apoptotic and necrotic condition in which there is a considerable component of tubular intestinal inflammation and the response seems to be triggered not by nitric oxide but by reactive oxygen species.
Changes in blood vessel permeability with gaps and leukocyte adhesion and activation of (inaudible) and so forth, must play a role. What we don’t know anything about is what happens in the long term. There are studies in animals, which show that repeated hemoglobin injections or a single instance of ischemia or reperfusion will lead to long-term changes with tubular interstitial scarring.
So my conclusion is that some patients and some animals respond poorly to the stimuli or simulation of acute renal failure and we don’t have any data in the older trials that -- to say how many had stage 1 and stage 2 acute kidney injury and we have no long-term follow-up on either HBOCs or red blood cells. Thank you.
MR. WEISKOFF: Thank you.
(Applause)
MR. WEISKOFF: Our next speaker is Mitch Fink who will be talking to us about GI system.
MR. FINK: So good morning, again, my appreciation to Dr.Weiskoff for inviting me to participate in this panel and to be able to attend this very entertaining and informative meeting. There is certainly no shortage of controversy in this field, and I think the only thing that everyone really agrees on is that the medical need is enormous and we all really do have an interest in solving this important problem.
So my task was to spend a minute or two talking about GI complications. I interpreted the GI tract to mean the tube that goes from your mouth to your rectum and all the organs that are connected to it, and in her presentation yesterday, Dr. Silverman presented you with a lot of data related to organ system toxicities that have been associated with HBOCs and I simply extracted some of the data that she so carefully collected and presented, just to outline that.
Of the eight HBOC products, at least five of them have been associated with GI-related AEs and at least three of them have been associated with at least biochemical evidence of acute pancreatitis.
So although there are all kinds of GI complications that have been reported, really the three most consistent ones have been evidence of pancreatic injury, evidence of hepatocellular injury, and chest pain of a sort that’s consistent with esophageal spasm.
Pancreatic injury has been evidenced by increased circulating concentrations of the pancreatic enzyme, lipase, increased circulating concentrations of amylase, and in much more rare instances, clinically apparent evidence of acute pancreatitis.
Hepatocellular injury has been evidenced almost exclusively by biochemical changes, specifically increased circulating levels of transaminases and the most consistent finding of esophageal spasm has been fairly classic chest pain findings.
I would point out that the biochemical changes associated with pancreatic injury and hepatocellular damage are likely the tip of the iceberg, and if HBOCs were used in a epidemiologically significant way, that is, hundred of thousands or millions of exposures per year, it is very likely that massive hepatocellular damage and massive acute necrotizing pancreatitis would turn up as rare, but clinically very important problems, just as been the case for when hepatocellular enzyme changes in initial phase studies have turned up later, once a drug is widely available in the market, as rare instances of acute hepatocellular necrosis.
So what are the mechanisms responsible for these changes? I am not going to talk about all of them, but I am going to focus on acute pancreatitis. There is probably two non-mutually -- mutually compatible mechanisms. And the first, ENO scavenging is known to be able to cause spasm of the sphincter of Oddi and that would increase intraductal pressure in the pancreas, and in animal models increasing intraductal pressure is one of the ways that you can cause acute pancreatitis.
Secondly, ENO scavenging can diminish or impair pancreatic microvascular perfusion, and again, in animal models, causing pancreatic ischemia is one of the ways that you can induce acute pancreatitis. A combination of intraductal hypertension and pancreatitic ischemia is a really bad combination, and is very likely to be associated with the development of acinar cell damage and the induction of pancreatic inflammation and pancreatitis.
Additionally, as was pointed out yesterday, there is a possibility that a non -- or a mechanism that is not directly nitric oxide related or related to the scavenging of nitric oxide might be important.
And that’s, for example, the liberation of reactive oxygen species or hypervalent iron in the pancreatic milieu causing redox- mediated damage to the pancreatic parenchyma. Thank you very much for your attention.
