Letters
Mineral
to the Editor
deficiency
and
atherosclerosis
To the Editor:
1.
In the June, 1978, issue of the JOURNAL Drs. Chipperfield and Chipperfield’ published their interesting findings regarding differences in the mineral contents of normal and atherosclerotic heart muscle. I do not question the factual contents of the paper, but would like to comment on the conclusions the authors draw from them, namely that Western diet may be deficient in some minerals and this deficiency may be a factor in the prevalence of coronary disease. I do not agree that thii conclusion follows from the facts published in the article and, in any case, it is unlikely to be true. Any mineral we need is probably also needed by other animals, possibly also by plants, and is likely to be obtainable from food. No animal species could survive if it had to rely on nutrients which are not obtainable without undue difficulties in its normal habitat. In the course of evolutionary history no animal has ever lived on a more varied and abundant diet than modem man in a prosperous society. The whole world is combed for delicacies for his table, not even mentioning the vitamin supplement, calcium enrichment, iron tablets and whatever else is contained in food additives, drugs, medicines and the like. It is unlikely that there is any substance of which his intake is less than that of the inhabitants of the poorer countries of Asia and Africa. Yet it is he who suffers from atherosclerosis, the disease is virtually unknown in the poorer countries of the world. Another point to note is that atherosclerotic coronary disease was virtually unknown in Europe 300 years ago. Was the substance in question still abundant then and became scarce only in the recent past? This seems the main argument against the assumption that atherosclerosis can be a deficiency disease. There is, however, one item of diet to which special consideration must be given, namely water. The fact that cardiovascular and cerebrovascular mortality rates are lower in hard water than in soft water areas could signify that hard water contains some substance of importance which soft water lacks. In the tropics, where atherosclerosis is virtually non-existent, a large volume of water, in extreme cases 10 liters in a day, can be lost by sweating and has to be replaced by drinking. If the hypothetical substance were obtainable solely from water, the intake of the inhabitants of tropical countries could be much more than ours. The supposition, however, gives rise to a number of difficult questions. Is there no water supply in Europe and North America with an exceptionally high content of this substance? Is there no water supply in Asia and Africa with a particularly low content? The apparent atherogenic properties of soft water have given food to a great deal of thought and various possibilities have been suggested, including one by myself.’ Alternatives to the deficiency hypothesis rest on the fact that soft water is a better solvent of some substances than hard water.
Stephen Seely, B.Sc. 3 Truro Drive Sale, Cheshire, England
American
Heart
REFERENCES
Journal
2.
Chipperfield, B., and Chipperfield, J.R.: Differences in metal content of the heart muscle in death from ischemic heart disease, AM. HEART J. 95:732, 1978. Seely, S.: Surfactants and atherogenesis, Med. Hypotheses 3:259, 1977.
Reply To the Editor: There seems to be more speculation than solid fact in Mr. Seely’s criticism of our paper. The possibility of a deficiency in mineral salts in the diet contributing to the development of ischemic heart disease has been suggested independently in a dietary investigation published since our paper was submitted. Morris, Marr, and Clayton’ found that normal men with a high calorie intake had a lower incidence of ischemic heart disease than those with a lower total calorie intake. This unexpected result might be accounted for if a low energy intake means that the diet is deficient in mineral salts or possibly vitamins. They also found that those subjects eating large quantities of brown bread had a lower incidence of ischemic heart disease. We have calculated that the increased consumption of brown bread by their high-fiber group would provide 5 to 10 per cent of the magnesium needed to remain in balance,’ so the increased mineral salt content of brown bread as opposed to white bread might account for the benefit derived from the consumption of brown bread. The possible importance of the mineral salt content of foods in the development of ischemic heart disease is discussed in more detail in a forthcoming article.3
Barbara Chipperfield, M-4, Ph.D. J. R. Chipperfield, MA, Ph.D. Depts. of Biochemistry and Chemistry University of Hull Hull, HU6 7RX England REFERENCES 1. 2. 3.
Morris, J. N., Marr, J. W., and Clayton, D. G.: Diet and heart: a postscript, Br. Med. J. ii:1307, 1977. Chipperfield, B., and Chipperfield, J. R.: Diet and heart: the importance of metals, Br. Med. J. i:720, 1978. Chipperfield, B.: Dietary factors in the development of ischaemic heart disease, Chest Heart & Stroke J. 3(3): 3, 1978.
