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MERCURY IN THE URINE OF CHILDREN WITH ACRODYNIA
829 for various reasons ; but some healthy children and a few adults were included in the control group. The difference between the two groups is obvious. Of the 20 children in the acrodynia group, 18 had mercury DONALD M. HUBBARD JOSEF WARKANY in the urine, and in 15 of them the amounts excreted Ch.E. M.D. were over 50 µg. per litre. The 2 children(*) in whose ASSISTANT PROFESSOR OF ASSISTANT PROFESSOR OF urine no mercury was found were the older patients, INDUSTRIAL HYGIENE PEDIATRICS aged 8 and 14 years ; they belonged to an age-group UNIVERSITY OF CINCINNATI in which acrodynia is unusual. Both these cases were From the Children’s Hospital Research Foundation and the atypical in other respects ; the girl aged 8 years had
MERCURY IN THE URINE OF CHILDREN WITH ACRODYNIA
Kettering Laboratory of Applied Physiology, Cincinnati IN 1945 a child, aged 14 months, with a severe form of acrodynia was observed in the Children’s Hospital of Cincinnati. On May 5 a specimen of urine was examined for mercury by means of the di-beta-naphthylthiocarbazone method of Hubbard1 and 360 µg. of mercury per litre was found ; two days later a specimen contained 320 µg. per litre. Since these are appreciable amounts of mercury, the determinations were repeated on May 31 and June 20, when amounts of 90 and 140 (1.g. ’per litre The source of mercury could ’not be were found. established in that child. Acrodynia is rare in Cincinnati and only 8 additional cases have been seen in the Children’s Hospital up to now. Through the coöperation of paediatricians from other cities we were able to examine the urine of 11 more children who had been diagnosed as acrodynia elsewhere. Thus a total of 20 children with the acrodynia syndrome could be studied for excretion of mercury in the urine up to the present time. In the urine of 18 children appreciable amounts of mercury were found, and in some of those who could be followed the excretion of mercury continued for several weeks or even months. As a rule, values of the same order were found in repeated I-MERCURY
CONTENT OF FIRST SPECIMEN OF URINE EXAMINED IN ACRODYNIA PATIENTS AND IN CONTROLS
TABLE
No. of persons:
No. of persons:
lIercury
in urine (µg. per
Mercury
Clinically
litre) diagnosed
Controls
as
in(µg.urine per
acrodynia,
Over 400 301-400 201-300
2
5 2
* Older children.
Controls
as
acrodynia
1
101-200
Clinically diagnosed
litre)
Nil
I, ,,,
"
"
51-100
I
1-50 0
Total
i
1†
5 3 2*
20
,
I
8
40
49
t Child had taken calomel tablets.
examinations of the same patient but occasionally unexplained variations were encountered. From some patients only a single specimen of urine could be obtained. Of the 20 children in the acrodynia group, 18 were j under 4 years of age, the remaining 2 being aged 8 years and 14 years. The patients were in different stages of the disease, the severity of their illness varied, and some of them were treated with BAL following the suggestion : ofBivings and Lewis.2 It is therefore difficult to summarise the results briefly. In table i the values found in the first determination in the urine of patients diagnosed as acrodynia are com, pared with those of controls. The controls were mostly ,
!
children, patients 1. 2.
of the Children’s
Hospital
admitted
Hubbard, D. M. Industr. Engng. Chem. 1940, 12, 768. Bivings, L., Lewis, G. jun. J. Pediat. 1948, 32, 63.
PROFESSOR BORST: REFERENCES—continued McCance, R. A., Widdowson, E. M. (1946) Chemical Composition of Foods. London. Peters, J. P. (1944) Fed. Proc. 3, 197. — Van Slyke, D. D. (1946) Quantitative Clinical Chemistry. Baltimore ; vol. I. pp. 691, 699. Smith, M. (1926) J. biol. Chem. 68, 15. Thorn, G. W. (1943) New Engl. J. Med. 229, 33. Volhard, F. (1942) Nierenerkrankungen und Hochdruck. Leipzig.
