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The Effect of Sedatives on Diuresis
Medical Clinics of North America May, 1940. New York Number
CLINIC OF DRS. LINN
J.
BOYD AND DAVID SCHERF
FROM THE DEPARTMENT OF MEDICINE, THE NEW YORK MEDICAL COLLEGE, FLOWER AND FIFTH AVENUE HOSPITALS THE EFFECT OF SEDATIVES ON DIURESIS
CARDIAC patients who are decompensated and edematous frequently suffer from intractable insomnia which is often provoked by respiratory disturbances. Under these circumstances the somnifacient drugs often find consideration in the therapeutic program. Presumably morphine and its derivatives occupy first place among the measures which are utilized to relieve the dyspnea of cardiac patients. Accordingly, the physician is often confronted with a situation in which he must treat the edematous cardiac patient simultaneously with diuretic and sedative drugs. Analgesic preparations may also be indicated for the relief of pain. Under these circumstances the narcotics, hypnotics and analgesics may exhibit a very pronounced influence on diuresis: They may depress it, and in this manner thwart therapeutic endeavors aimed to set diuresis into motion. Under certain conditions, however, they may initiate or promote diuresis, and accordingly exert an extremely useful and desirable effect. An awareness of the influence upon diuresis by agents which act upon the nervous system therefore possesses considerable practical significance. One aspect of this problem may be illustrated by a few excerpts from some recent case histories: Case I.-M. G., a fifty-two-year-old Puerto Rican female, entered the Hospital because of shortness of breath and palpitation. Effort dyspnea and ankle edema had been present for two years. On the day before. admission dyspnea became extreme and palpitation marked. Examination disclosed an enlarged heart with a systoIic murmur at the aortic area and an accentuated 869
LINN
J.
BOYD, DAVID SCHERF
second aortic sound. The blood pressure was 160/90. There were fine crackling rales at both bases and the liver edge was palpable three fingers below the costal margin; there was marked edema of the extremities. The cause of her congestive failure was cardiac dilatation secondary to coronary sclerosis. On the sixth day of hospitalization the patient was given 2 cc. of mercupurin intravenously. The fluid intake during the next twenty-four hours' was 1,000 cc. and the output 1,300 cc. For experimental purposes, she was given the same dose of the diuretic on the eleventh day of hospitalization. On the day preceding the injection and the day of the injection, she received 1.5 gm. of aminopyrine. 'The fluid intake was 1,000 cc. and the output 600 cc. during the twenty-four-hour period following the injection. Accordingly, the output was less than one-half the, excretion when no aminopyrine was used, despite the fact that the edema and related symptoms were as severe as at the time of the first injection. Case n.-M,. W., fifty-two years old, entered the hospital because of extreme shortness of breath. She had suffered from dyspnea on slight eff~rt, palpitation and swelling of the ankles for ten years. There had been attacks of palpitation, nocturnal dyspnea, and precordial pain. In addition to marked dyspnea, orthopnea and cyanosis, examination revealed a markedly enlarged heart with systolic and diastolic murmurs at the mitral area and asystolic murmur together with an accentuated second sound at the aortic area. The blood pressure was 190/110. There were crackling rales in both lung fields, the liver edge was palpated four fingers below the costal margin, and there was marked edema of the legs. With a fluid intake of 1,000 to 1,200 cc. per day, the output amounted to approximately 600 cc. per day. Following the injection of 2 cc. of mcrcupurin intravenously, the output rose to 1,750 cc. during the next twenty-four hours. After two days of aminopyrine, 1.5 gm. each day, mercupurin was injected in the same dose as before and the ouput was 300 cc. on that day; on the followiJtg day, the aminopyrine was continued and the output fell to less than 200 cc. When aminopyrine was discontinued the output rose to its original level.
