The following excerpts are from the E-mail discussion of the committee on chronic mountain sickness, prior to The 3rd World Congress on Mountain Medicine and High Altitude Physiology and The 18th Japanese Symposium on Mountain Medicine carried out in Matsumoto, Japan (May 20th – 24th, 1998). This is part 2/2
Respiratory studies in the Hyperoxic/Hypoxic Adaptation Chamber
Date: 31 Mar 1998 08:23:27 U From: “John Reeves” Subject: Re: CMS discussion To: “Gustavo Zubieta” Cc: “Ingrid Asmus” , “Linda Curran” , “Dr. Gerilli” , “GUSTAVO ZUBIETA, M.D. * IPPA *” , “Toshio Kobayashi” , “Fabiola Leon-Velarde” <firstname.lastname@example.org>, “Shigeru Masuyama” , “Prof. Mirrakhimov” , “Carlos Monge” , “Hideki Ohno” , “Lorna G. Moore”3/31/98 8:20 AM
Thank you so much for the thoughtful remarks. They are extremely useful for the purposeof initiating discussion. As a bystander who does not see CMS patients, but who is interested in consensus, I do see differences of opinion that could and should be laid out on the table for friendly discussion, where everyone benefits. Getting these diverse opinions in ahead of the meeting should make people aware of the differences, and allow them to think about the problems. I hope you agree. Final answers may not come from the meeting, but the process of discussion will have been initiated. I am trying to keep Wu informed by fax of these discussions, but am not sure the faxes are getting through. I have taken the liberty of sending your thoughtful comments around, as I believe they deserve wide distribution. I hope that is O.K.
Date: 3/30/98 4:05 PM To: John Reeves From: GUSTAVO ZUBIETA, M.D. * IPPA *
Here goes the homework requested by you, Lorna Moore and her colleagues. We feel troubled by the subject of scoring CMS. As you can read from our publications, we are confident that there is no “loss of adaptation of life at altitude”, but rather an adaptation of pulmonary, cardiac, renal or other disease to the hypoxia at high altitude. (And to tell you the truth, CMS patients do remarkably well, provided their basic disease is treated or looked after).
In general, patients with CMS are examined while attending a regular consultation. Most often, after suffering the disease during many years and only when they and their family become aware of the change in the color of the skin, particularly in the face. Also, when the consultation is for another kind of disease and the routine laboratory tests report increased polycythemia. At this time, the signs and symptoms can be present in different degrees and are prominent or more evident in THS. The score will only be valid for some patients with CMS and exclude others.
Gastrointestinal ulcers, are frequent findings. Gastro-intestinal bleeding, will change the score. The same happens with Gout. Several patients with CMS have increased uric acid, and some with evident signs of Gout by deposits in the ear helix. Gout can lead to well known pulmonary alterations. Similarly, hypertension is also present in some of them. This generally implies kidney disease. Finger clubbing is present in some, even when they are very young.
In broncho-pulmonary lesions of smokers, for example, there can be severe cyanosis, low saturation, increased polycythemia and pulmonary hypertension. If they stop smoking there is significant improvement. This is the same as at sea level, but in chronic hypoxia they reach lower saturation. Another example are some patients with asthma. This shows that CMS patients have a different etiopathogenesis. If all these examples are not included, are they going to be considered a different kind of disease? It does not seem so.
At altitude, “cyanotic pulmonary diseases and asymptomatic high altitude polycythemia” (as defined by Hultgren) are, in our experience, CMS, and the later approaches more exactly CMS present at moderate altitude. If you use a score, you have to be aware that it will apply for that moment only and it will most probably change even within the next few days. Also, great differences in scoring will be found, depending on the degree of compromise of lung or cardiac function, the type of disease, and of course the altitude. Why? Because patients that have CMS are subject to viral diseases, bronchitis, colds or even seasonal climate changes (we have a CMS patient with allergies). This we described as triple hypoxia syndrome (THS), an acute condition overimpossed on CMS (please see further down and the article in our Web page below). So, if the score pretends to be used to access the moments’ clinical state of the patient with CMS, that is fine. About scoring CMS: In the score used by Dr. Wu in CMS, the signs are present particularly in AMS and the triple hypoxia syndrome, that we also call “sorojche (AMS) in bed”. With the exception of hyperaemia in conjunctivae and mucosae, which are chronic. The scores 0, 1, 2 and 3 for none, mild, moderate and severe, seem adequate.