(Applause)
MR. WEISKOFF: Thank you very much. Each of these speakers really has a daunting task of trying to put together the myriad amount of sources of information and what we have heard over the past day-and-a-half, and perhaps the most difficult of this taskforce our next speaker, David Warltier, who is going to try and make sense out of the various pieces of cardiovascular information we have heard.
MR. WARLTIER: I thank Dr. Weiskoff and the organizing committee for the opportunity to participate today. The -- I thought, first, we’d take a look at some hemodynamics, and when I was deciding what subject matter we should take, and which of the many different HBOCs we should look at, I though maybe I’ll just take one that we worked with in our research laboratory, and this is data from dogs, and it’s with the recombinant human hemoglobin from Somatogen, the first generation product.
If you take a look at this data, it is change in mean arterial pressure from baseline, with three different doses of this drug; plateau is around 35 millimeters of mercury, at a dose of between 1 and 2 grams per kilogram. So large increases in arterial pressure and the mechanism for this was an increase in peripheral vascular resistance.
In fact, this produced a decrease in cardiac output. The decrease in cardiac output was not related to ionotropic state. Here is left ventricular DPDT measured at 50 millimeters of mercury and there was no significant change in this.
Large impedance for left ventricular ejection produced by an increase in afterload is associated with an increase in left ventricular and diastolic pressure here at the high dose increasing to almost 10 millimeters of mercury; this increases, despite control of intravascular volume.
Now, just one last thing I would like to mention is there is a significant decrease in heart rate and one would think that this is probably related to baroreceptor reflex, but in fact, the decrease in heart rate actually occurs in isolated heart preparations.
Some more data with this Somatogen product, and this shows a vascular resistances in a number of different regional circulations, the data in rats using radioactive microspheres. And in almost all these beds, we can see an increase in vascular resistance.
This was especially true in the kidney. There were a couple of exceptions to this. A skeletal muscle, which has such low flow to begin with, it is really difficult to decrease it any further in the anesthetized rat, and -- but also in the left ventricular myocardium there was no visible change of vascular resistance, probably due to the importance of metabolic autoregulation in this preparation.
Now, interestingly enough, the second generation product, this is again recombinant human hemoglobin, but that’s been genetically modified so that it does not bind to nitric oxide. There were no changes in any vascular resistance with this compound.
Those were typical physiological changes. Although we would all agree that these HBOCs clearly are different chemicals, this is important I think anatomical, morphological data. Hemoglobin myocardial lesions were first noted during dosed escalation studies of the diaspirin cross-linked hemoglobin. There were first seen in cynomolgus monkeys; it's species-specific, at least certain species are, primates are, more sensitive to this.
Now, what these lesions are, are punctate degenerative very diffuse lesions across the left ventricle, and they're very, very small. What you see is a formation of vacuoles in the lysis of nuclei in cardiomyocytes. It's actually very similar to chronic confusions of sympathomymedica means or even the chronic confusion of L-NAME a non-specific inhibitor of NOS.
These degenerative lesions are associated with only very small increases in creatinine and phosphokinase and it's only very minor changes in the T-wave, probably so, because only a very small amount of myocardium is involved. Finally, the recombinant hemoglobin does not bind nitric oxide, there is less lesions with this, nevertheless they're still present.
Now, this is the slide that everybody is using in a different format or another, these are different products of companies and HBOCs and over here lists adverse –- serious adverse events in –- that may be related to the cardiovascular system.
I would just have you focus on this one line, again, that everyone’s been talking about, and this is myocardial infarction. The numbers here are treatment versus control. There may be different control numbers of patients, there certainly may be –- this slide is a snapshot of some studies and there may be ways to explain changes, post hoc analysis. But just let's just go through six MIs to one MI in the control; 14 MIs to 4, 14 to 7, 29 to 2 and 2 to 0.
This is a –- it's really a disturbing finding. I think what we have to do is understand before we move on with these agents or other new agents is the mechanism of how this occurs. It's certainly not due to the vasal constriction. There's other –- there's some other mechanism for this and that's what we have to understand.
