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NOTES ON TWO CASES OF VERONAL POISONING.
1736 from the hepatic duct. It is interesting to note that of the same character as the others, and composed for the most part of cholesterin. A small tube was placed in the common bile-duct and the peritoneal edges restitched. Owing to the presence of stones in the hepatic duct, and as the cystic duct was patent, the gall-bladder was not removed and a tube was placed in it. A tube was also placed in the kidney pouch. The patient made very satisfactory progress, at first both the gall-bladder and bile-duct tubes draining freely. At the end of a week the tubes were out and the discharge of bile soon ceased. She had an attack of pain with temperature on April 22nd, which made one suspicious of a lurking stone in the hepatic duct, but this soon subsided, and there seemed no further evidence that such was the case. Chemical examination of the stones i showed that they consisted of cholesterin with a calcium bilirubin nucleus. ’, came
they
were
I,
eyes,
Upper Wimpole-street, W.
NOTES
ON
TWO CASES OF VERONAL POISONING.
BY MARGARET H. LATE MEDICAL
REGISTRAR,
but they also came on without any provocation, A large amount of mucus was constantly accumulating in the mouth and pharynx in spite of frequent swabbing. The bowels remained calomel and croton oil had obstinately constipated, All the no effect, and all enemata were retained. urine had to be drawn off by catheter. On the second day there appeared on the right buttock a. bright red circular patch about two inches in diameter. The appearances suggested a bed-sore, but the following day somewhat similar patches, some forming definite bullae, appeared on parts of the feet, where there could be no question of pressure. On the third day there was a slight temporary improvement. The patient opened her she winced when a hypodermic needle was. inserted, attempted to cough, but made no effort to swallow. The patient was fed entirely by the rectum. On the fourth day purplish erythematous patches appeared in different parts in succession, generally symmetrical, on the face, chest, and about, the elbows, and gradually faded in about six hours. The temperature, which had been steadily rising since the onset, now registered 103’8°. Some physical signs appeared in the lungs. The patient died at about 7 o’clock on the morning of the fifth day, probably rather more than a hundred hours after the veronal was taken.
FRASER, M.B., B.S. LOND.,
HOSPITAL, GRAY’S INN-ROAD, LONDON, W.C.
ROYAL FREE
I
MANY cases of veronal poisoning have been recorded since the drug was introduced by von Mering and Fischer in 1903. The following two cases show no symptom that has not been noted before. Changes in connexion with the kidneys TABLE I.-Giving the Results of Examinations of the have been described in many of the cases, such as U1’ine in Case 1. albuminuria, suppression of urine, in one case polyuria, and a larger quantity of veronal has been extracted from the urine, but neither in the clinical accounts nor in the post-mortem records have I found mention of destructive changes affecting the kidney tissue, which were so marked a feature in both these cases, and which I think make them of special interest. CASE 1.-The patient was a healthy woman of about 48 years of age, who for six months had occasionally taken veronal for insomnia. On I May 12th, 1911, I was called in at 5 P.M. to ’ see the patient, who was apparently suffering from I an overdose of veronal taken presumably about 18 hours before. She was perfectly well on the evening of May llth. The amount taken is uncertain, but ’, a prescription for 12 cachets containing 10 grains 1 in each had been made up ten days before, and the box was found empty. There was not the slightest suspicion of an intentional overdose. When I first saw the patient she was comatose; the face was flushed and the lips were cyanosed; the skin was moist and the extremities were warm. RespiraTotal quantity of veronal extracted, 24-2 grains. The colour sugtions were 40 to 45 per minute and very shallow; presence of haematoporphyrin. which is described as the pulse was 100, full, but somewhat variable in gested the occurring after sulphonal poisoning, but a spectroscopic examination force ; the temperature was 100’4° F. The pupils of the urine showed the absorption bands of urobilin and urinary no other blood pigments. were small; they reacted to light, but there was no pigments ; On There was muscular reflex. ’, post-mortem examination the changes were conjunctival general of urine ounces drawn off by slight. The right heart was dilated and contained flaccidity. Twenty clot. The muscle was soft and in a condition catheter showed, nothing abnormal by the ordinary tests. The cyanosis passed off, the breathing im- of brown atrophy. The lungs were congested and proved, and the conjunctival reflex was obtained, showed scattered septic broncho-pneumonia. The but during the night the patient relapsed into the liver showed some nutmeg change and some same condition for a few hours, the finger-tips as granular degeneration of the liver cells. There was
’I
dark
well
as
the
face
became
dusky,
the
breathing
shallow and stertorous and increasingly rapid, the pulse weak and irregular, rising to 140. The condition of coma, however, persisted till the time of death, five days later, with a slight improvement on the third day. Attacks of cyanosis with rapid shallow breathing recurred at intervals. They were specially liable to occur when the patient was disturbed for any purpose,
no
peritonitis.