The above examples are unselected except in the sense that the writers avoid this type of sedation as far as possible prior to or coincident with diuretic therapy and these experiments were conducted simply to exemplify an important point. It would be expected from the start that diuresis would be influenced by narcotics. There is an extremely rich nerve supply to the kidneys; ,the action of drugs affecting the autonomic nervous systems upon diuresis has been established. There is clinical and experimental evidence which indicates that diuresis is influenced by the central' nervous system. Moreover, drugs acting upon the nervous system can also affect the blood supply of the kidney and modify its secretory func-
THE EFFECT OF SEDATIVES ON DIURESIS
87 I
tion by an alteration of vasomotor tonus; they can also influence the production of hormonal substances which promote and depress diuresis. Finally, drugs can also influence the processes of fluid exchange between tissue and blood, in the tissues, and can act particularly upon the renal tissue itself .. The very multiplicity of these possible modes of action makes it comprehensible why an exact analysis of them soon , encounters difficulties. Two factors may act in the same direction, complement or antagonize each other, so that very complex situations, difficult to unravel, are presented. Although medicine is only imperfectly informed about the diuretic and antidiuretic action of somnifacients, clinical and experimental investigations are available concerning the extent and frequency of this effect and provide, to some extent, quite uniform results: Effect of Hypnotics on Diuresis.-The first animal experiments on the effect of hypnotics upon diuresis extend quite far into the past. In 1888, v. Schroeder found that the diuretic effect of caffeine was partly abolished by the stimUlating action of this drug upon the vasomotor nerves and the diminution of the blood supply of the kidney resulting from this. For this reason the author attempted to abolish the vasoconstriction produced by caffeine in rabbits by combining caffeine with chloral or paraldehyde; he found that diuresis was actually augmented by this. Earlier, Langgaard had studied caffeine diuresis in chloralized rabbits and subsequently Huchard warned against using morphine since it "paralyzes the kidneys." A series of investigations concerning the influence of hypnotics on diuresis were published by E. P. Pick and his pupils. They emerged from studies on pituitrin antidiuresis and its influence by narcotics. These studies not only prove that diuresis is altered by hypnotics and sedatives, but also indicate that the individual narcotics do not act uniformly. Narcotics can be divided into two large groups in respect to their action on diuresis. The so-called mesencephalic group (phenobarbital,' chloretone) depress diuresis, an action ascribed to depression of the diuresis centers. Drugs acting upon the cortex (chloral, paraldehyde) augment spontaneous diuresis as well as the diuresis provoked by caffeine and theobromine, since
LINN
J.
BOYD, DAVlD SCHERF
they abolish the normal depressant action of the cerebral centers. Water and salt diuresis are not affected in a parallel manner but in entirely different ways. Subsequently, many contradictory results were obtained. Contradictions chiefly arose owing to the fact that animal experiments were not always performed under identical conditions: For example, various species as well as various races of animals were employed, and this is not without significance in rabbit experiments. The nutriment of the animal was not always the same; the administration, of fluid in an experiment at times was accomplished through an esophageal or duodenal sound, but at other times intravenously; likewise, the amount of liquid varied and the experiments extended over various lengths of time and the intervals elapsing between the individual experiments on the same animal were not always identical. Finally, different doses of the narcotic led to entirely different results. In this manner, to mention but one example, Epstein found that luminal, which otherwise depresses diuresis, increases diuresis when the intravenous introduction of water is employed in an experiment. He explains this as an abnormal central regulatory event which is produced by the sudden hydremia; thus the centers react differently to various narcotics.
If the least alteration of the experimental arrangement suffices to modify the results even in the animal kingdom, naturally this situation prevails to a vastly greater extent in the human, and especially in the sick, individual. In patients, both the tissues and centers may react in an entirely different manner than in the healthy individual, so that "paradoxical" reactions appear just as they are encountered in animal experiments when the animal has received preliminary treatment with certain poisons. Not rarely the extent and manner of response varies from day to day since the individual factors regUlating diuresis undergo frequent alterations in cardiac patients. Thus it happens that even brief experiments in man cannot be compared with one another. Despite these difficulties a large amount of data has also been assembled in the clinic. Effect of Morphine on Diuresis.-Many years ago morphine and its derivatives were recommended as important agents for supporting digitalis therapy in patients with cardiac decompensation. Obligatory indications for morphine are cardiac asthma and pulmonary edema. After the administration of moderate amounts of morphine one may observe not only an amelioration of the dyspnea, but also a decrease of
THE EFFECT OF SEDATIVES ON DIURESIS
873
hepatic enlargement and an increase of diuresis. These therapeutic actions may be explained as indirect effects on the circulation through the reduction of dyspnea and the subsequent improvement of the heart. In older literature morphine was designated as a cardiac tonic: "Morphine is a second digitalis!" Accordingly cases of myocardial disease may be observed in which massive diuresis and decisive improvement appear without any other therapy save one injection of morphine. On the basis of abundant clinical material it has been demonstrated that a definite increase of urinary output occurs after morphine, pantopon, and chloral hydrate. On the other hand, phenobarbital and veronal were without effect, according to Hopmann. This observer believes that the promotion of diuresis by means of morphine is the result of a decrease of motor unrest rather than a consequence of lessened dyspnea. According to the same investigator, the increase of diuresis after the administration of morphine often is not distinct in dyspneic individuals and, on the contrary, may be very apparent in patients without dyspnea. Hopmann also believes that an influence on renal blood supply (effect on vasomotor centers) by morphine can be eliminated. He stresses the observation that morphine particularly increases nocturnal but not diurnal diuresis, so that morphine effects recall, to some extent, nycturia. According to Macrez, chloral is preferable to the barbiturates in decompensated cardiac patients. On the other hand, if renal function is tested by the administration of 1500 cc. of water given within a period of thirty minutes while the patient is under the influence of morphine, an unequivocal depression of diuresis is found in normal individuals; the same results were obtained in renal diseases of various types. The addition of atropine or epinephrine to morphine did not abolish the depression. The results of these investigations, performed on healthy individuals, do not contradict those obtained in decompensated cardiac patients. The effect of morphine is complex and the indirect diuretic effect in cardiac patients has other points of attack than the inhibitory effect on tbe normal kidney. Morphine assumes an intermediate position between the cerebral and mesencephalic narcotics.