We think that everybody agrees that the disorder regresses on descent to sea level, in around one month. Patients who reascend to high altitude, and are exposed again to hypoxia, develop CMS once more. This is a mechanism of adaptation, to supply the necessary oxygen to the tissues. The patients from low lands with chronic pulmonary diseases commonly unnoticed at sea level, develop CMS at altitude. Are we going to consider these cases as a loss of adaptation?. Certainly not, it is hard to think in such a way. We agree that the most appropriate approach to score the disease, are the laboratory findings: hemoglobin or hematocrit and oxygen saturation, with or without carbon dioxide retention, depending of the severity of the case. For over 15 years now, we have been using a classification by number of red blood cells (“El mal de montaña crónico y los mineros”, published in the magazine of the Academia Nacional de Ciencias de Bolivia,1985;4:109-116), and it has proved to be a good guide in our medical practice. Originally, diagnosis was based on clinical examination, chest x- rays film and hemogram only, due to the lack of equipment. It is as follows: moderate 6.5 to 7.5 million RBC/mm3 severe 7.5 to 8.5 million RBC/mm3 grave > 8.5 million RBC/mm3 For 3600 m. of altitude only. We feel now that it would have been better to name them as mild, moderate and severe and to use the hematocrit or hemoglobin, which amount to the same thing.
———————- With respect to your 7th question, (a very good one, indeed); yes, there is an altitude at which everyone gets CMS. Please see the abstract “Pulmonary disease, CMS and gender differences at high altitude” that we plan to present as a poster. When the respiratory frequency and ventilatory capacity are unable to compensate the extreme hypoxia, the last resort for the human being is to develop severe pulmonary hypertension (right heart hypertrophy) and increase the number of the red cells. All permanent residents will be sick with CMS at 5500 m, for example at the mine of Chorolque located at 5562 m. Since not everyone has equal capacity of adaptation, the CMS will be more severe in some than in others, and still they will survive. Of course, in miserable conditions. In terms of genetic predisposition, CMS is most probable for some individuals, over 40 years old, who have a tendency to gain weight, but this is due to the predisposition to get sick from respiratory disorders. Also, about impairment of intelligence in these patients, and intelligence itself in chronic hypoxia, we drop the subject for the moment. It is important to mention that chest X-rays films as a test of diagnosis of CMS is mandatory, (and now CAT scan or NMR) as is the clinical history of pulmonary diseases, and the pulmonary function tests.
In summary, to answer the first question about Chronic Mountain Sickness, “What is it?”. We feel that the most simple description of CMS, is going to be the most adequate for the moment. In that respect we are closer to John Weil’s definition.
Our definition is: “CMS or Monge’s disease is found in residents at high altitude with some abnormal pulmonary function (increased shunt, impaired diffusion, uneven ventilation and/or hypoventilation), sequelae of diseases of diverse etiopathogenesis. These lead to a sustained (and variable) low oxygen saturation and cyanosis, giving rise to pulmonary hypertension and increased polycythemia as compensatory mechanisms of adaptation to the disease under chronic hypoxic conditions. The symptoms and signs are reversible by descent to sea level or by increasing the PIO2.”
Both of us (Gustavo Sr. and Jr.) discuss this subject profoundly and we only write down the subjects in which we are in full agreement. We are expectant of the discussion on the scoring system.
Gustavo Sr and Gustavo Jr.
