ML20237G077
| ML20237G077 | |
| Person / Time | |
|---|---|
| Site: | 07001331 |
| Issue date: | 03/17/1972 |
| From: | Gage A VETERANS ADMIN. MEDICAL CENTER, BUFFALO, NY |
| To: | Malaro J US ATOMIC ENERGY COMMISSION (AEC) |
| Shared Package | |
| ML20236P571 | List: |
| References | |
| 0794, 794, NUDOCS 8708130302 | |
| Download: ML20237G077 (9) | |
Text
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J 3495 DAILEY AVENUE BUFFALO. NEW YORK 14215 l
March J7,1972 YOUR FRE REFERENCE
-1 Mr. James Malaro
. IN REPLY REFE.R TOs
. Assistant Chief, Materials Dranch Divisio,n of Materials Licensing
.j United States Atomic Energy Commission j
Washington, D. C. 20545 lq
Dear Mr. Malaro:
I Enc.osed are the additional data and information, which you requested i
in your letter dated September 30, 1971, in response to the application w e filed with you on September 13, 1971 for authorization to perform clinical q
investigations involving the implantation of a radioisotope powered cardiac i
pacemaker in man.. We regret our late answer but much of these data had I
to be procured from abroad and the delays involved were beyond our control.
A. At the time of this writing, we are informed that 70 radioisotope powered pacemakers of the Medtronic-Laurens-Alcatel type have been j
implanted in patients in Europe. The first ten cases have been treated m France and in West Germany between April 1970 and December of 1971.
j Seven of these ten patients were treated at the Hospital Broussais in Paris I
and a complete transcript of their clinical record has been made available i
to us by Drs. Laurens and Piwnica. These records are enclos ed. The remaining three patients (of the first ten) have been treated at the University.
Surt;ical Clinic in Dusseldorf, West Germany, in December 1971. Detailed
. clinical and follow-up records on these three patients are as yet not available -
but their course has been uneventful and has been summarized by Dr. Laurens l
in a memorandum dated 31 December 1971, a copy of which, labelled "B," is.
attached. Ten patients have been treated within the past two months and their clinical records are not yet available. How ever, we have been informed by Drs. Laurens and Piwnica that their clinical course has also been uneventful.
The records of the first seven patients are obviously of the greatest relevance to this application since a follow-up ranging from six months up to two years is now available. Copies of these records are enclosed and have been labelled Al through A7. Each document covers the operative procedure, l
data on the pulse generator and its performance, electrocardiographic and l
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8708130302 070730 REG 1 LIC70 Page 1.
Include Zip Code in your return address and give veteran's social security number.
Show veteran's full name and VA fle number on all correspondence. If VA number is unknown, show service number.
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Mr. James Malaro March 17,1972 laboratory observations, and pertinent postoperative observations. The last name of the patient and some other data which could lead to personal identification have been deleted at Dr. Laurens' request, merely to protect the confidentiality of the physician gatient relationship.
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'The clinical course of six of the seven patients has been entirely uneventful. In one of the patients (case A3), an " escape interval" of the
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demand pulse generator in excess of one second was observed after each
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spontaneous cardiac depolarization. This long compensatory irterval was I
felt by the patient and he was reoperated upon three months after the initial implantation. One electrode was surrounded by heavy scar tissue and the impedanco measured at that electrode site was unusually high. The electrode was moved to a new position with subsequent normal function of the sensing and demand circuitry of the pulse generator. It was thought that the high impedance of the initial electrode site may have been a contributory factor in the "re-setting" of the pulse generator leading to a long " escape interval. "
A second cause under consideration was a change in the circuitry which had been requested by the investigators and which also involved a slight prolonga-tion of the " escape interval" following a spontaneous depolarization. In s ub-sequent patients, the electronic circuitry was modified to res lt in a shorter
" escape interval" and the phenomenon described above has not been observed again. We wish to emphasize that the sequence of events observed in this patient constitutes a minor complication, easily corrected, and one which has been observed on occasion in patients treated with conventional demand pulse g enerat or s. This problem is well known and bears no relationship to the radioisotope power source of the pulse generator.
