12

evidence of axonal degeneration. In the 3 years after biopsy there has been no evidence of motor-nerve involvement in this patient. All ten patients with neuropathy in this series had either serum-M-components or Bence-Jones proteinuria and were classified clinically as having either primary amyloid or amyloid associated with maligOf the eighty-seven nant B-cell dyscrasia (table II). patients with systemic amyloidosis, thirty-one had serum or urinary M components. Ten of these thirtyone had neuropathy. However, none of the fiftyTABLE II-AMYLOID NEUROPATHY AND

found to be associated with malities.

immunoglobulin

abnor-

These investigations were supported by grants from the United States Public Health Service, National Institute of Arthritis and Metabolic Diseases (AM-04599 and TI-AM5285), the General Clinical Research Centers Branch of the Division of Research Resources, National Institutes of Health (RR-533), the Massachusetts Chapter of the Arthritis Foundation, the Arthritis Foundation, and the John A. Hartford Foundation.

Requests for reprints should be addressed to M. D. B., University Hospital, New Evans Building, 75 East Newton Street, Boston, Massachusetts 02118, U.S.A.

M COMPONENTS REFERENCES

Koenigstein, H. Arch. Derm. Syph. 1925, 149, 330. DeNavasquez, S., Treble, H. A. Brain, 1938, 61, 116. Kernohan, J. W., Woltman, H. W. Archs Neurol. Psychiat. 1942, 47,

1. 2. 3.

132.

4. Davies-Jones, G. A. B., Esiri, M. M. Br. med. J. 1971, ii, 444. 5. Goldberg, A., Brodsky, I., McCarty, D. Am. J. Med. 1964, 37, 653. 6. Dayan, A. D., Urich, H., Gardner-Thorpe, C. J. neurosurg. Sci.

1971, 14, 21. Cohen, A. S. in Metabolic Basis of Inherited Diseases (edited by J. Stanbury, J. Wyngaarden, and D. Fredrikson); p. 1273. New York, 1972. 8. Brandt, K. D., Cohen, A. S., Cathcart, E. S. Am. J. Med. 1968, 44,

7.

patients without serum or urinary components had neuropathy. Although it has been noted previously that neuropathy is associated with amyloid having a primary " pattern of involvement, this striking correlation between dysproteinaemia and amyloid neuropathy has not been appreciated in the past. The strong correlation between neuropathy and dysproteinæmia in amyloidosis is important, since the interval between onset of neurological symptoms and diagnosis of amyloidosis in our patients ranged from 6 months to 4 years (mean 1-5 years). The diagnosis of amyloidosis was established by nerve biopsy in only one patient and by appropriate histological studies of a flexor-retinaculum biopsy in one other patient. In the other eight cases definite diagnosis was delayed until other features of systemic amyloidosis (e.g., nephrotic syndrome, macroglossia, hepatomegaly) led to appropriate studies. These findings are comparable with those reported by others 5,6,10,11 and emphasise the importance of appropriate histological examinations on all biopsy specimens from patients with neuropathy, especially the carpal-tunnel syndrome. six

"

for the strong correlation between amyloid neuropathy and dysproteinaemia are not clear. In multiple myeloma, neuropathy may also occur without deposition of amyloid and presumably has a different pathogenesis.12.13 Several amyloid proteins of primary type have been shown to contain monoclonal immunoglobulin light chain 14 and, therefore, the protein deposited in amyloid neuropathy is probably of immunoglobulin origin. Thus far there is no apparent correlation between type of light chain (lambda vs. kappa) and neuropathy. The

reasons

In secondary amyloidosis the major protein constituent of amyloid deposits (A protein) is not related to immunoglobulin. Neuropathy has not been reported as a sign of secondary amyloidosis and the present study accords with this observation. Follow-up of the thirty-six patients in the present series with secondary amyloidosis extends to 11 years (mean 3 years) with no evidence of neuropathy, including the carpal-tunnel syndrome. Also the neuropathies seen in the hereditary forms of amyloidosis have not been

955. 9. Cathcart, E. S., Ritchie, R. F., Cohen, A. S., Brandt, K. D. ibid. 1972, 52, 93. 10. Franklin, E. C., Castleman, B. New Engl. J. Med. 1972, 286, 534. 11. Sullivan, J. F., Twitchel, T. E., Gherardi, G. J., Vanderlaan, W. P., Jr. Neurology, 1955, 5, 847. 12. Victor, M., Banker, B. Q., Adams, R. D. J. Neurol. Neurosurg. Psychiat. 1958, 21, 73. 13. Aguayo, A., Thompson, D. W., Humphrey, J. G. ibid. 1964, 27, 562. 14. Glenner, G. G., Terry, W., Harada, M., Iserky, C., Page, D. Science, 1971, 172, 1150.

