JOHN BEARD: I wanted to ask Gail Butterfield a question about the changes in energy requirements at altitude. Reed Hoyt mentioned some changes in mechanical efficiency that perhaps figure into that equation. Would either or both of you want to discuss whether or not all of the change in energy requirements is accounted for by change in BMR?
GAIL BUTTERFIELD: In the studies we did, it probably is. We increased their energy intake only by the equivalent of the increase in basal metabolic rate. Our studies were in sedentary individuals. They did some routine bicycling to maintain their training level so that they remained essentially as untrained as they were at sea level. By simply addressing the increase in BMR, we were able to maintain body weight.
REED HOYT: Clearly, soldiers can have high rates of exercise energy expenditure at altitude due to the high cost of traversing mountainous terrain. This high cost is not unexpected given the steep grades and poor footing that characterize mountainous terrain, as well as the heavy loads soldiers often carry. Further research is needed to understand the more subtle effects of hypoxia on exercise efficiency and BMR. Clearly, one needs to acknowledge
how much physical work soldiers do and explore ways to get food into them in spite of anorexia and other problems.
ROBERT SCHOENE: I heard twice this morning—once from Reed Hoyt and maybe from Al Cymerman—that this initial fluid depletion—diuresis—that occurs at high altitude had some effects on optimizing oxygen consumption at the cellular level. I had not heard that before, and I need to have it explained a little bit more. Reed, do you want to address that?
REED HOYT: The observation at high altitude is that there are improvements in endurance performance that are not explained. In our experience, there is a transition to more fat metabolism. Our suggestion is that changes in the conductance of oxygen down to the cell level may be responsible for these observed changes.
It is not associated with an increase in o2max, because clearly, the number of capillaries and the number of mitochondria are not increasing. In our minds, it is a change in the geometry that facilitates the conduction of oxygen. The change in geometry accompanies diuresis. Clearly, those places where there are no transport pigments between the red cell and the target cell are particularly high resistance points in the conduction of oxygen. So I think that the resistance at those junctures is changing with the changes in fluid distribution. You are familiar with the pathological aspects of anti-diuresis, fluid retention, and altitude illnesses, too, and that is the other side of the coin.
INDER ANAND: One question and a comment. The comment is that the studies that suggest an increase in efficiency came from work on the Quechua Indians.
REED HOYT: Right, you are referring to Hochachka's work.
INDER ANAND: Yes, and those studies were done on subjects whose fluid status was not assessed. So I do not think we can make a deduction from this data regarding efficiency and fluid status.
REED HOYT: Right. The connection with body water is not clear from most studies. It is Hochachka's view, however, that oxygen transport is more tightly coupled. That is, skeletal muscle ATP demand and ATP supply are more tightly linked. Closer coupling means that increases in work rate are accompanied by smaller than expected changes in cell phosphorylation potential, phosphocreatine, and pH, and consequently less stimulation of glycolysis and
less lactate accumulation1. Clearly, that means a more effective oxygen delivery system, much as one would see in an endurance-trained individual. You see improved oxygen delivery and an increased reliance on fat oxidation. But I agree with you, we need to explore further.
INDER ANAND: My question is to you or to Gail. I want to know whether studies from Operation Everest II can account for all the weight loss simply on the basis of less food intake and more energy expenditure. My interest is that Operation Everest II showed that expenditure went down, as you indicated in your slide, and the intake went down as well. Therefore, when you take the two into account, you cannot account for the 7 1/2-kg loss of weight. You can only account for about a kilogram and a half loss of weight.
GAIL BUTTERFIELD: They do not account for the increase in basal metabolic rate; Operation Everest II (OE II) just looked at activity patterns. So there is approximately 250 kcal/d in their estimate of energy expenditure that is not accounted for.
INDER ANAND: So you believe that you can account for all the weight loss by increases in expenditure and intake?
GAIL BUTTERFIELD: I think you can. As I showed in one of the last slides, there is some diuresis even in the fed individual, but it amounts to less than a half a kilogram effective weight loss over a long period of time.