Fatal hypotension therapy
in normal-dose
nitroprusside
To the Editor: We would like to report one death by hypotension that occurred two hours after an average-dose nitroprusside infusion was withdrawn. A la-year-old male, that weighed 50 kilograms and was
541
Letters
to the Editor
to have scleroderma for two years, abruptly developed malignant hypertension, rapidly deteriorating renal function, and heart failure. On admission, in addition to extensive sclerodermatous involvement of the skin, physical exammation disclosed a blood pressure of 210/130 mm. Hg, bilateral exudates and hemorrhages in the optic fundi, a third heart sound, moderate neck vein distension, and bibasilar crepitant &es. Serum creatinine was 5.3 mg./dl., hematocrit value was 28 per cent, and arterial blood gases showed: pH: 7.31, pC0,: 32 mm. Hg, and total C01:18 mmol./L. The electrocardiogram demonstrated left ventricular strain and there were early signs of pulmonary edema in the chest x-ray. Central venous pressure was 15 cm. H,O. Aside from diuretics, the patient had not received any antihypertensive medication previously. In an attempt to lower blood pressure and to reduce cardiac afterload, a nitroprusside infusion was then begun, under constant electrocardiographic monitoring and with BP measurements at 3 minute intervals. The nitroprusside was given at an initial rate of 1 pg per kilogram per minute, which was subsequently increased to 3 pg/Kg./minute in order to maintain a BP of 160195 mm. Hg. Ninety minutes after the infusion had been started and when the patient had received a total nitroprusside dose of approximately 13 mg., the BP fell to a systolic level of 80 mm. Hg and the nitroprusside administration was immediately stopped. Upon discontinuation of the drug, the BP failed to rise, and continued to drop slowly over the following 2 hours, not responding to leg elevation, the intravenous administration of norepinephrine or dopamine or a fluid challenge. Central venous pressure remained at 12 cm. H,O and serum potassium was 5.3 mEq./L. Simultaneously, the patient developed severe metabolic acidosis (pH = 7.10, pCO,= 21 mm. Hg, total CO?= 8 mmol./L.) that was treated with bicarbonate, and became progressively obtunded. Finally, 125 minutes after discontinuation of nitroprusside, and when the BP had reached a systolic level of 30 mm. Hg, the patient sustained a cardiac arrest and could not be resuscitated. At autopsy, there was no myocardial infarction, pericardial effusion, pulmonary embolus, central nervous system lesion, or internal hemorrhage that could explain the hypotension. Therefore, it seems logical to assume that nitropm&de was responsible for the progressive circulatory failure that ended in this patient’s death. This is surprising, since it is generally accepted that when administration of the drug is stopped, the blood pressure rises to pretreatment levels within one to ten minutes.’ Dangerous but transient episodes of hypotension have occurred when nitroprusside is used in combination with clonidine* or methyldopa? More significantly, three fatalities associated with the use of nitroprusside for induction of hypotension during surgery have been reported.‘-6 All the fatal cases had received large total doses of nitroprusside (from 400 to 750 mg.) in short periods of time and developed progressive hypotension and metabolic acidosis after discontinuation of the drug. Cyanide is the immediate byproduct of nitroprusside metabolism and it has been suggested that cyanide toxicity caused the death of all these patients.’ A check of blood cyanide levels alone cannot be expected to detect evidence of significant cyanide poisoning, since much of the freed cyanide can bind quickly to tissue cytochrome oxidase.’ Cyanide toxicity should not be confused with thiocyanate excess, which is an entirely different problem. Our patient, as well as all the human fatalities previously reported, developed progressive hypotension and metabolic known
542
acidosis despite discontinuation of the nitroprusside infusion. This strongly suggests a common underlying cause, namely, cyanide toxicity. However, the case herein reported differs from ‘the previous ones in that: (1) renal insufficiency was present, (2) the patient had neither received any antihypertensive drug other than nitroprusside nor was he anesthetised, and (3) the total dose of nitroprusside received was 30 to 60 times lower. We suggest that irreversible hypotension probably caused by cyanide toxicity can occur even after small doses of nitroprusside, and therefore the drug must be used with great caution, Considering that hydroxocobalamin has been shown recently to prevent cyanide toxicity from large doses of nitroprusside,” it would appear appropriate to administer this drug prophylactically to all patients receiving nitroprusside, even in small dosages.