Preliminary Communication THE DIVING REFLEX USED TO TREAT PAROXYSMAL ATRIAL TACHYCARDIA KERN WILDENTHAL JAMES M. ATKINS

STEPHEN J. LESHIN C. LYNN SKELTON

Departments of Internal Medicine and Physiology, University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texas 75235, U.S.A. Induction of the diving reflex, by immersion of the face in cold water (2°C) while the breath was held, converted paroxysmal atrial tachycardia to sinus rhythm within 15-35 Four had seconds in seven patients (aged 22-66). histories of attacks that had previously required vasopressor therapy, and two had been digitalised; three had no history of prior paroxysmal atrial tachycardia The reported procedure, which is or heart-disease. convenient, non-invasive, and can be self administered by the patient after brief instruction, may offer a useful adjunct to carotid-sinus massage and intravenous infusion of vasopressors for the treatment of paroxysmal atrial tachycardia.

Summary

INTRODUCTION

IN

conventional therapy for paroxysmal atrial tachycardia, efforts are made to increase vagal tone to the heart and thus convert it to normal sinus

13

rhythm. Manual

massage of the carotid sinus carries

with it the small but real danger of inducing ventricular fibrillation/ as well as a tendency to reduce cerebral blood-flow, either by mechanical occlusion or as a consequence of the hypotension that normally accompanies activation of the carotid-sinus reflex. Vasopressors have to be administered by intravenous infusions and also risk complications from acute hypertension. Furthermore, conventional therapy is not always successful in some patients.

In animals breath holding and submersion of the and mouth in water produce a complex cardiovascular reflex resulting in peripheral vasoconstriction (except to the brain), decreased cardiac output and heart-rate, and stable or slightly increased arterial pressures The changes are potentiated by deep inspiration and by cold temperatures. Apnoea, alone, causes similar but much less extreme cardiovascular responses. The changes occur rapidly, and in man, as in many other species, they are initiated before nose

important hypoxaemia or hypercapnia develops. In man apnoeic face immersion usually induces a 15-30% decrease in heart-rate from normal resting values, as compared to more than an 80% decrease in seals and ducks. The diving reflex enables aquatic animals to remain submerged for long periods because it reduces their oxygen requirements. In man the reflex can override other, seemingly more vital, reflexes -i.e., it can completely obliterate the tachycardia that accompanies moderately severe exercise on a bicycle ergometer and abruptly reduce heart-rate from 130140 beats per minute to 80 or less, despite continuation of the exercise.’ This stimulus

is mediated primarily by increasing vagal tone to the heart.2,3 It is one of the few instances in which vagally mediated cardiac to

bradycardia

depressor responses are simultaneously accompanied by peripheral pressor responses and well-maintained blood-pressure, and in theory the diving reflex would seem ideal as a means of converting paroxysmal atrial tachycardia to normal sinus rhythm. We report the results of inducing the diving reflex in seven patients with paroxysmal atrial tachycardia. METHODS AND RESULTS

Patients with definite paroxysmal atrial tachycardia, as established by electrocardiographic (E.C.G.) criteria, who had no evidence of angina pectoris, acute myocardial infarction, or severe distress, and who gave informed consent to the procedure, were studied. The seven patients were aged 22-66; five of them were women, and four of them had a past history of paroxysmal atrial tachycardia (1 previous episode in one, 1-2 per year in one, and more than 20 per year in two). Two were on maintenance digitalis therapy at the time of study, and one had underlying heart-disease-i.e., arteriosclerotic heart-disease with one previous myocardial infarction. Carotid-sinus massage had been tried in three patients and had been successful in one. of the rhythm disturbance by E.C.G. the informed of the principles of the diving reflex and instructed on how to simulate " diving " in the laboratory.4 After resting in an upright, seated position for 1-3 minutes, each subject breathed deeply several times and, while leaning forward and holdAfter