Thanks.
(Applause)
MR. WEISKOPF: Thank you, David, I'm sure we'll hear more about that in the Powell (phonetic) discussion.
Our next speaker is going to address a topic that has been touched upon but only lightly in our preceding sessions and that is central nervous system and Professor Raymond Regan will be talking about that.
MR. REGAN: Thank you, Dr. Weiskopf, and thank you for the invitation to speak here today and to revisit the HBOC field after several years of absence. There’s –- as Dr. Weiskopf alluded to, there's relatively little information about what happens when HBOCs enter the CNS –- if they do enter the CNS. I began studying HBOC neurotoxicity and hemoglobin neurotoxicity several years ago, back in the early ’90s at Letterman Army Institute of Research using a cell culture model –- and up here we see cell culture, cortical cell culture containing neurons and astrocytes. On the right is a sham-washed culture, just subjected to medicexchange, not injured and the neurons are identified by the immunostainings to a neuronal market called neuron-specific enolase, and this is a healthy-looking culture, you really can’t make out the astrocytes very well, because they're not stained. This is a culture treated for 24 hours with 25 micromolar hemoglobin, and all the neurons were just completely wiped out with a few sick-looking exceptions.
So we were really surprised to see this degree of neurotoxicity from a relatively this low concentration of hemoglobin. We subsequently discovered that this toxicity was not due to the hemoglobin per se but due to its breakdown products, particularly iron. It could be blocked completely with deferoxamine and other iron chelators and also by reducing hemoxygenase activity in the neurons by knocking out HO2.
Looking at this toxicity and Hemoglobin A0 versus the Army’s alpha-alpha cross-linked product we found that the neurotoxicity was very similar quantitatively and mechanistically. Cultures were exposed to hemoglobin in a constitution of heme 1 or 10 micromolar again for 24 hours and a alpha-alpha cross-linked hemoglobin and hemoglobin A0 had a similar release of LDH indicating a similar neuronal death, with about 75 percent with 10 micromolar, very toxic, both products.
Subsequently, about –- well, 5 years ago or so, we looked at Sangart’s product in this model, NP4, comparing it with stroma-free hemoglobin in this experiment. And you’ll see here that the concentrations used were much higher here than here. The reason for that is that this experiment was conducted in the presence of serum, and we serum we have to increase the hemoglobin concentration about 40-fold to see a similar effect in a serum-free model.
The Sangart product was similarly cytotoxic, actually a little bit more than stroma-free hemoglobin in this Sanvitra (phonetic) model. Subsequent studies done by Vandergriff and colleagues at Sangart suggested that this may be related to an in vitro artifact of this product. It tends to autooxidize faster in vitro, but not in vivo. At any rate, it was neurotoxic in at least a similar fashion to stroma-free hemoglobin.
One other hemoglobin -- blood product has been tested in vitro and that’s Biopure’s product that was published in Journal of Trauma by Ortegon and colleagues back in 2002. This used a neural cell culture system, neuroprogeniter cells, not differentiated neurons and they looked at various concentrations of HBOC 201 versus human hemoglobin, and surprisingly HBOC 201 was relatively non-toxic in this model compared to human hemoglobin.
The reduction of proliferation which was the endpoint used in this particular experiment was observed with the HBOC 201, only to very high concentration. So this would suggest that HBOC 201 may be less toxic. However, it's important to note that in this study, serum was present in the medium and also selenium and transferrin, both of which are strongly neuroprotective in neural models, against hemoglobin. So the absolute neurotoxic potential of HBOC 201 is difficult to determine based on this study.
The most –- the more important question, the more relevant question is, are these compounds neurotoxic in vivo. I think we can stipulate that it's very unlikely in the setting of an intact blood-brain barrier that a sufficient amount of these products get into the brain to cause neurotoxicity. That's based on a fairly limited amount of data that's available in the public domain.