TABLE II-MERCURY CONTENT OF ALL SPECIMENS OF URINE EXAMINED IN ACRODYNIA PATIENTS AND IN CONTROLS
No. of specimens Ifrom:
No. of specimens from:
Mercury
Mercury
in urine
Patients
(,ug. per litre)
clinically diagnosed Controls
urine inlitre)
(µg.
per
as acrodynia 400
Over 301-400 . 201-300 101-200
I
5 4
(
14
Patients
I
clinically
diagnosed acrodynia as
Controls
20 23 6
2&dager; 10 60
96
72
51-100 1-50 ,,00
Nil
24
Total
-
t Child had taken calomel tablets.
been ill for three years and the boy aged 14 years was having a third attack of a condition which resembled acrodynia. On account of these unusual features the diagnosis of acrodynia was made with reservation by the physicians of the 2 children. However, we thought it advisable to include these children in the acrodynia group, since it seemed important to emphasise that the symptom complex of acrodynia’ can occur without
excretion of mercury in the urine. Over 80% of the control cases had no mercury in the urine ; of the 8 controls listed in the 1-50 µg. column, 4 had only 10 mg. per litre, a value near the limit of error of the method ; and in 3 children who had 20, 35, and 40 (1.g. per litre respectively in the first sample none or minimal amounts were found in subsequent samples, so that contamination of the first specimens cannot be excluded. In one control child (&dag er;) 70 µg. per litre was found in the first urine specimen and in two subsequent samples 40 and 80 (1.g. per litre was present. We were able to get in contactwith the physician who had taken care of this child before admission to the hospital and we were told that the child had received calomel tablets from him. We also observed 3 other children who were treated with mercury preparations and excreted in the urine 50, 70, and 180 (1.g. of mercury per litre without showing signs of acrodynia. These children are not included in the control series since we selected them knowing of their exposure to mercury. These cases are important since they demonstrate that a child, after treatment with mercurial drugs, may excrete mercury in the urine without signs of acrodynia. In table II all the values obtained in the acrodynia group are compared with all the values found in the controls and again a significant difference becomes apparent. The two values above 50 µg. per litre found in the control series (t) refer to the child who had received calomel. DISCUSSION
In the first cases of acrodynia that we examined, the source of the mercury excreted in the urine could not be ascertained. The parents usually do not know whether or not tablets, ointments, and other medication given to their children contain mercury. But recently a history of the ingestion of calomel, of the application of ammoniated mercury ointment to the skin, or of the use of a " teething powder " containing calomel has been obtained in a number of cases.
830 The fact that mercury is excreted in the urine of many children with acrodynia suggests that in small children a causal relationship may exist between exposure to and resorption of mercury and the symptom complex of acrodynia. The fact that after mercury medication children may excrete mercury in the urine in appreciable amounts without developing acrodynia suggests that an individual susceptibility (idiosyncrasy) to mercury intoxication exists in the children who develop acrodynia. Since 2 of the older children of our series showed signs of acrodynia without excreting mercury, and since chronic arsenical poisoning sometimes causes an acrodynia-like picture, it seems that the symptom complex of acrodynia can arise from more than one cause. We have not had sufficient experience in the treatment, of acrodynia with BAL to venture judgment concerning this form of therapy. So far our study of mercury in acrodynia has been on But we hope a small scale and progress has been slow. that in the near future the laboratory facilities for this investigation can be extended and that then some of the outstanding questions will be answered more definitely. Meanwhile it is recommended that in every case of acrodynia the possibility of exposure to mercury should be considered and investigated, and whenever possible the mercury content of the urine should be determined.
’-
A PHOTO-ELECTRIC DROP RECORDER FOR
INVESTIGATING CARDIOVASCULAR EFFECTS OF DRUGS IN MAN
R. H. GOETZ M.D. Berne, M.B. Cape Town RESEARCH
ASSOCIATE
PROFESSOR OF OF CAPE TOWN
SURGERY,
UNIVERSITY
important that the subject should not be aware of the injection, because psychic changes in vasomotor tone will modify the reaction in the non-sympathectomised limb to ’such an extent that even with the greatest care it is extremely difficult to compare the reaction of the normal with that of the sympathectomised limb to physiological doses of adrenaline. Therefore adrenaline was given by intravenous drip in the following way : TwoVacoliters,’ one for normal saline and the other 1 in 500,000 adrenaline, are set up (fig. 1) and connected via a two-way tap to the intravenous needle. After insertion of the needle saline is given at a rate just sufficient to prevent clotting in the needle. By merely turning the tap it is possible to switch over from saline to adrenaline without the patient being aware of the change. Thus
containing
"
any psychic vasomotor reactions when starting the administration of adrenaline can be eliminated.