The
mucous
membrane
of the
intestine showed slight injection; the large bowel was empty and contained no accumulation of fseces in spite of five days’ constipation. The little showed the cortex kidneys naked-eye change ; was somewhat swollen, but the surface was smooth, the capsule stripped easily, and the consistence was
They weighed 6’2 ounces each. Microscopically, the epithelium of the convoluted tubules
-normal.
1737
throughout both kidneys showed marked degenera- no explanation other than the toxic action of the tion-i.e., complete absence of nuclear staining and drug. The pulse was regular, of low tension, and .detachment of cells, the lumen of the tubules being the rate never exceeded 112. The respirations were billed with granular debris. There was no evidence little raised, except that when moved transient .of congestion, no interstitial change, and the glome- attacks of dyspnoea with some pallor and increase ruli appeared normal. I am indebted to Dr. B. H. Spilsbury for the opportunity of examining the organs, and to Mr. F. F. .Shelley for the estimation of the veronal. CASE 2.-The patient, a man aged 54 years, was .admitted to the Royal Free Hospital on May 8th, 1913, under the care of Dr. J. W. Carr, to whom I am indebted for permission to publish the case. He had taken a bottleful of tablets of veronal about .15 hours before ; the exact amount is uncertain. He was comatose, the face was cyanosed, the tem’perature was 99’2°F., the pulse was 84, soft and ,regular, and the breathing was stertorous and- 24 to the minute. The pupils were contracted; they reacted to light; the corneal reflex was absent, but the conjunctival and supraorbital reflexes were were somewhat rigid and the retained ; the limbs The condition of coma in this knee-jerks present. -case lasted for six days, and was followed by com-
plete
recovery.
The rigidity noticed on admission passed off in .about 24 hours, and there was complete muscular flaccidity, the knee-jerks being abolished. The marked contraction of the pupils lessened; the ’corneal and conjunctival reflexes were variable, sometimes present, sometimes absent. No attempt was made to swallow; the patient was fed through .a nasal tube. On the day after admission 17 ounces -of urine were drawn off by catheter. There was ’complete incontinence for the subsequent eight days, but the quantity passed appeared fairly normal; there was no evidence of suppression or The character of the urine is described retention. in Table II. ’TABLE
the Results of Examinations the Ur.ine in Case 2.
IL-Giving
of
On the second day 7 ounces of urine yielded from 4 to 5 grains of veronal. On the sixth day the quantity of veronal was too minute to
estimate.
An
the
irregular pyrexia persisted evening rise registering 102 °.
for over a week, For this there is
pulse-rate were liable to occur. Mucus collected large quantity in the mouth and pharynx. Some general bronchitis developed. The tongue, which was clean on admission, became dry and caked. Constipation was marked, but an action was in in
obtained almost daily with aperients and enemata. Three small blisters were noticed on the feet and right leg on admission ; these increased in size and local inflammatory areas developed round the sites of the ether injections. About the fifth day four or five small, slightly raised erythematous patches appeared on the left thigh and one over the olecranon, but it was not till the eighth day that a general erythema developed, with a symmetrical distribution over the neck, trunk, arms, and to a smaller extent on the legs. The rash persisted for two days and a few pustules appeared. Signs of commencing return of consciousness appeared on the fifth day with some movement of the eyelids and limbs, and resistance on the patient’s part to the passage of the stomach tube. During the next two days there was increasing evidence of recovery, but the patient relapsed at intervals into complete unconsciousness. On the eighth day the patient wastaking food by the mouth; complete control of bladder and bowels was regained. He spoke at times quite intelligently, and the kneejerks were present. Convalescence progressed satisfactorily and rapidly, being disturbed only by the erythematous rash already mentioned on the eighth day, and swelling of the left parotid gland The patient got up on the on the eleventh day. fourteenth day and was discharged from the hospital a fortnight later. He still felt somewhat weak in the legs, but was otherwise free from symptoms and signs. The signs and symptoms in the two cases were The special points of interest are very similar. the following. 1. The length of the coma in the second case, which though lasting six days was followed by complete recovery. 2. The changes in the urine, following the elimination of veronal in large quantity. In Case 1 it was possible to examine the whole amount of urine secreted. During the first (approximately) 18 hours it was normal, except that it contained a certain quantity of veronal ; during the next day a large amount of the drug was eliminated through the kidneys, and within the following 24 hours the character of the utfine had completely changed, pointing to an acute affection of the kidney tissue, large numbers of epithelial and granular casts being passed, the cells showing all stages of degeneration. In Case 2, though owing to the presence of incontinence the total quantity of urine could not be collected for examination, the urine showed changes identical with those in Case 1. The kidney tissue in Case 2, though damaged, apparently recovered completely. The elimination of veronal had practically ceased by the sixth day, and by the twelfth day the urine was normal. When the patient was discharged from the hospital the urine showed no evidence of any permanent affection of the kidney tissue ; a normal quantity of urea was excreted. As veronal apparently does in large doses cause necrosis of the kidney cells, is it not possible that repeated small doses may also in the end affect the renal epithelium ? Nottingham-plae, W. .
they
were
I,
eyes,
Upper Wimpole-street, W.