Received: from Pmail on IPPA_0 by PegWaf v0.24 93.03.15 id 3382 ; Mon, 30 Mar 98 18:10:51 To: “John Reeves” From: ZUBIETA@oxygen.bo (GUSTAVO ZUBIETA, M.D. * IPPA *) Date: 30 Mar 98 18:10:51 Subject: CMS discussion Priority: normal X-mailer: Pegasus Mail v2.3 (R5). ————————————————————- Date: 10 Apr 1998 16:47:23 +0100 From: “John Reeves” Subject: FWD>Comments, please To: “Inder Anand” , “Ingrid Asmus” , “Peter Bartsch” , “Buddha Basnyat”
, “Linda Curran” , “Marlowe Eldridge” , “Bob Grover” , “Peter Hackett” <email@example.com>, “Toshio Kobayashi” , “Fabiola Leon-Velarde” <firstname.lastname@example.org>, “Shigeru Masuyama” , “Professor Mirrakhimov” , “Carlos Monge” , “Susan Niermeyer” , “Hideki Ohno” , “Akio Sakai” , “Tatiana Serebrovskaya” , “Peter Wagner” , “Gustavo Zubieta” , “Lorna G. Moore” Mail*Link(r) SMTP FWD>Comments, please
Very interesting and important comments from the Zubieta’s. Dr. Leon-Velarde and myself, the Zubieta’s and others would like to hear some comments on these points.
Date: 4/10/98 8:59 AM From: GUSTAVO ZUBIETA, M.D. * IPPA *
We completely agree with you, that we should be aware of the differences in opinions and also of the similarity in the approach to clarify some aspects in CMS. The paramount point of this forthcoming congress, I am sure (Gustavo Sr.), is that the assistants, while enjoying the friendship, try to find out some clues that will benefit thousands of people, who live, get sick and are treated at high altitude, all around the world. We are sure that everything you are doing is OK and please feel free and confident to make us notice any illogical digression of our part. Regarding the difficulty in making sure lungs are normal in CMS, because severe polycythemia itself alters gas exchange, Dr. West points out: “I would like to add a small point. Jack Reeves stated that ‘severe polycythemia itself alters [pulmonary] gas exchange’. I do not think this issue is settled. We induced severe normovolemic polycythemia in dogs (hematocrits up to 76%) and found no broadening of the distribution of ventilation perfusion ratios (J. Appl Physiol. 65:1686-1692, 1988). In the introduction to that article we reviewed the published studies on whether polycythemia impairs pulmonary gas exchange and no clear message emerged.” These interesting remarks, show us that many people think that polycythemia (of unknown etiopathogenesis), affects pulmonary function in CMS. According to Dr. West’s research, this would not be so.
Gustavo Sr, believes that those experiments resemble more what would happen in polycythemia Vera (Vaquez-Osler disease), where, according to the scarce bibliography, he has, there are no cardio-pulmonary alterations. If these experiments were repeated at high altitude, probably the results would be the same: No broadening of the distribution of ventilation-perfusion ratios. Some authors found that in polycythemia Vera, the pulmonary diffusing capacity was greater than in normals, attributed to increased hemoglobin concentrations (Journal of Clinical Investigation, Vol 4, NO. 7, 1963).
Polycythemia increases the total surface of red blood cells exposed to oxygen, which is another advantage. In Monge Medrano’s original paper, he thought that he found polycythemia Vera of high altitude (1928). Then he realized that it was not exactly the same so he changed his point of view to “loss of adaptation” and CMS (1937 & 1943).
The clinical description and observation of increased polycythemia was an important contribution to high altitude pathology, made 70 years ago. We look forward to the presentation by Carlos Monge and Fabiola Leon Velarde, our distinguished friends, on the history of how CMS was discovered . If the disease exists at high altitude, with the original description, Gustavo Sr. has not been able to see it in over 40 years of medical practice (and we were always looking for it). As you know there are thousands of people with increased polycythemia, in the Bolivian high plateau (abnormal), that can be easily diagnosed by simple observation in the streets, when there is the experience.