ALLEN CYMERMAN: I am in the position of having supported three studies now that showed three different findings on fat metabolism. I would like to know, does altitude acclimatization occur to the point where glycogen stores are spared as Andy originally showed?
GAIL BUTTERFIELD: The 1988 study that we did found no change in glycogen stores. We did not measure fat in that study. In 1991 when we studied fat, we showed that fat utilization was down at rest and during exercise. I do not know what the glycogen data are, but I would assume that the conditions were essentially the same, that glycogen was spared. The question that Reed asked me, and I do not have the answer, is what are they burning then? Clearly, glucose utilization goes up.
ROBERT SCHOENE: But Reed shows just the opposite. It is a different situation.
GAIL BUTTERFIELD: Yes, you have a fed- versus a fasted situation.
IRA JACOBS: I have a comment related to Dr. Cymerman's question. I think you are confusing apples and oranges here. In some of our studies, we are looking at utilization at the same absolute work load, and in some we are looking at the same relative work load. Those are two entirely different conditions. Let us assume, as you said, that the same amount of oxygen is required to perform the same amount of work at high altitude. But the ceiling that each individual has is reduced. Nobody will debate that, at high altitude. I have not seen any data showing that with acclimatization o2max does come back to normal. This is different from what we heard from Robert Schoene, when he suggested that oxidative enzyme adaptations also cannot be restored to normal. They can be trained somewhat, but they are never restored.
Although the 100 percent ceiling is reduced, you have to do the same absolute work load from a military perspective. You have to take apart an artillery piece, or you have to move 100 m (328 ft) or 200 m (656 ft) or 1 km up a hill. To perform that same amount of work at high altitude is going to cost more carbohydrates, because carbohydrate oxidation is solely a function of relative exercise intensity, everything else being equal. So carbohydrate requirements have to be greater for the same absolute work load. I would be interested in knowing if there is debate about that.
ROBERT REYNOLDS: I might mention what we saw with respect to carbohydrate and fat intake on the Everest 1989 expedition. We saw, like everybody else, a decrease in total caloric intake, yet the ratio of energy consumed from fat was maintained at 30 percent, regardless of whether they were at base camp or camps one, two, three, or four, which goes up to 8,000 m (26,230 ft). So before we give fat a bad name in consumption, consider the calls on the radio from camp four to send up more of those sausages and more of the cheese. Now, these were acclimatized individuals, as much as you can be at 8,000 m (26,230 ft). But there was a 30 percent intake of energy from fat, and that did not change as a function of altitude.
ROBERT NESHEIM: I am not surprised at that, because there has to be a certain amount of caloric density in the diet, or they will not get enough food. I am surprised it was not more than 30 percent fat.
ELDON W. ASKEW: I have a comment with regard to what Dr. Anand brought up about Operation Everest II. We had the same question when we reviewed the data. Madeleine Rose and I both arrived at about the time OE II was getting going, and we did not really have any input into the design of it. If we could have, I think we would have called for some 24-h urine collections and fecal collections to rule out that there was any malabsorption. Those were our questions: what happened to the nitrogen balance, and what happened to
the efficiency of the absorption? But I agree, there is a little bit of noncorrespondence here.
A. J. DINMORE: I have a question about malabsorption at high altitude. You say that at 4,000 m (13,333 ft.) you did not show any decrement. But at extreme altitude, we actually measured mediated uptake of glucose analogs, and we showed there was a roughly 50 to 60 percent reduction from sea level at 5,000 m (16,393 ft) and above. We have published these results in abstract form, and we have papers coming out shortly.
DAVID SCHNAKENBERG: I was quite interested in Dr. Butterfield's results. I believe that with a primarily liquid diet, she was able to maintain energy balance. It is interesting that Frank Consolazio's studies showed benefits to reducing high-altitude symptoms when he used a liquid diet. Eldon Askew did a study on a mountain in Hawaii where he gave a liquid supplement, and he was able to reduce symptoms and enhance running endurance time at high altitude. Al Cymerman said earlier that although you must lose weight you must lose fluids because that is an adaptive response to prevent symptoms. If you do not reduce your intake and lose water, you are going to have a high incidence of altitude symptomatology. What happened with your subjects?