Jesfis Montoliu, M.D. Albert Botey, M.D. Juan M. Pans, M.D. Luis Revert, M.D. Nephmlogy Service Hospital Clinico y Provincial University of Barcelona Barcelona, Spain REFERENCES 1. 2.
3.
4. 5. 6.
7.
8.
Sodium nitroprusside for hypertensive crisis, Med. Letter Drugs Ther. 17:82, 1975. Cohen, I. M., Mottet, M. M., Francis, G. S., and Alpert, J. S.: Danger in nitroprusside therapy, Ann. Intern. Med. 86205, 1976. Berdoff, R. L., Chalal, R. L., and Madden, M.: Hazards in a&hypertension therapy, Ann. Intern. Med. 86:111, 1977. Merrilield, A. J., and Blundell, M. D.: Toxicity of sodium nitroprusside, Br. J. Anaesth. 46:324, 1974. Jack, R. D.: Toxicity of sodium nitroprusside, Br. J. Anaesth. 46:952, 1974. Davies, D. W., Kadar, D., Steward, D. J., and Munro, I. R.: A sudden death associated with the use of sodium nitroprusaide for induction of hypotension during anaesthe&, Can. Anaesth. Sot. J. 2%547, 1975. Tinker, J. H., and Michenfelder, J. D.: Sodium nitroprusside: Pharmacology, toxicology and therapeutics, Anaesthesiology 45:349, 1976. Cottrell, J. E., Casthely, P., Brodie, J. D., Patel, K., Klein. A., and Tumdod H.: Prevention of nitronrusside induced cyanide toxicity with hydroxocobalamin, N. Engl. J. Med. 298:809, 1978.
CPR and seizure To the Editor: The cardiopulmonary resuscitation (CPR) manual for Basic Cardiac Life Support for instructors’ is certainly most complete and impressive. The 132 pages, appendix, and test are thorough, readable, and basic. It seems to me, however, that there is a gap in the manual leaving “uncovered” a common resuscitative event, namely the occurrence of seizure activity with syncope. During major motor seizure due to a primary focus or hypoxic in origin, finding pulses may be difhcult if not impossible, apnea is standard, and breathing for a patient is impossible. These problems and others are great enough for medically trained personnel, but what about the numbers of
April,
1979, Vol. 97, No. 4
Mineral
to the Editor
deficiency
and
atherosclerosis
To the Editor:
1.
In the June, 1978, issue of the JOURNAL Drs. Chipperfield and Chipperfield’ published their interesting findings regarding differences in the mineral contents of normal and atherosclerotic heart muscle. I do not question the factual contents of the paper, but would like to comment on the conclusions the authors draw from them, namely that Western diet may be deficient in some minerals and this deficiency may be a factor in the prevalence of coronary disease. I do not agree that thii conclusion follows from the facts published in the article and, in any case, it is unlikely to be true. Any mineral we need is probably also needed by other animals, possibly also by plants, and is likely to be obtainable from food. No animal species could survive if it had to rely on nutrients which are not obtainable without undue difficulties in its normal habitat. In the course of evolutionary history no animal has ever lived on a more varied and abundant diet than modem man in a prosperous society. The whole world is combed for delicacies for his table, not even mentioning the vitamin supplement, calcium enrichment, iron tablets and whatever else is contained in food additives, drugs, medicines and the like. It is unlikely that there is any substance of which his intake is less than that of the inhabitants of the poorer countries of Asia and Africa. Yet it is he who suffers from atherosclerosis, the disease is virtually unknown in the poorer countries of the world. Another point to note is that atherosclerotic coronary disease was virtually unknown in Europe 300 years ago. Was the substance in question still abundant then and became scarce only in the recent past? This seems the main argument against the assumption that atherosclerosis can be a deficiency disease. There is, however, one item of diet to which special consideration must be given, namely water. The fact that cardiovascular and cerebrovascular mortality rates are lower in hard water than in soft water areas could signify that hard water contains some substance of importance which soft water lacks. In the tropics, where atherosclerosis is virtually non-existent, a large volume of water, in extreme cases 10 liters in a day, can be lost by sweating and has to be replaced by drinking. If the hypothetical substance were obtainable solely from water, the intake of the inhabitants of tropical countries could be much more than ours. The supposition, however, gives rise to a number of difficult questions. Is there no water supply in Europe and North America with an exceptionally high content of this substance? Is there no water supply in Asia and Africa with a particularly low content? The apparent atherogenic properties of soft water have given food to a great deal of thought and various possibilities have been suggested, including one by myself.’ Alternatives to the deficiency hypothesis rest on the fact that soft water is a better solvent of some substances than hard water.