W e wish to draw your attention to paragraph 3 (b) in the summary labelled "B" prepared by Dr. Laurens. This paragraph points out that the stimulation frequency of the pulse generator is a function of the power of the l radioisotope source. At the time this paragraph was prepared, a postopera-tive follow -up of 20 and 18 months respectively had been available for the first tw o patients. In the cours e of the follow-up period, a change in the stimulation rate was observed of 0.2 and 0.12 beats per minute respectively.
This change conformed with the calculated expectations and supports an anticipated service life of the puls e generator in excess of ten years, f
B.
The experimental studies conducted in animals are described by Dr. Laurens in the memorandum labelled "C" and dated February,1971.
The objective of the studies was a verification of the long-term effect of
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radiation and heating of tissues in contact with the pulse generator. Two i
dogs, a female and a male, were operated upon in June, 1969 and implanta-tion was performed of a scaled power source containing 238 Plutonium and
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Mr. James Malaro March 17,1972 e ) n' Bismuth Telluride thermocouple. The operations w ere performed at the f j
Veterinary School at Maisons-Alfort.
The power source was shielded by a double layer of tantalum and platinum and contained 144.2 mg and 147.5 mg of Plutonium respectively.
The power sources were encased in an outer shield of stainless stec1 which, in turn, was covered by silastic. The power sources were placed into the abdominal wall, 2 cms deep to the level of the skin. The radiation on the surface of the power source was measured at 3. 5 mrem /hr (gamma: 2 mrem /
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h, neutrons 1. 5 mrem /hr). These power sources generated 75 thermal milli-I watts and the temperature measured in the tissues immediately adjacent to the power source was less than 0.1 degrees Centigrade above that measured in neighbo' ring tis sues.
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A pulse generator powered by mercury cells but containing the same electronic circuitry as the isotopic pacemaker was implanted in a dog in
_Januag,1970 for the purpose of verifying the function and performance of
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the circuitry. This procedure was performed at the Hospital Broussais and the animal is still in good health.
A second animal received a complete radioisotopic pacemaker system
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with myocardiac electrodes early in April,1970. The pulse generator was placed into the soft tissues of the neck. Two months after the operation, a wound dehiscence occurred and the site of implantation of the pulse generator became infected and the pacemaker was removed. The animal is in good health and the pulse generator is under observation and continues to function normally.
Of the two dogs operated upon in June, 1969, the female remains in good health after a follow-up of two years and eight months. Tite male dog f
was in apparently good health until September,1971 at which time edema of the hindlegs developed. An x-ray of the chest demonstrated s everal opacities in the right and left lungs and the animal was sacrificed in October, 1971. An autopsy was performed by Dr. A-L Parodi, Associate Professor at the Laboratory of Pathology at the National Veterarian School at Alfort. A copy of the original reports on the gross and microscopic findings are enclosed and are labelled "C" and "D".
The pertinent findings w ere limited to the pocket containing the puls e generator and the lungs. The pocket containing the pulse generator was situated in the left subcostal area between the rectus and the external oblique mus c les. The walls of this pocket w ere thin and soft and the lining of the pocket was smooth and free of any vascular reaction. There were two nodules
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Mr. James Malaro March 17,1972 in the apical lobe of the right lung; the cardiac lobe of the right lung was completely replaced by a tumor mass as was the azygos lobe. Thes e pulmonary lesions were firm consisting of whitish homogeneous tissue with the exception of the center of the mass in the azygos lobe which showed some degeneration. The trachco-bronchial lymph nodes were somewhat hypertr ophied. There was pas sive congestion of the liver. All other organs w ere normal. Tissue specimens for microscopic examination were obtained from the tumor masses in the lung, the tracheo-bronchiallymph nodes, liver, pancreas, esophagus, stomach, from several levels of small and large intes-tines, the spleen, sternum, heart, kidneys, adrenals and the left testicle.
- Specimens were procured from the skin and from the wall making up the pocket which contained the pulse generator. Additional specimens were taken from the soft and bony structures of the extremities and the spinal cord.