Some of the participants in the CMS discussion affirm that they have found people with CMS but with no anatomical or functional alterations. It seems to us that we are observing a different kind of pathology. By the way, we have neither seen one case of Polycythemia Vera. When one of us was in USA, nobody gave an adequate explanation about this last disease. The only thing I know for sure is that polycythemia vera is accompanied by leucocytosis, increased platelet count and can evolve to a very severe hematological disease.
As we previously pointed out, AFTER PROVING THAT THESE PEOPLE HAVE CARDIO-PULMONARY PATHOLOGY, ARE WE GOING TO EXCLUDE THEM FROM CMS OR MONGE’S DISEASE? For this reason, our point of view is that pulmonary diseases, that leave sequelae, give rise to low saturation and consequently CMS.
Lets suppose that 3 individuals, apparently normal, one 20 years old, and two 40 years old, move from the lower part of the city of La Paz, at 3000 m. They remain 3 months at 3500 m, and 3 months at 4100 m (in the city of El Alto, the highest part). The blood tests will show that the 20 years old and one of the 40 years old have their hemoglobin and hematocrit normal, for each altitude. The other has increased his hemoglobin to around 20 gm%. Can we say that this last one has “lost his adaptation”? and that the other two have adapted?. The last one has developed chronic mountain sickness. Do we call this: “adaptation” or “loss of adaptation” ?. This is not a hypothesis, it is a fact of common observation. Furthermore, if he has “lost his adaptation”, is he unable to live there any longer ?. Here, we are in the most critical point, in health problems. Should this man go to the lowlands, even though he feels well in the intellectual and physical conditions? When he becomes aware that he has CMS, it turns into a big economical and social problem. Of course, he will, from time to time, suffer from colds with headaches, lassitude, sleep disturbance and so on (as any healthy subject with a cold) that will be diagnosed by physicians as the CMS alteration, but in reality it is the triple hypoxia syndrome in CMS, that is transitory and treatable.
Since the participants are unable to go to discuss the cases in the different hospitals, clinics or laboratories, of each country, may we suggest that you ask each participant in the liberal discussion on CMS (if feasible), bring a color photograph of the patient, the clinical history, the laboratory findings, the cardio-pulmonary function tests or any additional data, to the meeting so that we can all see the differences and discuss them, in a friendly way. These results will show us more than a thousand words.
Gustavo Zubieta Sr. & Gustavo Zubieta Jr.
To: “John Reeves” From: ZUBIETA@oxygen.bo (GUSTAVO ZUBIETA, M.D. * IPPA *) Date: 10 Apr 98 10:12:34 Subject: CMS discussion Priority: normal X-mailer: Pegasus Mail v2.3 (R5). ———————————————————– Date: 20 Apr 1998 08:47:15 -0600 From: “Lorna G. Moore” Subject: Re: Lorna’s questions on “adaptation” To: “GUSTAVO ZUBIETA, M.D. * IPPA *” Cc: john.reeves@UCHSC.edu Reply to: RE>Lorna’s questions on “adaptation” Thank you for your interesting reply. If I interpret your remarks correctly, you are asking if the effects of CMS on life expectancy (mortality) are similiar to those of COPD at sea level (or at altitude). That might be an interesting way to get at the seeming confusion over the uniqueness of CMS as a high-altitude condition. Looking forward to seeing you in Japan!
Date: 4/19/98 7:28 PM To: Lorna G. Moore From: GUSTAVO ZUBIETA, M.D. * IPPA *
Dear Lorna: Your fundamental points regarding the term “adaptation”, stimulated and gave an electrifying boost to everyone’s thoughts. Thank you for letting us know the interesting definition of “adaptation” by Theodosious Dobzhansky. We had not heard it previously. First of all, I (Gustavo Sr) am compelled to explain the importance of the term “adaptation”, which concerns me very strongly.