So the question then becomes, in the setting of a disruptive blood-brain barrier, traumatic brain injury or stroke, are these compounds, or is this class of compound toxic? After many years, after reviewing all the data I could find in the public domain, I think this is still an open question.
Looking at recent studies, most of them have been done with HBOC 201 in a traumatic-brain-injury-with-hemorrhage model, and I've highlighted three of those recent studies here. These are studies in swine, rat, and swine.
Various outcome measures were recorded, all of them are reasonable measures commonly used in traumatic brain injury research. The problem is they're not particularly sensitive to the neurotoxic effect of hemoglobin. Those of us who inject hemoglobin into the intact brain and look at injury have found that these tend to be the most sensitive markers, protein carbonyls, malonic dialdehyde and 8-hydroxy- 2-deoxyguanosine, and they weren't measured in any of those models or in fact any models I've seen of traumatic brain injury or stroke when these products were given.
But what you look and what you measure is probably less important than when you measure it. Hemoglobin is a very slowly acting neurotoxin. If we injected hemoglobin into the mouse brain or the rat brain and look for injury 5 hours or 6-1/2 hours later, we invariably see nothing. It takes a while for the hemoglobin to oxidize, to release its heme and to be broken down to iron which is ultimately what's causing the injury.
At 24 hours if you have a severe injury you might see something that the best time to look is not 5 hours, 6 hours or 24 hours, best time is 72 hours. So until those studies are done, I can’t say with any certainty whether HBOC are neurotoxic if they get into the CNS.
How about in clinical trials? We heard Dr. Sloan’s excellent summary earlier this morning about the traumatic brain injury DCLHb trial. I want to recap that this trial, however, focused on patients all of whom had a disruptive blood-brain barrier. Saxena et al controlled safety study of hemoglobin-based oxygen-carrier, DCLHb and acute ischemic stroke published in 1999 –- the trial was done back in ’94 and ’96 –- and the intervention, DCLHb 2550 or 100 milligrams to a kilogram every 6 hours, so they’ve got a total of 12 doses, within 18 hours of symptom onset or saline placebo, very small trial, total of 85 patients.
Now, we know now this trial had absolutely no chance of showing any benefit from this product, because of its faulty design. The therapeutic window is 18 hours. The therapeutic window for ischemic stroke is 3 hrs. No matter what you do at 18 hours it's not going to work.
That said, it doesn't show any evidence of toxicity and the results, while not conclusive are not encouraging either. Eighty five percent of patients treated with DCLHb had and an unfavorable outcome, defined as a modified ranking score of 3 to 6 versus 51 percentage controls at 3 months. And there were 23 deaths in the treated group and only 9 in the placebo group.
There are some limitations to this trial, the randomization was not perfect, there were more severe strokes in the treated group than the placebo group. But that said, the trend tends to be that there was perhaps a deleterious effect.
So in summary there's pretty good evidence that HBOCs, at least some HBOCs are neurotoxic in vitro. Whether that's true in vivo remains an open question in my opinion. I think further pre-clinical trials, pre-clinical studies looking at relevant oxidative injury markers at relevant time points are important before TBI patients or stroke patients are involved in further clinical trials.
Thanks very much.
(Applause)
MR. WEISKOPF: Many of the trials that we heard about today, I mean much of the development is in our inpatients who are experiencing shock in one format or another, and Professor Parrillo will address this issue.
MR. PARRILLO: Good morning. I'd like to thank Harvey Klein and Richard Weiskopf and the committee for inviting me to be here today. By way of introduction I'm a cardiologist who's been interested in critical care medicine, somewhat uncommon combination for the last 30 years or so and specifically I've been interested in shock. I also will mention that I am the editor-in-chief of Critical Care Medicine, one of the journals in the field for the last 11 years, and as I look at –- on this audience a lot of you are reviewers for the journal. I want to say thank you for all of your help over the years; journals would be nothing without the great reviews that are necessary in order to make decisions.
In thinking about this topic I made the assumption that the cardiac manifestations and a lot of the other issues were going to be handled by other speakers who have, I think, done a great job of telling you about all the different issues. So I decided to kind of take a broad view, considering the fact I had three slides and five minutes.