GAIL BUTTERFIELD: In the two studies we did, we had one young man who was taken down from the mountain the first night due to severe headache. He was brought back up the next day, and he did fine. About half of the subjects in each experiment experienced slight headaches. Some of them had to take Tylenol to alleviate those symptoms. This is only anecdotal, but the frequent comment to me in the morning was "Hurry up and get that food on the table. I want to eat because it makes me feel better."
DAVID SCHNAKENBERG: Did you give out Al Cymerman's symptoms questionnaire?
GAIL BUTTERFIELD: Yes.
ALLEN CYMERMAN: We did, but I do not remember the results.
GAIL BUTTERFIELD: I never saw the results, so I do not know.
DAVID SCHNAKENBERG: It might provide useful data to compare with the same instruments used time and time again at high altitude, even though you did not have a control group.
GAIL BUTTERFIELD: We did have a control group at sea level.
ALLEN CYMERMAN: To answer your question, when weight was controlled, these subjects, from what I remember, were not overly sick from acute mountain sickness.
DAVID SCHNAKENBERG: So you do not think that feeding them adequately made them more sick?
ALLEN CYMERMAN: No. There was no vomiting. There was nothing that I saw along those lines. Anecdotally, the time that I saw the worst acute mountain sickness was at Pike's Peak. They had gone to Denny's the night before and had overindulged on buttermilk pancakes and milk with the works. The next morning, every one of them was vomiting.
DAVID SCHNAKENBERG: One more quick comment on two studies, Reed Hoyt's and Gail Butterfield's, as to whether the subjects stayed with carbohydrate metabolism or were shifting to lipid metabolism. In Reed's study, they were in caloric insufficiency, and in Gail's they were calorically adequate. I think much of the confusing literature about whether high altitude shifts people to lipid metabolism is debated on energy balance.
I will go back to my first study on altitude. I pair-fed rats and took half to a high-altitude while half were kept in Denver. The purpose of the experiment was to answer the question of whether the weight loss and change in body composition in rats at high altitude is due to the altitude or to an altitude-induced reduction in appetite. Both sets of rats experienced the same weight loss and change in body composition.
ELDON W. ASKEW: I want to clarify one thing that Dr. Schnakenberg said, which relates to what Dr. Schoene said regarding carbohydrate diets and acute mountain sickness. We did a study on Mauna Kea, and we reported it in a technical report. We got a significant increase in physical performance at high altitude, both running time and endurance time in subjects consuming a carbohydrate supplement.2 It was not a large increase—about 12 percent—but it was significant. However, we did not observe a similar decrease in symptoms of acute mountain sickness that Frank Consolazio reported3 in response to carbohydrate. The regimen he used was that subjects exercised
very intensely and for a very short period of time, and basically they were sedentary the rest of the time. Maybe they had more time to reflect on their symptomatology; I do not know. But we did not see a big change. The high carbohydrate diet is what I am talking about.
MARY MAYS: It is also true that these Marines and Special Forces troops pride themselves on having attained a 5 percent fat-free mass. Gail, you characterized your subjects as "couch potatoes" on several occasions. It is true in other studies that expedition people bulk up before they go. They try to put on some insulation, as well as do some carbohydrate loading. Does that account for any of this?
GAIL BUTTERFIELD: I characterized my gentlemen as "couch potatoes," but their body fat was between 10 and 12 percent, so they were not bulked up.
EDWARD HIRSCH: Pursuing the question that Dave asked of Gail and Reed, it struck me during Gail's presentation that her subjects were professional Pike's Peak subjects. Were they?
GAIL BUTTERFIELD: No, they were students from Stanford, world travellers. There was one from Australia, another from Israel; they were adventurers of some sort.
EDWARD HIRSCH: This relates to the question of which comes first: low intake or sickness? This morning Allen Cymerman told us about how sick people become at high-altitude. You do not have to study food intake to know that sick people do not eat. Neither one of you reported it as acute mountain sickness.