On microscopic examination, the important positive findings w ere as -
follows: the tumor mass in the lung was found to be a glandular epithelioma of the alveolar type invading and compressing surrounding pulmonary paren-chyma. In the azygos lobe, the tumor was also bronchiolar at the periphery of the mas s but in the center there was epidermoid metaplasia. The tracheo-bronchial lymph nodes show ed lymphoid hyperplasia but there was no evidence of metastases from the pulmonary growth. The skin overlying the pocket, site of the pulse generator, was normal and the pocket its elf consisted of a thin envelope of conjunctive tissue formed by thin and dense collagen fibers.
In one of the adrenal glands, a small adenoma was found, a not unusual occurrence in a dog of that age.
The microscopic slides (unstained), procured from the tumor found in the lung and the tissue of the wall of the puls e generator pocket, w ere made available to us by Dr. Laurens. They were stained in the laboratory of this hospital and were examined by ourselves and one of the pathologists at this institution, Dr. Franco Legnami. Photomicrographs of relevant sections were made and are enclos ed labelled "E1" through "E6. " Colored photo-graphs of the tumor mass in the azygos lobe, of the whole right lung and the right hemithorax were made available to us by Dr. Laurens and are enclosed labelled "E7 (A-B-C)" in that order.
Two o ections obtained from one of the nodules in the right lung (E2 thz ough E4) were examined by Dr. Legnami who described " irregular acini i
having also some intraluminal papillary projections lined by a single row of l
tall columnar cells, having an eosinophilic and occasionally vacuolated cyto-plasma with a round to oval shaped vesicular nucleus, exhibiting one or more prominent nucleoli. Few mitotic figures are present. Many areas of this l
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Mr. James Malaro March 17,1972
" epithelium resemble closely that of the bronchiolus. In s ome of the spaces,
mucous was pres ent. The tumor was sharply s eparated from surrounding and compressed normal pulmonary parenchyma. " In another section (E1),
"the tumor is a w ell differentiated epidermoid carcinoma which is forming large amounts of keratin and keratin pearls. The tumor in this area show s areas of focal necrosis and is infiltrated by acute inflammatory cells. At the periphery of this section (E5), the two types of tumor are closely adjacent and colliding without evidence of transition. "
The section procured from the pulse generator pocket (E6) shows only " minimal fibrotic thickening and the lining of the pocket shows no atypical findings. " Dr. Legnami felt there was no causal relationship between the presence of the radioisotope powered pulse generator and the presence of the pulmonary carcinoma. The conclusion was reached because of the tissue type of the tumor and also because of the lack of abnormality in the tissues surround-ing the isotopic unit.
We have reviewed the slides and the findings of the pathologist and concur with the conclus ion that the development of carcinoma in this animal was purely coincidental.
The appearance of neoplasia in irradiated skin is, of course, well known and typically appears after many years following massive exposure. The appear-ance of neoplasia in an internal organ is an extreme rarity. The applicant has no special expertire in this field but had the opportunity of observing a relevant case which formed the subject of a publication by Dr. Ols on, Dr. Chardack and the applicant. A reprint of this case report is enclosed because of the characteristic sequence of events in the case and because the report contains several references to the subject. The total radiation dose which the patient had received was 11,637 rads. and a carcinoma developed in the stomach 16 years following treatment, beginning with ulceration of the skin. In contrast, in the anirral the duration of exposure totalled 27 months, The tis sues immediately adjacent to the pulse generator received a dose of 70 ri'As. The dose received by the lungs, at a distance judged to be at least 20 cms from the pulse generator, was minute since it roughly decreases by an order of magnitude t.s the distance betw een the source and the tissue increases by approximat ely 2. 5 cms. The pulse generator retrieved from the animal functioned normally and has continued to do so and radiation levels conformed to specifications. The mature and differentiated appearance of the tumor is inconsistent with neoplasia caused by radiation and no evidence of metaplasia or neoplasia was found in the soft tissues and the skin in close anatomic relationship with the pulse generator.
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Mr. James Malaro March 17,1972 The developn 2nt of neoplasia as an irradiation hazard has been the 3
subject of many investigations. A copy of a recent study by Huffman is enclosed because it deals with the 1cvels of heat and irradiation produced by totally implanted radioisotope pow ered circulatory as sist. The levels of radiation are over two orders of magnitude higher than those associated with nuclear powered pacemakers and the authors reached the conclusion that even these levels would not present a limiting factor in the application of such devices to human beings.