NOTES
ON
TWO CASES OF VERONAL POISONING.
BY MARGARET H. LATE MEDICAL
REGISTRAR,
but they also came on without any provocation, A large amount of mucus was constantly accumulating in the mouth and pharynx in spite of frequent swabbing. The bowels remained calomel and croton oil had obstinately constipated, All the no effect, and all enemata were retained. urine had to be drawn off by catheter. On the second day there appeared on the right buttock a. bright red circular patch about two inches in diameter. The appearances suggested a bed-sore, but the following day somewhat similar patches, some forming definite bullae, appeared on parts of the feet, where there could be no question of pressure. On the third day there was a slight temporary improvement. The patient opened her she winced when a hypodermic needle was. inserted, attempted to cough, but made no effort to swallow. The patient was fed entirely by the rectum. On the fourth day purplish erythematous patches appeared in different parts in succession, generally symmetrical, on the face, chest, and about, the elbows, and gradually faded in about six hours. The temperature, which had been steadily rising since the onset, now registered 103’8°. Some physical signs appeared in the lungs. The patient died at about 7 o’clock on the morning of the fifth day, probably rather more than a hundred hours after the veronal was taken.
FRASER, M.B., B.S. LOND.,
HOSPITAL, GRAY’S INN-ROAD, LONDON, W.C.
ROYAL FREE
I
MANY cases of veronal poisoning have been recorded since the drug was introduced by von Mering and Fischer in 1903. The following two cases show no symptom that has not been noted before. Changes in connexion with the kidneys TABLE I.-Giving the Results of Examinations of the have been described in many of the cases, such as U1’ine in Case 1. albuminuria, suppression of urine, in one case polyuria, and a larger quantity of veronal has been extracted from the urine, but neither in the clinical accounts nor in the post-mortem records have I found mention of destructive changes affecting the kidney tissue, which were so marked a feature in both these cases, and which I think make them of special interest. CASE 1.-The patient was a healthy woman of about 48 years of age, who for six months had occasionally taken veronal for insomnia. On I May 12th, 1911, I was called in at 5 P.M. to ’ see the patient, who was apparently suffering from I an overdose of veronal taken presumably about 18 hours before. She was perfectly well on the evening of May llth. The amount taken is uncertain, but ’, a prescription for 12 cachets containing 10 grains 1 in each had been made up ten days before, and the box was found empty. There was not the slightest suspicion of an intentional overdose. When I first saw the patient she was comatose; the face was flushed and the lips were cyanosed; the skin was moist and the extremities were warm. RespiraTotal quantity of veronal extracted, 24-2 grains. The colour sugtions were 40 to 45 per minute and very shallow; presence of haematoporphyrin. which is described as the pulse was 100, full, but somewhat variable in gested the occurring after sulphonal poisoning, but a spectroscopic examination force ; the temperature was 100’4° F. The pupils of the urine showed the absorption bands of urobilin and urinary no other blood pigments. were small; they reacted to light, but there was no pigments ; On There was muscular reflex. ’, post-mortem examination the changes were conjunctival general of urine ounces drawn off by slight. The right heart was dilated and contained flaccidity. Twenty clot. The muscle was soft and in a condition catheter showed, nothing abnormal by the ordinary tests. The cyanosis passed off, the breathing im- of brown atrophy. The lungs were congested and proved, and the conjunctival reflex was obtained, showed scattered septic broncho-pneumonia. The but during the night the patient relapsed into the liver showed some nutmeg change and some same condition for a few hours, the finger-tips as granular degeneration of the liver cells. There was
’I
dark
well
as
the
face
became
dusky,
the
breathing
shallow and stertorous and increasingly rapid, the pulse weak and irregular, rising to 140. The condition of coma, however, persisted till the time of death, five days later, with a slight improvement on the third day. Attacks of cyanosis with rapid shallow breathing recurred at intervals. They were specially liable to occur when the patient was disturbed for any purpose,
no
peritonitis.
The
mucous
membrane
of the
intestine showed slight injection; the large bowel was empty and contained no accumulation of fseces in spite of five days’ constipation. The little showed the cortex kidneys naked-eye change ; was somewhat swollen, but the surface was smooth, the capsule stripped easily, and the consistence was
They weighed 6’2 ounces each. Microscopically, the epithelium of the convoluted tubules
-normal.