GAIL BUTTERFIELD: As I said, in both studies there was only one fellow who had a severe-enough headache that we took him down the hill. He was the only one who had previously been to high altitude. He spent a lot of time in Tibet, and he knew that he got mountain sick. We took him on the expedition anyway; I do not know why. The rest of them had not been exposed to high altitude.
ALLISON YATES: Gail, could you talk about when your subjects were at sea level? How long did you feed them and how long did it take for you to determine their energy requirements? How long did they stay at that kcal level and protein intake before you took them up there?
GAIL BUTTERFIELD: Good question. The baseline period was a 2-wk feeding period. Because we were doing nitrogen balance studies, we put them on the diet for a week before we brought them into the metabolic unit. During
that week, we adjusted energy intake to try to maintain body weight. We had a fair amount of experience at guessing at energy requirements to start with, so we were pretty good at determining their energy requirement during that first week, and their body weight was fairly constant.
During the second week, when they were in the unit for the entire time and we measured body weights in the morning, their body weights were constant. By the time those 2 weeks were over, we were pretty sure what their energy requirement was. Then there was a 3-wk period between the end of baseline and the time they went on the diet again. They were on the diet for 1 week before they went on the mountain. Thus they were in the same shape when we did the acute measurements as they were when we did the sea-level measurements.
ALLISON YATES: Regarding your baseline measurements at sea level where there was some fat utilization, were you pretty sure at that point that they were getting adequate intake?
GAIL BUTTERFIELD: Yes. They were in nitrogen balance during that time.
ALLISON YATES: What did you use to increase their caloric intake; what food component?
GAIL BUTTERFIELD: Carbohydrate and fat. We kept the protein constant because we were doing nitrogen balance, and we did not want to interfere with that. So we increased their carbohydrate, primarily in the form of the fluid electrolyte drink that they consumed, and we increased their fat with cookies that were approximately 85 percent fat. They did not like those much.
JOHN BEARD: I would like to return to the carbohydrate question again and perhaps add an additional glitch to it. Perhaps the driving force for this increased carbohydrate utilization might be that the individuals are experiencing another aspect of hypoxic drive. George Brooks and Peter Dallman have shown it, and we have shown it a number of times. Peter Farrell and I have published a couple of papers that show that iron-deficient anemic animals in which we used hyper-insulinemic euglycemic clamps, had increased glucose utilization, and an increased sensitivity to insulin. If in fact the underlying biology here is another aspect of hypoxic drive, then perhaps these acute high-altitude exposures are one of the influences.
GAIL BUTTERFIELD: That has been remarked upon as well.
DAVID SCHNAKENBERG: I would like to ask a question on the use of enhanced levels of antioxidants in the diet. Being a soldier exposes a person to lots of different types of what I think to be oxidative stress. Imagine
yourself operating in a combat vehicle in which there is the smoke and the exhaust, as well as the gasses that may come from the repeated firing of weapons. You might also be operating next to a microwave-emitting system. You may be even firing a shoulder-fire weapon with a blast-over pressure phenomenon.
Do we need to give some serious consideration to examining these data and whether we should consider pumping up the antioxidant nutrients in our combat rations over and above what might be needed for the person who works in a laboratory in Beltsville all day long?
ROBERT NESHEIM: Maybe Orville will respond to that.
ORVILLE LEVANDER: Vitamin E is a remarkable substance. It protects against a lot of different things. Our own work has shown that it protects against lead toxicity, and ethyl mercury poisoning. People have shown that it protects against ozone, sulfur oxides, nitrogen oxides, carbon tetrachloride; you name it, vitamin E just seems to have a very good effect.
What impressed me, however, is the high biological specific activity of this substance, and how little is needed to offer protection in a variety of animal experiments. It is very easy to demonstrate effects between deficient and normal levels of vitamin E. It is not quite so easy to go from normal to, shall we say, super normal or super nutritional levels. I take your comments at face value, that going from 20 to 400 is not a dose-response curve. I think that under the condition of so many stresses on one individual, it may be necessary to have more than the usual RDA. I find it hard to accept that you need 400 units.