And so I'm going to give you kind of an overview of my thought about handling shock for these compounds, HBOCs, and really for any compound. Here we go. Okay, so this is the –- this is actually an adaptation of the Weil-Shubin classification of shock, hypervolemic cardiogeneric extracardiac obstructive and distributive shock, and I wanted to really make one major point which is that what we learned about all these different forms of shock is that the timing, the reversal of the form of shock is absolutely critical and our colleagues in trauma surgery area have done a beautiful job this morning of telling us how dramatic and important it is to stop the hemorrhage in hemorrhagic shock.
Cardiogenic shock, very important to get that vessel open. Getting the patient into the cath lab in 60 to 90 minutes is absolutely critical in cardiogenic shock. We all know that in a tension pneumathorax or pericardial tamponade or pulmonary embolus, you have to really lyse the embolus, or you have to drain the pericardium in a matter of minutes if you're going to have a chance of making a difference. And it appeared for a number of years that septic shock might be an exception to this idea that being quick and being very, very urgent about doing your therapy in shock was not that important.
In fact in septic shock, an area I've been particularly interested in, there are a number of abnormalities that occur in the cardiovascular system and the thought was that maybe it didn’t make as much difference in terms of timing.
And I'm showing you an editorial I was asked to write about, in the New England Journal, asked to write about vasopressin norepinephrine; this appeared actually in the February issue of the New England Journal of Medicine and I'm showing it really because of the slide limitation in order to bring a number of concepts together.
And I made the point that clinicians don’t feel the same sense of urgency to initiate therapy in cases of septic shock as they do in cases of myocardial infarction or in cases of traumatic shock or in other cases of shock such as cardiogenic shock.
Yet, there are studies now and there are a number of them, I'm going to just show you one in terms of time, that suggests that initiating therapy rapidly even in septic shock may play a critical role in reducing mortality associated with septic shock. And in septic shock it's known that it makes a difference, the antimicrobial that you choose; you have to choose an appropriate antimicrobial. And this is data from Nandakumar, a big observational trial done multicenter in which he looked at the time to giving the antimicrobial versus the odds-ratio of death in this particular trial, and "1" is obviously the baseline. And if you compared the first hour of giving antimicrobials to any hour subsequently, you found a statistically significant increase in mortality.
For instance, if you gave antimicrobials in the first hour of septic shock you had a survival rate of 80 percent. If you gave it at 6 hours it was down to 40 percent. If you gave it at 36 hours it was down to about 10 or 20 percent.
My point here is that depending upon where you are in the sequence of shock, the HBOCs or any therapy may make a big difference if you do it in do it in the first hour, second hour of –- or it may make very little difference. If you're out at 36 hours –- in fact this study I was commenting on had many patients out at 24 hours, 30 hours after the onset of shock. I would argue that vasopressin or any agent would have made very little difference at that point in shock.
So, I wanted to kind of bring us back to one of the major concepts in handling shock, I believe, of any type and that is that the major therapy has to be homogenous and it has to be applied very early and that urgency is important in all forms of shock.
Thank you very much.
(Applause)
MR. WEISKOPF: Thank you for those insights. I'm sure those in the audience are taking home that message.
Our final panelist to speak in this session is Mark Gladwin here from the NIH and he will talk also about a subject that has been touched upon but only relatively lightly and that is pulmonary issues.
MR. GLADWIN: I’ll review these potential conflicts in more detail prior to my next talk for which I think they're more relevant. I was asked to comment on potential pulmonary toxicity of these HBOCs, and as you know there's very little of data available to us. While some of these complications have been listed in the table that was provided to us by the FDA, for most of these complications there's an asterisk indicating we don’t know or haven't measured the rates of these complications.
I’ll point out that pulmonary hypertension could be a very important complication and could effect right heart function and contribute to arrest, but we really haven't measured this parameter in these clinical trials.