patients

diagnosis were

ing the breath in inspiration, immersed his face in a pan of cold water (2°C) for up to 35 seconds. Throughout the period, the physician spoke calmly to the patient, reminding him to avoid performing a Valsalva manoeuvre and reassuring him about the progress of the test. The patients had been told that they should come up for air at any time they felt the need, but that the success of the test depended on their continuing the test for more than just a few seconds. In practice, as had been noted with normal subjects in our laboratory, none of the patients experienced distress or anxiety on carrying out the test for up to 35 seconds. One discontinued the test after 15 seconds, after mistakenly assuming that the paroxysmal atrial tachycardia had been converted to sinus rhythm. 3 minutes later she was retested, and this time her rhythm became normal after 25 seconds. A second patient, a 22-year-old woman who had had numerous bouts of paroxysmal atrial tachycardia during prolonged hospital stay, did not respond during her first trial of 35 seconds, but was converted to normal rhythm during her second trial a few minutes later. Carotid-sinus massage and vasopressors had rarely been effective in aborting this patient’s attacks, and electrical cardioversion had been required on three occasions before the diving reflex was used. On one subsequent occasion, after repeated trials of carotid-sinus massage had been unsuccessful, the combination of diving plus massage converted her rhythm promptly. In response to their initial trial of apnoeic face immersion all other patients were converted from paroxysmal atrial tachycardia to normal sinus rhythm within 15-35 seconds, and no complications were encountered. One of the patients was a 56-year-old woman who often had episodes of paroxysmal atrial tachycardia despite digitalis therapy. Her attacks often responded to carotid-sinus massage at home, but occasionally she required admission to hospital for administration of vasopressors. She was instructed in the use of the diving reflex and has been successful in stopping attacks at home which would otherwise have required hospital treatment.

DISCUSSION

Our early results using the diving reflex to treat paroxysmal atrial tachycardia are most encouraging. The procedure is quick, simple, and inexpensive, and was effective in all seven patients, even those who were

resistant

to

carotid-sinus massage.

Almost

certainly, extensive experience will disclose many patients who do not respond; but for some it promises a useful adjunct to conventional therapy for the conversion of paroxysmal atrial tachycardia to normal sinus rhythm. It does not, of course, provide protection against future episodes of paroxysmal atrial tachycardia nor should it supplant conventional prophylactic therapy. We encountered no complications in our first seven patients (nor in dozens of normal subjects), but, although the diving reflex is generally not associated with the excessive hypertension or hypotension that may beset vasopressor therapy or carotid-sinus massage, the response to the reflex

can

be rather

variable in different subjects, and prolonged periods of asystole are occasionally precipitated in some. In one normal subject we observed sinus arrest for 4-5 seconds before resumption of a regular bradycardia during diving, and others have described nodal and ventricular escape beats during apnaeic manoeuvres of various types: It seems prudent to avoid using

14 the diving reflex in patients with a history of multifocal premature ventricular contractions, a recent myocardial infarction, or other evidence to suggest susceptibility to ventricular tachycardia or fibrillation. Defibrillation machines and resuscitation equipment may be indicated for at least the first trial of diving therapy in any given patient. Similarly, instruction in the self-administration of the diving reflex by the patient at home should be reserved for those subjects who have consistently displayed benign responses to diving under medical supervision both during paroxysmal atrial tachycardia and during normal rhythm. Also, even though the diving reflex is initiated well before the development of important blood-gas changes in normal subjects, it seems advisable to avoid the procedure in patients with hypoxaemia or acidosis and to limit the duration of the test to approximately 30. seconds, even in patients with normal blood-gas concentrations. In normal subjects heart-rate has already fallen to a nadir 20-30 seconds after induction of the reflex, and there seems little benefit in prolonging the test unduly; however, as was the case in two of our patients, a repeat test after an interval of a few minutes may be worthwhile if the initial test is un-

productive. Finally, Wolf

et al.6 observed that distraction or harassment could obliterate the normal bradycardia response in healthy subjects, whereas anxiety or fear could facilitate the response. They also noted that habituation to the procedure could lead to a situation in which the mere suggestion that diving was about to be performed could precipitate the full complex of normal responses to the event itself. However, Asmussen and Kristiansson’ have described a tendency in some subjects for the magnitude of the vagal response to diving to be blunted after repeated performance of the procedure. We have not observed such effects in normal subjects or patients, but if they are widespread it is possible that excessive use of the procedure could render the diving reflex less useful in some subjects, or that extreme anxiety might theoretically make it hazardous.8 Nevertheless, the ease of administration, general safety, and efficacy of the procedure in many subjects suggest that the diving reflex is a valuable addition to the therapy of paroxysmal atrial tachycardia under properly controlled circumstances.