I. SIMON-SCHNASS: I did not intend to imply that you need 400 units. What I am trying to say is that 20 units is not enough, and 400 units is enough. We don't know the minimum amount of vitamin E necessary to prevent the adverse changes observed in the placebo group.
ORVILLE LEVANDER: I understand that, but I just want to make it clear to this group.
I was curious about your methodology. I wondered what technique you used to measure the red cell filtration, for example, in your subjects.
I. SIMON-SCHNASS: It was a simple filtration via a micropore filter with a 5-nm force and without any pressure.
ORVILLE LEVANDER: These were done on site?
I. SIMON-SCHNASS: On site, yes.
ORVILLE LEVANDER: That is a pretty tricky technique. We have some experience with that ourselves, and it is vulnerable to a lot of influences.
I. SIMON-SCHNASS: It is difficult to compare results from different studies, that is true, because it depends a lot on the handling of the samples by different persons. But I did all filtrations myself in both studies using the same techniques, so that error is minimized. It is hard to compare with other studies, that is true, but not these two studies with each other.
ORVILLE LEVANDER: It is a remarkable accomplishment to do that kind of study under those conditions. I congratulate you for that.
IRWIN TAUB: I want to pursue this point about the vitamin E as an antioxidant. Your results are very interesting because they parallel those from radiation chemistry and even from lipid oxidation in food. Whereas you correctly indicate the key to vitamin E effectiveness is the interaction with the lipid peroxyl radical, what then becomes important is that the amount of vitamin E is limiting. It can be consumed by that and other processes. So in radiation chemistry and in lipid oxidation, we enhance the effectiveness of the vitamin E. Actually we regenerate it by having ascorbyl palmitate in the system, and that becomes a sacrificial lamb and regenerates the vitamin E.
Could you consider in any future studies making sure that the combination of vitamin E and perhaps ascorbyl palmitate, if that can survive digestion, would be equally if not more effective, so that you would not even have to go to the 400 mg. I wonder if that would be objectionable to use in food. We do use it in food, but I mean pumping it up.
I. SIMON-SCHNASS: I agree with you that vitamin C enhances the effectiveness of vitamin E to handle oxidative stress. That is why in the first two expeditions (Solo Khumbu and Annapurna) the subjects were supplemented with a multivitamin which contained one RDA equivalent of vitamin C and the other vitamins. This was done in order to prevent a reduced regeneration of vitamin E because of not enough vitamin C present. So I think that the effect I found is really and effect of vitamin E alone.
This was different in the expedition to Solo Khumbu. This was a purely scientific expedition during which a variety of tests were done on the same subjects. This included some psychological tests, and the psychologists refused to permit supplementation of the subjects. I do not agree with them that supplementation might have interfered with the results of their psychological tests, but rather a deficiency might interfere with their results. And the diet at that time was deficient in some vitamins and minerals.
K. K. SRIVASTAVA: I would like to make a comment on the nature of oxidant injury in high mountains. When you are moving up, the partial
pressure of oxygen is coming down, and therefore there is very little chance of oxidative radicals going up. On the other hand, when you come down from the high altitude and then you get a resurging oxygen intake, it is very well known that at that time free radical injury is very common. Therefore, for the people who stay a long time in high mountains and keep on sequencing from lower altitudes to higher altitudes or vice versa, and also for the people who leave and then go back to the high mountains, the incidence of oxidant injury is much more common.
Therefore, perhaps because these mountaineers kept moving from lower to higher elevations, there might have been a total oxidant injury, and their requirement of vitamin E or other antioxidants might become much greater. I would like you to consider this point. For military operations, this becomes important because soldiers stay in the mountains for a longer period of time. They keep on sequencing during patrols and other operations from lower to higher altitudes. They go on leave or training, and then they return to the high mountains. In those cases, the oxidant injury is much more important than in the case of mountaineers.
I. SIMON-SCHNASS: That is true, but with oxygen metabolism it is very complicated. You have this oxygen paradox. That is, if you have hypoxia, you have increased oxidative stress. That means if there is not enough oxygen to produce enough reducing equivalents, then the oxygen cannot be reduced completely to water. This results in all these reactive oxygen species.