However, it was soon discovered that, when a vasoconstrictor substance, such as adrenaline, is injected into a vein, the vessel-owing to the direct effect of the drug on its wall-may contract to such an extent that the rate of drops decreased considerably.This makes it difficult to administer adrenaline (for instance) at the same rate continuously, and experiments showed that, unless this was done, it was
impossible to get comparable highly controversial1 results and to reach reliable question of adrenaline hypersensitivity of the vessels in conclusions. This difficulty was sympathectomised human limbs, it was found (1) that overcome by increasing the slight differences in the initial vasomotor tone are of height of the bottle containconsiderable importance in determining the degree of the ing the adrenaline, and thus reaction, and (2) that the slightest difference in the speed increasing the pressure under and amount of adrenaline administered will produce vastly which it was administered different results, rendering evaluation extremely difficult. (fig. 1). It was essential, Our plethysmographic method2 could give information however, to devise some about the first point. Further, it had been found method by which the drops DURING
a
re-examination of the
1. Ascroft, P. B. Brit. J. Surg. 1937, 24, 787. Fatherree, T. J., Adson, A. W., Allen, E. V. Surgery, 1940, 7, 75. Freeman, N. E., Smithwick, R. H., White, J. C. Amer. J. Physiol. 1934, 107, 529. Smithwick, R. H., Freeman, N. E., White, J. C. Arch. Surg., Chicago. 1934, 29, 759. 2. Goetz, R. H. Brit. J. Surg. 1939, 27, 506 ; S. Afr. J. med. Sci. 1943. 8, 65; Amer. Heart J. 1946, 31, 146.
’
!
Fig. I—Apparatus for intravenous drip set up with drop recorder: A,clip; ; B, test solution ; D, drop recorder; E, saline ; F, two. way tap
with intravenous
needle ;
G, lead to gaivano. ’
meter.
’
could be recorded on the film as the experiments were carried out ; therefore the drop recorder now to- be described was developed. An intravenous in which an
drip is
electric-light
fitted in an ebonite block (fig. 2), fed from a dry battery or a
globe,
Adrenaline I : 50SOA,A00
Fig. 3-Typical plethysmogram obtained with drop recorder when adrenalineI in SOb,000 (18 drops per mi.)
was
given.
MERCURY IN THE URINE OF CHILDREN WITH ACRODYNIA
Kettering Laboratory of Applied Physiology, Cincinnati IN 1945 a child, aged 14 months, with a severe form of acrodynia was observed in the Children’s Hospital of Cincinnati. On May 5 a specimen of urine was examined for mercury by means of the di-beta-naphthylthiocarbazone method of Hubbard1 and 360 µg. of mercury per litre was found ; two days later a specimen contained 320 µg. per litre. Since these are appreciable amounts of mercury, the determinations were repeated on May 31 and June 20, when amounts of 90 and 140 (1.g. ’per litre The source of mercury could ’not be were found. established in that child. Acrodynia is rare in Cincinnati and only 8 additional cases have been seen in the Children’s Hospital up to now. Through the coöperation of paediatricians from other cities we were able to examine the urine of 11 more children who had been diagnosed as acrodynia elsewhere. Thus a total of 20 children with the acrodynia syndrome could be studied for excretion of mercury in the urine up to the present time. In the urine of 18 children appreciable amounts of mercury were found, and in some of those who could be followed the excretion of mercury continued for several weeks or even months. As a rule, values of the same order were found in repeated I-MERCURY
CONTENT OF FIRST SPECIMEN OF URINE EXAMINED IN ACRODYNIA PATIENTS AND IN CONTROLS
TABLE
No. of persons:
No. of persons:
lIercury
in urine (µg. per
Mercury
Clinically
litre) diagnosed
Controls
as
in(µg.urine per
acrodynia,
Over 400 301-400 201-300
2
5 2
* Older children.