Even though the evidence in this case clearly indicates that the tumor found in this dog is purely coincidental, the French investigators have requested that these findings be held confidential. Their concern is that public knowledge of these findings based on limited documentation and possibly out of context could become an unjustified source of worry and anxiety on the part of the involved patients. Their observations are now in the process of being published and they have requested that these data re-main confidential and that disclosure be limited to members of the medical profession until their fully dccumen,ted repg;1_ app. carp,jn_prjnt. The findings in the experimental dog have been made available not only to the applicant but to all other physicians and surgeons who have or are proposing to use the l
radioisotope powered pulse generator in other countries. We agree that it is l
important that these findings be appraised on the basis of full documentation.
l In addition to the clinical and animal experience, laboratory observa-tions are also available on a total of 173 radioisotope power sources of the type used for the Medtronic-Alcatel-Laurens implantable pacemaker system.
Two hundred and seventy-six thousand, two hundred and ten (276,210) hours of continual function had been accumulated on November 15, 1971, the equiva-lent of 31. 5 years. No diminution of output has been observed, with some units under observation for three years.
C.
You have requested a description of Dr. Chardack's medical specialty, clinical radioisotope training and research experience. Dr.
Chardack's medical specialties are General and Thoracic Surgery and he has been certified in thes e ficids by the American Board of General Surgery and the American Board of Thoracic Surgery. He has been on the faculty of the State University of New York at Zuffalo School of Medicine since 1952 and holds the rank of Ass ociate Professor of Surgery. Dr. Chardack has not had any clinical radioisotope training. His experience with radioisotope materials is limited to the indications for use and the interpretation of results in clinical medicine.
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Mr. James Malaro March 17,1972 Dr. Chardack's research experience began with his appointment to the Surgical Service of this hospital. He became Assistant Chief of Surgery in 1952 and Chief of the Surgical Service in 1954. He held that position until the applicant succeeded him in this position in 1968. He established the Surgical Research Laboratory at this hospital in 1952 and his investigative work and publications over the ensuing two decades have covered a variety of topics in General and Thoracic Surgery in addition to the field of cardiac pacemakers.
Since this application has been filed, Dr. Chardack has been in poor health and he has been advised to strictly limit his professional activities and commit-ment s. He has indicated that his health will require a t least a prolonged 1 cave of absence and at the time of this writing it is not anticipated that he will remain associated with this project of a long-term nature. How ev er, it is not expected that this will affect the project since the applicant has been associated with Dr. Chardack throughout his entire research activitics. A bibliography covering both Dr. Chardack's and the applicant's experience in the field of cardiac pacemakers is enclosed. Furthermore, coverage in depth of the project is in no way compromised since other original investigators associated with tne development of cardiac pacemakers at this institution still remain active on the staff.
D.
In regard to our request to withhold from public disclosure certain information contained in our original application, we wish to state that this was done at the request of Medtronic, Inc. and Society Alcatel. The request originated with Medtronic, Inc. and as far as w e know is bas ed upon contractual obligations on their part to Society Alcatel. W e will ask Medtronic, Inc. to submit to you a detaned explanation of this request.
E. Since the filing of our initial application, a number of suitable cases have come to our attention. Some of these are patients of our own who are particularly suitable candidates because of their young age. Replacement of a conventional pulse generator has been deferred f5iiding decision on this
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application.
Yours sincerely, uk Ah Andr ew A. Gage, M. D.
Chief, Surgical Service I,C Chief of Staff Associate Professor of Sdrgery State University of NY at Buffalo School of Medicine Encl.
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Bibliography _
l 1.
Chardack, W.M., Gage, A. A. and Greatbatch, W. : A transistorized, scif-contained, implantable pacemaker for the long-term correction of complete heart block. Surgery 48: 643-654, 1960.
2.
Greatbatch, W., Chardack, W.M. and Gage, A. A. : A transistorized, implantable cardiac pacemaker.
1960 IRE International Convention Recor<1, Part 9: 107-115, 1960.
3.