Any term in medicine implies a concept (knowledge) of the diseases which will set the rules for prevention and treatment (CMS in this case). I include in CMS many kinds of pulmonary disease in chronic hypoxia. By associating CMS with the term “loss of adaptation”, attention has been focused only in the increase of the number of red blood cells. This, mislead many studies. With such a concept, many people with pulmonary disorders have been sent to the lowlands in order to reduce their hematocrit and they die very soon. Due to the hot, humid and oxygen rich environment (an optimum medium for bacteria) there is worsening of infectious diseases (tuberculosis, for example). Some remain living their life as anyone in the lowlands in any part of the world, with unnoticed mild respiratory or ventilatory impairment.
Another form of treatment was targeted to decrease the hematocrit, by using radioactive compounds (such as phosphorous) or cytolytic drugs (such as fenilhidrazine). Nowadays, the pharmaceutical market is full of “medicines” announcing that they can “reduce” the number of red blood cells. Phlebotomy has to be revised, in lieu of the advance of knowledge in hypoxia, but we will not deal with this subject in this letter.
In relation to impaired fertility: We don’t know of any specific studies, however it is a common observation that the fastest growing city (over 600,000 inhabitants) in Bolivia happens to be El Alto “the high plateau” (4100 m). There, according to a presentation we will give in Matsumoto, about 52% of the males and 28 % of females that receive medical attention in all diseases, have a hematocrit above 58 %. The people of the city of El Alto, reproduce even in the most disadvantageous conditions of poverty, lack of adequate housing, lack of hygiene and so on.
On the other hand, I (Gustavo Sr.) have studied sick miners of high altitude mining centers in Bolivia, who had increased polycythemia with pulmonary diseases and several of them had over 8 children. Many of the children died, because of bad sanitary, nutritional and infectious conditions in the mines. They only stopped having children when the women reached menopause. Incidentally, it is well known that human fetuses live in hypoxic conditions (and that they are polycythemic! ). That is probably why they don’t die, and can tolerate very long apneas and extreme hypoxia during delivery. At high altitude, it surprises us more.
By the way, breath-holding in CMS is one of our subjects of presentation in Matsumoto. In dealing with hypoxia, environmental factors should never be overlooked. For example, impotence that has to do with fertility, is not a common complaint at high altitude, as it happens in developed countries (paradoxical?) About life expectancy: There are no great differences between disease at sea level and at high altitude, in the course of life. Again, we know of no studies on life expectancy in respiratory disease at high altitude. For example, at sea level, chronic obstructive pulmonary disease (COPD) and emphysema affect 20-30 % of the adult population, with more than 60,000 deaths/year. The predominant age is over 40 and the predominant sex is male. This is strongly similar to our clinical observations here (except the death incidence per year, that is not quantified).
If patients with CMS, have reduced life expectancies, it will probably be due to a reduced life expectancy of chronic lung disease, just as at sea level. Depending on the severity of the cases, naturally. We have followed patients with CMS, for over 14 years, into their 80’s and we have never looked after one, the moment he died. No one has reported, up to date, an autopsy of CMS. Probably, because when the pathological alterations were discovered, they were classified as cardio-pulmonary disease. By the way, malnutrition, cor-pulmonale, hypercapnia and a pulse > 100 are all poor prognostic indicators in COPD at sea level. The same happens at high altitude.
Furthermore, cor-pulmonale in patients with CMS is probably an advanced and untreated consequence of respiratory disease. Increased polycythemia can’t be absent in many cases. At sea level, supplemental oxygen, has been shown to increase survival. This is conflictive for us. It would imply that there is a shorter life expectancy for high altitude residents, but that does not seem to be so. Ever since the use of penicillin, life expectancy has expanded also at high altitude. Previously, many people died of pneumonia in their forties. With better nutrition, improved health care, and more hygiene, we are seeing people, more and more, that live well into their nineties. We are not saying that altitude is the best place to live in, but just that we live here. We are aware of how easy it is to make a mistake or fall into speculation, but what you just read comes from our on-site experience, a lot of hypoxia and its interpretation….
Gustavo Sr. & Gustavo Jr.
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