Controls
as
acrodynia
1
101-200
Clinically diagnosed
litre)
Nil
I, ,,,
"
"
51-100
I
1-50 0
Total
i
1†
5 3 2*
20
,
I
8
40
49
t Child had taken calomel tablets.
examinations of the same patient but occasionally unexplained variations were encountered. From some patients only a single specimen of urine could be obtained. Of the 20 children in the acrodynia group, 18 were j under 4 years of age, the remaining 2 being aged 8 years and 14 years. The patients were in different stages of the disease, the severity of their illness varied, and some of them were treated with BAL following the suggestion : ofBivings and Lewis.2 It is therefore difficult to summarise the results briefly. In table i the values found in the first determination in the urine of patients diagnosed as acrodynia are com, pared with those of controls. The controls were mostly ,
!
children, patients 1. 2.
of the Children’s
Hospital
admitted
Hubbard, D. M. Industr. Engng. Chem. 1940, 12, 768. Bivings, L., Lewis, G. jun. J. Pediat. 1948, 32, 63.
PROFESSOR BORST: REFERENCES—continued McCance, R. A., Widdowson, E. M. (1946) Chemical Composition of Foods. London. Peters, J. P. (1944) Fed. Proc. 3, 197. — Van Slyke, D. D. (1946) Quantitative Clinical Chemistry. Baltimore ; vol. I. pp. 691, 699. Smith, M. (1926) J. biol. Chem. 68, 15. Thorn, G. W. (1943) New Engl. J. Med. 229, 33. Volhard, F. (1942) Nierenerkrankungen und Hochdruck. Leipzig.
TABLE II-MERCURY CONTENT OF ALL SPECIMENS OF URINE EXAMINED IN ACRODYNIA PATIENTS AND IN CONTROLS
No. of specimens Ifrom:
No. of specimens from:
Mercury
Mercury
in urine
Patients
(,ug. per litre)
clinically diagnosed Controls
urine inlitre)
(µg.
per
as acrodynia 400
Over 301-400 . 201-300 101-200
I
5 4
(
14
Patients
I
clinically
diagnosed acrodynia as
Controls
20 23 6
2&dager; 10 60
96
72
51-100 1-50 ,,00
Nil
24
Total
-
t Child had taken calomel tablets.
been ill for three years and the boy aged 14 years was having a third attack of a condition which resembled acrodynia. On account of these unusual features the diagnosis of acrodynia was made with reservation by the physicians of the 2 children. However, we thought it advisable to include these children in the acrodynia group, since it seemed important to emphasise that the symptom complex of acrodynia’ can occur without
excretion of mercury in the urine. Over 80% of the control cases had no mercury in the urine ; of the 8 controls listed in the 1-50 µg. column, 4 had only 10 mg. per litre, a value near the limit of error of the method ; and in 3 children who had 20, 35, and 40 (1.g. per litre respectively in the first sample none or minimal amounts were found in subsequent samples, so that contamination of the first specimens cannot be excluded. In one control child (&dag er;) 70 µg. per litre was found in the first urine specimen and in two subsequent samples 40 and 80 (1.g. per litre was present. We were able to get in contactwith the physician who had taken care of this child before admission to the hospital and we were told that the child had received calomel tablets from him. We also observed 3 other children who were treated with mercury preparations and excreted in the urine 50, 70, and 180 (1.g. of mercury per litre without showing signs of acrodynia. These children are not included in the control series since we selected them knowing of their exposure to mercury. These cases are important since they demonstrate that a child, after treatment with mercurial drugs, may excrete mercury in the urine without signs of acrodynia. In table II all the values obtained in the acrodynia group are compared with all the values found in the controls and again a significant difference becomes apparent. The two values above 50 µg. per litre found in the control series (t) refer to the child who had received calomel. DISCUSSION
In the first cases of acrodynia that we examined, the source of the mercury excreted in the urine could not be ascertained. The parents usually do not know whether or not tablets, ointments, and other medication given to their children contain mercury. But recently a history of the ingestion of calomel, of the application of ammoniated mercury ointment to the skin, or of the use of a " teething powder " containing calomel has been obtained in a number of cases.