Pneumonia –- there appears to be a clear increase in risk of pneumonia as well as respiratory arrest. And considering the increased rates –- you've heard of a pancreatitis sepsis and multi-organ failure. One could imagine that there would be an increased risk of ARDS, but I think this has to be studied. And then there is a suggestion of a signal in terms of thrombotic complications that has to be considered.
So what I would have thought I would do is briefly touch on some mechanisms and some principles that I think may be worthwhile considering. The first thing I’ll mention in relation to pulmonary hypertension is this concept of NO scavenging versus premature oxygen delivery. So Winslow suggested that oxygen can vasoconstrict the arteriolar system which it clearly can. But what we have to consider then is how these HBOCs are constricted in the pulmonary circulation because oxygen in the pulmonary circulation is a vasodilator.
So I think exploring the vasoactivity of these systems in the pulmonary circulation will be informative about the relative importance of those two pathways.
The other thing I think we can learn from is the LNMA trials in septic patients which also –- there was a strong harm signal in the LNMA trials and we should probably study those trials when considering HBOCs that have NO scavenging properties.
And the last thing is we have been informed greatly by your research in HBOC field, in terms of extrapolating that data to hemolysis and hemolytic diseases. So I want to briefly do that in reverse now and share with you what we’ve learned over the last 3 years in terms of hemolytic anemias and what does that tell us about NO biology when you're infusing higher concentrations of these molecules.
And I’ll point out if you look at PNH, paroxysmal nocturnal hemoglobinuria, these patients suffer from many of the symptomatology that you see with HBOCs confusions: gastric dystonias, thrombosis, pulmonary hypertension, fatigue independent of total hemoglobin concentration –- that might be something we can discuss later.
But I’ll move very quickly through this data jut to describe that NO is scavenged by hemoglobin, that hemoglobin in a red cell generates diffusional barriers that reduce the rate of that reaction so that when you hemalyze or when you infuse a stroma-free hemoglobin you disrupt the cell-free zone in this unstirred layer. So you increase the rate of reaction of NO coming from endothelium with the hemoglobin.
In the case of sickle-cell disease, they have hemoglobin in their plasma and it's very low, from undetectable to 20 micromolar. This is slightly less than 20 mgs per deciliter. During crisis it can go up to 20 to 40. But remember, all the data we looked at yesterday, that there was a constrictive property of the HBOCs that occurs at the lowest concentrations.
And you can imagine the ability of that plasma from a patient with hemolysis to consume NO, using basic NO assays, and the injection of plasma into a solution of NO destroys the NO instantaneously. And a patient with sickle cell with more plasma hemoglobin has more NO consumption, and NO consumption is proportional to the amount of heme and plasma. And if you take the hemoglobin out of the plasma you reduce that NO consumption.
And I think important to HBOCs biology, you can infuse NO donors into human patients with sickle cell and depending on how much hemoglobin they have in the plasma you’ll impair that NO signaling. And just as shown in this experiment if you infuse sodium nitroprusside into the forearm of the patient with sickle cell, with low plasma hemoglobin, there's a normal response. Patients with higher levels of plasma hemoglobin, only 5 micromolar heme, and you have a near complete inhibition of NO signaling.
And this is the recapitulated and transgenic hemolytic mouse models, so that a sickle cell mouse that hemolyzes and has a high plasma heme has almost a complete inhibition of NO-dependent signaling. And a hemizygote with less hemolysis and then the control has progressive increase in NO-dependent signaling.
So, very low levels of hemoglobin and plasma creates an NO-resistant syndrome. And I also want to point out that NO inhibition does not necessarily equate with blood pressure changes. In fact the sickle cell patient and sickle cell mouse is hypotensive, and what we found is they have to regulate COX-2 and COX-2 activity. So they're maintaining vasodilation secondary to their requirement for oxygen-delivery with critical anemia by COX-2 not by NO. But the NO-signaling pathway is inhibited and that can create other problems.
And then pulmonary hypertension is an increasingly recogn