On the other hand, if you have hyperbaric oxygen, you have this classical oxygen toxicity. So oxygen is a very dangerous friend. You need it in any case, but it must be handled very carefully. That is why there are the antioxidants.
K. K. SRIVASTAVA: No, that shows that there is a need for the measurement of the free oxide radicals or hydroxy radicals in the environment of high mountains or in the hypoxia. These data are not yet available, to the best of my knowledge.
PATRICK DUNNE: I have a follow-up question to that. A couple of biochemical issues came to mind. This sounds very much like a reperfusion injury. When I used to teach metabolism, the question was, what is basal metabolic rate? A lot of it is pumping ions, and I wonder if anyone has looked at some of the ATPases, especially in light of what we are learning in reperfusion injury, and calcium ATPases. As far as cellular-level research in this area, it might be worth pursuing.
I have another mechanistic question. One way of shifting the oxygen-binding curve, which has not been discussed but birds do it and some people do it, is with organic phosphates. I wonder if any of this adaptation is being looked at, as far as shifting of the binding curve with 2,3-diphosphoglycerate
(2,3-DPG) or some of the other things? As we shift into different carbohydrate metabolism, we might shift some of these binding curves as well.
ROBERT SCHOENE: From the clinical perspective, we are talking about oxygen radicals and injury among mostly young, healthy people. When I hear people in my department talk about oxygen radical injury, they are really talking about long-term endothelial damage that may predispose people to thrombi and atherosclerosis and so forth.
I believe in vitamin E, but are we really talking about injury that is significant clinically or in terms of performance in young, healthy troops, for instance?
MURRAY HAMLET: I would suggest that much of what we have been discussing is endothelial cell dysfunction—the inability to manage fluids across membranes—not only in injury, but in cold injuries. Endothelial cells are probably the target organs. So it might be a subclinical injury to endothelial cell function.
K. K. SRIVASTAVA: It is functional damage, not real pathological damage. If you are typically going to the mountains, it might aggravate the situation. What remains a functional deterioration might become a permanent deterioration. That is an open question.
ALLEN CYMERMAN: I would like to respond to Pat Dunne's question about 2,3-DPG. That work was done about 20 or 30 years ago. They thought that the phosphate would shift the curve, and everybody would be very happy at high altitude. It turns out that it is a give and take, what you get on the delivery side, you lose on the pick-up side. People who, for example, climbed Mount Everest were extremely alkalotic. The importance of 2,3-DPG, as far as altitude acclimatization is concerned, has waned through the years, and no one thinks that it is the body's true response to oxygen. It shifts the curve to the right and unloads oxygen in the periphery.
K. K. SRIVASTAVA: This is true, but it depends on the altitude. If you are at moderate or low altitudes, the 2,3-DPG mechanism will deliver the goods. But if you are at a higher altitude, beyond 5,000 or 5,500 m (16,393 or 18,033 ft), then this 2,3-DPG mechanism does not work well. However, the concentration is increased.
ALLEN CYMERMAN: There is no question that the concentration is increased, but the respiratory alkalosis shifts the curve the other way.
K. K. SRIVASTAVA: That is right, but at higher altitudes.
ALLEN CYMERMAN: We could argue that. Lenfant said 4,000 m (13,115 ft), but it is borderline at 4,000 m. Above 5,000 m (16,393 ft), yes, there is no question.
ORVILLE LEVANDER: I would like to comment on the question about clinical aspects and whether we are talking about chronic or acute situations. We have used two infectious models to study vitamin E deficiency and requirements. One is a Coxsackie virus, which is implicated in Keshan disease in China. It is a cardiotoxic virus. We can increase the cardiotoxicity of the virus remarkably by giving it to a vitamin E-deficient animal. These are all animal model systems.
The other model is mouse malaria. In that case, the vitamin E deficiency protects against the malaria, because the parasite is more susceptible to the oxidative stress in the host. So you can choose your disease and get your results.
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