LINN
J.
BOYD, DAVID SCHERF
Effect of Analgesics on Diuresis.-The following. observation possesses greater practical significance and is illustrated by the clinical excerpts presented earlier: not only'outspoken narcotics, but also analgesic agents such as antipyrine and aminopyrine, which are more frequently employed, can influence diuresis: On the occasion of his observations on the antipyretic effect of aminopyrine, Gessler noted that in addition to numerous other metabolic effects, this agent also depresses water and salt diuresis. Averbuck also found a depression of water excretion but not of salt diuresis after the administration of this drug to rabbits. At the same time Scherf studied the effect of aminopyrine on the diuresis of man. In a patient suffering from endocarditis it was striking that a marked decrease in the output of urine occurred simultaneously with the fall of temperature after the administration of 1.5 gm. of aminopyrine per day. When the drug was discontinued, the fever rose again and a copious outflow of urine followed. Systematic investigation of the effect of aminopyrine on fifty individuals (healthy, compensated, or decompensated cardiac patients and those with various other illnesses) revealed that 84 per cent of those studied showed a distinct increase of weight produced by water and salt retention after the administration of 1.5-2.0 gm. of aminopyrine daily for five days. In many instances the increase of weight amounted to more than 2 kg. Those with normal circulations also showed decreased diuresis, but the reduction of urinary output was more evident in patients with edema or those tending to manifest it. No explanation was offered for the fact that 16 per cent of the group failed to react to aminopyrine. Not only spontaneous diuresis, but also the effect of the purine or mercury diuretics is completely abolished by aminopyrine in a majority of patients. Patients who lose 6 to 8 pounds within twenty-four hours as the result of marked diuresis following the injection of a mercurial diuretic, do not react at all if the same diuretic is administered in the same dose while they are under the influence of 1.5-2.0 gm. of aminopyrine daily; as a matter of fact the weight may be even increased on the following day. In the same manner aminopyrine diminishes the thirst and thereby the ingestion of water
THE EFFECT OF SEDATIVES ON DIURESIS
875
in diabetes insipidus. Here also the excretion of chlorides is depressed in a parallel manner to the excretion of water. Aug. mentation of diuresis by aminopyrine was not encountered. If a dog in which a bladder fistula has been produced is given a 5 per cent aminopyrine solution intramuscularly and, simultaneously, 200 cc. of water is introduced into the stomach by means of a tube, a complete depression of diuresis is observed (Fig. 111). This persists for several hours. If the same experiment is repeated and 8 gm. of urea are administered in addition, the urea being administered by mouth, then
/
10 C.c. I-+-+-t-t- t--+-+-+-+--{----+-I +.-H-+--H
/
.; c.c.
I-+-+-r-+-+-+--+-h/'-:-+--+-+-+-+-+-+-+-1
/
Ic.c.
I
--10'
I HOUR
+
Z HOu"
- - - I GRAM AMINOP ... jIlN~ + 200c.c. H.O ------1 'RAM AMINOPVRINE+200c.c.H.O+ 8 GRAMS UREA
Fig. lll.-Complete depression of diuresis by aminopyrine.
the decrease in urinary output is interrupted after forty to sixty minutes. Hypertonic glucose solution administered intravenously acts similarly. Accordingly, "renal diuretics" unfold their action despite the simultaneous administration of aminopyrine. The effect of hypnotics and sedatives on diuresis of patients with diabetes insipidus has been carefully studied. But it should be anticipated that the results of observations upon healthy individuals, compensated and decompensated patients cannot be compared with those observed in diabetes insipidus;
LINN
J.