Stephen Seely, B.Sc. 3 Truro Drive Sale, Cheshire, England
American
Heart
REFERENCES
Journal
2.
Chipperfield, B., and Chipperfield, J.R.: Differences in metal content of the heart muscle in death from ischemic heart disease, AM. HEART J. 95:732, 1978. Seely, S.: Surfactants and atherogenesis, Med. Hypotheses 3:259, 1977.
Reply To the Editor: There seems to be more speculation than solid fact in Mr. Seely’s criticism of our paper. The possibility of a deficiency in mineral salts in the diet contributing to the development of ischemic heart disease has been suggested independently in a dietary investigation published since our paper was submitted. Morris, Marr, and Clayton’ found that normal men with a high calorie intake had a lower incidence of ischemic heart disease than those with a lower total calorie intake. This unexpected result might be accounted for if a low energy intake means that the diet is deficient in mineral salts or possibly vitamins. They also found that those subjects eating large quantities of brown bread had a lower incidence of ischemic heart disease. We have calculated that the increased consumption of brown bread by their high-fiber group would provide 5 to 10 per cent of the magnesium needed to remain in balance,’ so the increased mineral salt content of brown bread as opposed to white bread might account for the benefit derived from the consumption of brown bread. The possible importance of the mineral salt content of foods in the development of ischemic heart disease is discussed in more detail in a forthcoming article.3
Barbara Chipperfield, M-4, Ph.D. J. R. Chipperfield, MA, Ph.D. Depts. of Biochemistry and Chemistry University of Hull Hull, HU6 7RX England REFERENCES 1. 2. 3.
Morris, J. N., Marr, J. W., and Clayton, D. G.: Diet and heart: a postscript, Br. Med. J. ii:1307, 1977. Chipperfield, B., and Chipperfield, J. R.: Diet and heart: the importance of metals, Br. Med. J. i:720, 1978. Chipperfield, B.: Dietary factors in the development of ischaemic heart disease, Chest Heart & Stroke J. 3(3): 3, 1978.
Fatal hypotension therapy
in normal-dose
nitroprusside
To the Editor: We would like to report one death by hypotension that occurred two hours after an average-dose nitroprusside infusion was withdrawn. A la-year-old male, that weighed 50 kilograms and was
541
Letters
to the Editor
to have scleroderma for two years, abruptly developed malignant hypertension, rapidly deteriorating renal function, and heart failure. On admission, in addition to extensive sclerodermatous involvement of the skin, physical exammation disclosed a blood pressure of 210/130 mm. Hg, bilateral exudates and hemorrhages in the optic fundi, a third heart sound, moderate neck vein distension, and bibasilar crepitant &es. Serum creatinine was 5.3 mg./dl., hematocrit value was 28 per cent, and arterial blood gases showed: pH: 7.31, pC0,: 32 mm. Hg, and total C01:18 mmol./L. The electrocardiogram demonstrated left ventricular strain and there were early signs of pulmonary edema in the chest x-ray. Central venous pressure was 15 cm. H,O. Aside from diuretics, the patient had not received any antihypertensive medication previously. In an attempt to lower blood pressure and to reduce cardiac afterload, a nitroprusside infusion was then begun, under constant electrocardiographic monitoring and with BP measurements at 3 minute intervals. The nitroprusside was given at an initial rate of 1 pg per kilogram per minute, which was subsequently increased to 3 pg/Kg./minute in order to maintain a BP of 160195 mm. Hg. Ninety minutes after the infusion had been started and when the patient had received a total nitroprusside dose of approximately 13 mg., the BP fell to a systolic level of 80 mm. Hg and the nitroprusside administration was immediately stopped. Upon discontinuation of the drug, the BP failed to rise, and continued to drop slowly over the following 2 hours, not responding to leg elevation, the intravenous administration of norepinephrine or dopamine or a fluid challenge. Central venous pressure remained at 12 cm. H,O and serum potassium was 5.3 mEq./L. Simultaneously, the patient developed severe metabolic acidosis (pH = 7.10, pCO,= 21 mm. Hg, total CO?