830 The fact that mercury is excreted in the urine of many children with acrodynia suggests that in small children a causal relationship may exist between exposure to and resorption of mercury and the symptom complex of acrodynia. The fact that after mercury medication children may excrete mercury in the urine in appreciable amounts without developing acrodynia suggests that an individual susceptibility (idiosyncrasy) to mercury intoxication exists in the children who develop acrodynia. Since 2 of the older children of our series showed signs of acrodynia without excreting mercury, and since chronic arsenical poisoning sometimes causes an acrodynia-like picture, it seems that the symptom complex of acrodynia can arise from more than one cause. We have not had sufficient experience in the treatment, of acrodynia with BAL to venture judgment concerning this form of therapy. So far our study of mercury in acrodynia has been on But we hope a small scale and progress has been slow. that in the near future the laboratory facilities for this investigation can be extended and that then some of the outstanding questions will be answered more definitely. Meanwhile it is recommended that in every case of acrodynia the possibility of exposure to mercury should be considered and investigated, and whenever possible the mercury content of the urine should be determined.
’-
A PHOTO-ELECTRIC DROP RECORDER FOR
INVESTIGATING CARDIOVASCULAR EFFECTS OF DRUGS IN MAN
R. H. GOETZ M.D. Berne, M.B. Cape Town RESEARCH
ASSOCIATE
PROFESSOR OF OF CAPE TOWN
SURGERY,
UNIVERSITY
important that the subject should not be aware of the injection, because psychic changes in vasomotor tone will modify the reaction in the non-sympathectomised limb to ’such an extent that even with the greatest care it is extremely difficult to compare the reaction of the normal with that of the sympathectomised limb to physiological doses of adrenaline. Therefore adrenaline was given by intravenous drip in the following way : TwoVacoliters,’ one for normal saline and the other 1 in 500,000 adrenaline, are set up (fig. 1) and connected via a two-way tap to the intravenous needle. After insertion of the needle saline is given at a rate just sufficient to prevent clotting in the needle. By merely turning the tap it is possible to switch over from saline to adrenaline without the patient being aware of the change. Thus
containing
"
any psychic vasomotor reactions when starting the administration of adrenaline can be eliminated.
However, it was soon discovered that, when a vasoconstrictor substance, such as adrenaline, is injected into a vein, the vessel-owing to the direct effect of the drug on its wall-may contract to such an extent that the rate of drops decreased considerably.This makes it difficult to administer adrenaline (for instance) at the same rate continuously, and experiments showed that, unless this was done, it was
impossible to get comparable highly controversial1 results and to reach reliable question of adrenaline hypersensitivity of the vessels in conclusions. This difficulty was sympathectomised human limbs, it was found (1) that overcome by increasing the slight differences in the initial vasomotor tone are of height of the bottle containconsiderable importance in determining the degree of the ing the adrenaline, and thus reaction, and (2) that the slightest difference in the speed increasing the pressure under and amount of adrenaline administered will produce vastly which it was administered different results, rendering evaluation extremely difficult. (fig. 1). It was essential, Our plethysmographic method2 could give information however, to devise some about the first point. Further, it had been found method by which the drops DURING
a
re-examination of the
1. Ascroft, P. B. Brit. J. Surg. 1937, 24, 787. Fatherree, T. J., Adson, A. W., Allen, E. V. Surgery, 1940, 7, 75. Freeman, N. E., Smithwick, R. H., White, J. C. Amer. J. Physiol. 1934, 107, 529. Smithwick, R. H., Freeman, N. E., White, J. C. Arch. Surg., Chicago. 1934, 29, 759. 2. Goetz, R. H. Brit. J. Surg. 1939, 27, 506 ; S. Afr. J. med. Sci. 1943. 8, 65; Amer. Heart J. 1946, 31, 146.
’
!
Fig. I—Apparatus for intravenous drip set up with drop recorder: A,clip; ; B, test solution ; D, drop recorder; E, saline ; F, two. way tap
with intravenous
needle ;
G, lead to gaivano. ’
meter.
’
could be recorded on the film as the experiments were carried out ; therefore the drop recorder now to- be described was developed. An intravenous in which an
drip is
electric-light
fitted in an ebonite block (fig. 2), fed from a dry battery or a
globe,
Adrenaline I : 50SOA,A00
Fig. 3-Typical plethysmogram obtained with drop recorder when adrenalineI in SOb,000 (18 drops per mi.)
was
given.