1737
throughout both kidneys showed marked degenera- no explanation other than the toxic action of the tion-i.e., complete absence of nuclear staining and drug. The pulse was regular, of low tension, and .detachment of cells, the lumen of the tubules being the rate never exceeded 112. The respirations were billed with granular debris. There was no evidence little raised, except that when moved transient .of congestion, no interstitial change, and the glome- attacks of dyspnoea with some pallor and increase ruli appeared normal. I am indebted to Dr. B. H. Spilsbury for the opportunity of examining the organs, and to Mr. F. F. .Shelley for the estimation of the veronal. CASE 2.-The patient, a man aged 54 years, was .admitted to the Royal Free Hospital on May 8th, 1913, under the care of Dr. J. W. Carr, to whom I am indebted for permission to publish the case. He had taken a bottleful of tablets of veronal about .15 hours before ; the exact amount is uncertain. He was comatose, the face was cyanosed, the tem’perature was 99’2°F., the pulse was 84, soft and ,regular, and the breathing was stertorous and- 24 to the minute. The pupils were contracted; they reacted to light; the corneal reflex was absent, but the conjunctival and supraorbital reflexes were were somewhat rigid and the retained ; the limbs The condition of coma in this knee-jerks present. -case lasted for six days, and was followed by com-
plete
recovery.
The rigidity noticed on admission passed off in .about 24 hours, and there was complete muscular flaccidity, the knee-jerks being abolished. The marked contraction of the pupils lessened; the ’corneal and conjunctival reflexes were variable, sometimes present, sometimes absent. No attempt was made to swallow; the patient was fed through .a nasal tube. On the day after admission 17 ounces -of urine were drawn off by catheter. There was ’complete incontinence for the subsequent eight days, but the quantity passed appeared fairly normal; there was no evidence of suppression or The character of the urine is described retention. in Table II. ’TABLE
the Results of Examinations the Ur.ine in Case 2.
IL-Giving
of
On the second day 7 ounces of urine yielded from 4 to 5 grains of veronal. On the sixth day the quantity of veronal was too minute to
estimate.
An
the
irregular pyrexia persisted evening rise registering 102 °.
for over a week, For this there is
pulse-rate were liable to occur. Mucus collected large quantity in the mouth and pharynx. Some general bronchitis developed. The tongue, which was clean on admission, became dry and caked. Constipation was marked, but an action was in in
obtained almost daily with aperients and enemata. Three small blisters were noticed on the feet and right leg on admission ; these increased in size and local inflammatory areas developed round the sites of the ether injections. About the fifth day four or five small, slightly raised erythematous patches appeared on the left thigh and one over the olecranon, but it was not till the eighth day that a general erythema developed, with a symmetrical distribution over the neck, trunk, arms, and to a smaller extent on the legs. The rash persisted for two days and a few pustules appeared. Signs of commencing return of consciousness appeared on the fifth day with some movement of the eyelids and limbs, and resistance on the patient’s part to the passage of the stomach tube. During the next two days there was increasing evidence of recovery, but the patient relapsed at intervals into complete unconsciousness. On the eighth day the patient wastaking food by the mouth; complete control of bladder and bowels was regained. He spoke at times quite intelligently, and the kneejerks were present. Convalescence progressed satisfactorily and rapidly, being disturbed only by the erythematous rash already mentioned on the eighth day, and swelling of the left parotid gland The patient got up on the on the eleventh day. fourteenth day and was discharged from the hospital a fortnight later. He still felt somewhat weak in the legs, but was otherwise free from symptoms and signs. The signs and symptoms in the two cases were The special points of interest are very similar. the following. 1. The length of the coma in the second case, which though lasting six days was followed by complete recovery. 2. The changes in the urine, following the elimination of veronal in large quantity. In Case 1 it was possible to examine the whole amount of urine secreted. During the first (approximately) 18 hours it was normal, except that it contained a certain quantity of veronal ; during the next day a large amount of the drug was eliminated through the kidneys, and within the following 24 hours the character of the utfine had completely changed, pointing to an acute affection of the kidney tissue, large numbers of epithelial and granular casts being passed, the cells showing all stages of degeneration. In Case 2, though owing to the presence of incontinence the total quantity of urine could not be collected for examination, the urine showed changes identical with those in Case 1. The kidney tissue in Case 2, though damaged, apparently recovered completely. The elimination of veronal had practically ceased by the sixth day, and by the twelfth day the urine was normal. When the patient was discharged from the hospital the urine showed no evidence of any permanent affection of the kidney tissue ; a normal quantity of urea was excreted. As veronal apparently does in large doses cause necrosis of the kidney cells, is it not possible that repeated small doses may also in the end affect the renal epithelium ? Nottingham-plae, W. .