Chardack, W.M., Gage, A. A. and Greatbatch, W. : Correction of complete heart block by a self-contained and subcutaneous 1y implanted pacemaker.
J Thor & Cardiovasc Surg 42: 814-830, 1961.
4.
Chardack, W.M., Gage, A. A., Schimert, G., Thomson, N. B. and Greatbatch, W. : The long-term treatment of complete heart block with an implantable pacemaker. Transactions of the IV World Congress of Cardiology, Sobretiro de Memorias del iv Congreso, Mundial de Cardiologic,
. TOMO III: Pages 2-12, Octubre de 1962. (Mexico City, Mexico) 5.
Chardack, W.M., Gage, A. A. and Greatbatch, W. : Treatment of complete
' heart block with an implantable and self-contained pacemaker. Bulletin de la Societe International de Chirurgie 21: 411, 1962.
6.
Chardack, W.M., Gage. A. A. and Greatbatch, W. : Experimental observa-tions and clinical experiences with the correction of complete heart block by an implantabic, self-contained pacemaker. Transactions of the Anurican Society for Artificial Internal Organs III: 286-294, 1961.
7.
Chardack, W.M., Gage, A. A., Schimert, G., Thomson, N.B., Sanford, C. E.
and Greatbatch, W. : Two years' clinical experience with the implantable pacemaker for complete heart block. Diseases of the Chest 43: 225-239, 1963.
8.
Greatbatch, W. and Chardack, W.M. : Myocardial and endocardiac electrodes for chronic implantation.
/ 9 Chardack, W. M. : Heart block treated with an implantable pacemaker - past experience and current developments. Progr. Cardiov. Dis. 6: 507-537, May 1964.
10.
Chardack, W. M. : A myocardial electrode for long-term pacemaking.
Ann NY Acad Sci Ill: 89 3-906, June 11,1964.
v' 11.
Chardack, W.M., Gage, A. A. and Federico, A. J. : Clinical experience with an implantable pacemaker. Ann NY Acad Sci 111: 1075-1092, June 11,1964.
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Bibliography ___
- 12. Chardack, W.M., Gage, A. A. and Dean, D.C. : Slowing of the heart by paired pulse stimulation. Amer J Cardiol 14: 374-384, Sep 1964.
- 13. Chardack, W.M., Gage, A. A. and Dean, D.C. : Paired and coupled electrical stimulation of the heart. Bull NY Acad Med 41: 462-480, May 1965.
- 14. Chardack, W.M., Gage, A. A., Federico, A. J., Schimert, G. and Greatbatch, W. : Five years' clinical experience with an implantable pacemaker - an appraisal. Surgery 58: 915-922, Nov 1965
/ 15. Chardack, W.M., Gage, M. D. (A. A. ), Federico, A. J., Schimert, G.,
Greatbatch, W. : The long-term treatment of heart block. Progr Cardiov Dis 9: 105-135, Sep 1966.
- 16. Chardack, W. M. : The after-care of patients with implanted cardiac pac emaker s. (Editorial) Circulation 36: 476-477, October 1967.
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- 17. Greatbatch, W. and Chardack, W.M. : Myocardial and endocardiac elec-
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v' trodes for chronic implantation. Ann NY Acad Sci 148: 234-251, Feb 1968.
- 18. Chardack, W.M., Federico, A. J., Greatbat ch, W., P Laurens, P.
and Piwnica, A.H. : Experience clinique d'un pacemaker implantable j
fonctionnant a la demande. Arch Mal du Coeur 61: 91-97, 1968.
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- 19. Chardack, W.M. : The current status of implantable pacemakers.
j J Electrocardiology 1: 135-140, 1968.
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- 20. Chardack, U. M., Ishikawa, H., Fochler, F. J., Souther, S. and Gage, A. A. : j Pacing and ventricular fibrillation. Ann NY Acad Sci 167: 919-933, Oct 1969
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/ 21. Chardack, W.M., Bakken, E. E., Bolduc, L., Giori, F. A. and Gage, A. A. :
3 Magnetically actuated pulse width control for implantable pacemakers -
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its significance for the follow-up of patients and the reduction of current drain. Ann. Cardiol Angeiol 20: 345-355, 1971.
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