This research was supported by the Moss Heart Fund and the National Institutes of Health.

Requests for reprints should be addressed to K. W., Departof Internal Medicine, University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235, U.S.A.

ment

REFERENCES

Cohen, M. V. Am. Heart J. 1972, 84, 681. Andersen, H. T. Physiol. Rev. 1966, 46, 212. 3. Strauss, M. B. Aerospace Med. 1970, 41, 1362. 4. Bergman, S. A., Jr., Campbell, J. K., Wildenthal, K. J. Appl. Physiol. 1972, 33, 27. 5. Lamb, L. E., Dermksian, G., Sarnoff, C. A. Am. J. Cardiol. 1958, 2, 563. 6. Wolf, S., Schneider, R. A., Groover, M. E. Trans. Ass. Am. Phyns, 1965, 78, 242. 7. Asmussen, E., Kristiansson, N.-G. Acta physiol. scand. 1968, 73, 1.

2.

527.

8.

Wolf, S. Am. Heart J. 1966, 71, 840.

Hypothesis THE ESSENTIAL ROLE OF GLUCAGON IN THE PATHOGENESIS OF DIABETES MELLITUS ROGER H. UNGER Veterans Administration Hospital, and University of Texas Southwestern Medical School, Department of Medicine, Dallas, Texas, U.S.A. LELIO ORCI Institute of

Histology

and

Embryology,

Geneva, Switzerland The following evidence suggests that diabetes mellitus may not be the simple relative or absolute insulin deficiency of consequence by itself, but may require the presence of glucagon: (1) relative or absolute hyperglucagonæmia has been identified in every form of endogenous hyperglycæmia, including total pancreatectomy in dogs; (2) insulin lack in the absence of glucagon does not cause endogenous hyperglycæmia, but when endogenous or exogenous glucagon is present, it quickly appears, irrespective of insulin levels at the time. These facts are compatible with a bihormonal-abnormality hypothesis, which holds that the major consequence of absolute or relative insulin lack is glucose underutilisation and that absolute or relative glucagon excess is the principal factor in the over-production of glucose in diabetes.

Sum ary

THEORY

unihormonal-deficiency hypothesis of diabetes mellitus, in which all of the metabolic derangements The

of the disease are attributed to absolute or relative insulin lack, originated with the classic experiments of von Mering and Minkowski in 18891 and was reinforced by those of Banting and Best in 1922.2 However, developments in glucagon research raise the possibility that diabetic abnormalities in glucose homoeostasis are the consequence of a bihormonal disorder in which a relative or absolute deficiency of insulin and a relative or absolute excess of glucagon are both astiological factors. According to this hypothesis, relative hyposecretion of insulin would account primarily for under-utilisation of glucose, while relative hypersecretion of glucagon would be the major factor in the over-production of glucose at a rate which exceeded its utilisation, resulting in endogenous

hyperglycasmia. EVIDENCE

Three lines of evidence now implicate glucagon as an essential co-factor in the development of endogenous hyperglycwmia. First, endogenous hyperglycaemia has never been observed in the absence of glucagon. Every form of diabetic and non-diabetic hyperglycaemia so far investigated, including spontaneous diabetes in man 3-7 and in Chinese hamsters 8; alloxan diabetes in dogs9 and in rats 10; streptozotocin diabetes in rats U.1.2; diazoxide 9,13 and mannoheptulose induced diabetes in dogs 9; anti-insulin serum diabetes in rats 9; and the stress hyperglycaemia observed in acute trauma, burns,15 myocardial infarc-

The diving reflex used to treat paroxysmal atrial tachycardia.

12 evidence of axonal degeneration. In the 3 years after biopsy there has been no evidence of motor-nerve involvement in this patient. All ten patien...
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