= 8 mmol./L.) that was treated with bicarbonate, and became progressively obtunded. Finally, 125 minutes after discontinuation of nitroprusside, and when the BP had reached a systolic level of 30 mm. Hg, the patient sustained a cardiac arrest and could not be resuscitated. At autopsy, there was no myocardial infarction, pericardial effusion, pulmonary embolus, central nervous system lesion, or internal hemorrhage that could explain the hypotension. Therefore, it seems logical to assume that nitropm&de was responsible for the progressive circulatory failure that ended in this patient’s death. This is surprising, since it is generally accepted that when administration of the drug is stopped, the blood pressure rises to pretreatment levels within one to ten minutes.’ Dangerous but transient episodes of hypotension have occurred when nitroprusside is used in combination with clonidine* or methyldopa? More significantly, three fatalities associated with the use of nitroprusside for induction of hypotension during surgery have been reported.‘-6 All the fatal cases had received large total doses of nitroprusside (from 400 to 750 mg.) in short periods of time and developed progressive hypotension and metabolic acidosis after discontinuation of the drug. Cyanide is the immediate byproduct of nitroprusside metabolism and it has been suggested that cyanide toxicity caused the death of all these patients.’ A check of blood cyanide levels alone cannot be expected to detect evidence of significant cyanide poisoning, since much of the freed cyanide can bind quickly to tissue cytochrome oxidase.’ Cyanide toxicity should not be confused with thiocyanate excess, which is an entirely different problem. Our patient, as well as all the human fatalities previously reported, developed progressive hypotension and metabolic known
542
acidosis despite discontinuation of the nitroprusside infusion. This strongly suggests a common underlying cause, namely, cyanide toxicity. However, the case herein reported differs from ‘the previous ones in that: (1) renal insufficiency was present, (2) the patient had neither received any antihypertensive drug other than nitroprusside nor was he anesthetised, and (3) the total dose of nitroprusside received was 30 to 60 times lower. We suggest that irreversible hypotension probably caused by cyanide toxicity can occur even after small doses of nitroprusside, and therefore the drug must be used with great caution, Considering that hydroxocobalamin has been shown recently to prevent cyanide toxicity from large doses of nitroprusside,” it would appear appropriate to administer this drug prophylactically to all patients receiving nitroprusside, even in small dosages.
Jesfis Montoliu, M.D. Albert Botey, M.D. Juan M. Pans, M.D. Luis Revert, M.D. Nephmlogy Service Hospital Clinico y Provincial University of Barcelona Barcelona, Spain REFERENCES 1. 2.
3.
4. 5. 6.
7.
8.
Sodium nitroprusside for hypertensive crisis, Med. Letter Drugs Ther. 17:82, 1975. Cohen, I. M., Mottet, M. M., Francis, G. S., and Alpert, J. S.: Danger in nitroprusside therapy, Ann. Intern. Med. 86205, 1976. Berdoff, R. L., Chalal, R. L., and Madden, M.: Hazards in a&hypertension therapy, Ann. Intern. Med. 86:111, 1977. Merrilield, A. J., and Blundell, M. D.: Toxicity of sodium nitroprusside, Br. J. Anaesth. 46:324, 1974. Jack, R. D.: Toxicity of sodium nitroprusside, Br. J. Anaesth. 46:952, 1974. Davies, D. W., Kadar, D., Steward, D. J., and Munro, I. R.: A sudden death associated with the use of sodium nitroprusaide for induction of hypotension during anaesthe&, Can. Anaesth. Sot. J. 2%547, 1975. Tinker, J. H., and Michenfelder, J. D.: Sodium nitroprusside: Pharmacology, toxicology and therapeutics, Anaesthesiology 45:349, 1976. Cottrell, J. E., Casthely, P., Brodie, J. D., Patel, K., Klein. A., and Tumdod H.: Prevention of nitronrusside induced cyanide toxicity with hydroxocobalamin, N. Engl. J. Med. 298:809, 1978.
CPR and seizure To the Editor: The cardiopulmonary resuscitation (CPR) manual for Basic Cardiac Life Support for instructors’ is certainly most complete and impressive. The 132 pages, appendix, and test are thorough, readable, and basic. It seems to me, however, that there is a gap in the manual leaving “uncovered” a common resuscitative event, namely the occurrence of seizure activity with syncope. During major motor seizure due to a primary focus or hypoxic in origin, finding pulses may be difhcult if not impossible, apnea is standard, and breathing for a patient is impossible. These problems and others are great enough for medically trained personnel, but what about the numbers of
April,
1979, Vol. 97, No. 4