BOYD, DAVlD SCHERF
this peculiarly obvious fact often has not received adequate consideration. More recently Kahn confirmed the beneficial effect of aminopyrine in diabetes insipidus and recommended it in combination with pituitary preparations. Comment and Summary.-In general the clinical and experimental investigations described above teach that agents which act upon the central nervous system influence diuresis even when they are administered in the usual therapeutic doses. This influence is exerted in the healthy individual, but it can also be demonstrated in patients suffering from renal diseases and in some individuals with cardiac disease and is expressed predominantly as a depression. Accordingly, care should be observed in the employment of the compounds mentioned in treating patients with edema or those exhibiting a tendency to it. But while aminopyrine and related preparations depress spontaneous diuresis, in some circulatory patients an increase of urinary output is observed after the use of morphine and chloral hydrate and, under definite conditions also, after phenobarbital. To some extent, at least, this depends upon the action of the agent on the inhibiting cortical centers. Exact details on the point of attack and concerning the working mechanism of these agents are unknown. If their employment should be necessary over a long period of time, then serial determination of the body weight is absolutely indicated in order to detect latent edema or to follow the course of manifest water retention.
CLINIC OF DRS. LINN
J.
BOYD AND DAVID SCHERF
FROM THE DEPARTMENT OF MEDICINE, THE NEW YORK MEDICAL COLLEGE, FLOWER AND FIFTH AVENUE HOSPITALS THE EFFECT OF SEDATIVES ON DIURESIS
CARDIAC patients who are decompensated and edematous frequently suffer from intractable insomnia which is often provoked by respiratory disturbances. Under these circumstances the somnifacient drugs often find consideration in the therapeutic program. Presumably morphine and its derivatives occupy first place among the measures which are utilized to relieve the dyspnea of cardiac patients. Accordingly, the physician is often confronted with a situation in which he must treat the edematous cardiac patient simultaneously with diuretic and sedative drugs. Analgesic preparations may also be indicated for the relief of pain. Under these circumstances the narcotics, hypnotics and analgesics may exhibit a very pronounced influence on diuresis: They may depress it, and in this manner thwart therapeutic endeavors aimed to set diuresis into motion. Under certain conditions, however, they may initiate or promote diuresis, and accordingly exert an extremely useful and desirable effect. An awareness of the influence upon diuresis by agents which act upon the nervous system therefore possesses considerable practical significance. One aspect of this problem may be illustrated by a few excerpts from some recent case histories: Case I.-M. G., a fifty-two-year-old Puerto Rican female, entered the Hospital because of shortness of breath and palpitation. Effort dyspnea and ankle edema had been present for two years. On the day before. admission dyspnea became extreme and palpitation marked. Examination disclosed an enlarged heart with a systoIic murmur at the aortic area and an accentuated 869
LINN
J.
BOYD, DAVID SCHERF
second aortic sound. The blood pressure was 160/90. There were fine crackling rales at both bases and the liver edge was palpable three fingers below the costal margin; there was marked edema of the extremities. The cause of her congestive failure was cardiac dilatation secondary to coronary sclerosis. On the sixth day of hospitalization the patient was given 2 cc. of mercupurin intravenously. The fluid intake during the next twenty-four hours' was 1,000 cc. and the output 1,300 cc. For experimental purposes, she was given the same dose of the diuretic on the eleventh day of hospitalization. On the day preceding the injection and the day of the injection, she received 1.5 gm. of aminopyrine. 'The fluid intake was 1,000 cc. and the output 600 cc. during the twenty-four-hour period following the injection. Accordingly, the output was less than one-half the, excretion when no aminopyrine was used, despite the fact that the edema and related symptoms were as severe as at the time of the first injection. Case n.-M,. W., fifty-two years old, entered the hospital because of extreme shortness of breath. She had suffered from dyspnea on slight eff~rt, palpitation and swelling of the ankles for ten years. There had been attacks of palpitation, nocturnal dyspnea, and precordial pain. In addition to marked dyspnea, orthopnea and cyanosis, examination revealed a markedly enlarged heart with systolic and diastolic murmurs at the mitral area and asystolic murmur together with an accentuated second sound at the aortic area. The blood pressure was 190/110. There were crackling rales in both lung fields, the liver edge was palpated four fingers below the costal margin, and there was marked edema of the legs. With a fluid intake of 1,000 to 1,200 cc. per day, the output amounted to approximately 600 cc. per day. Following the injection of 2 cc. of mcrcupurin intravenously, the output rose to 1,750 cc. during the next twenty-four hours. After two days of aminopyrine, 1.5 gm. each day, mercupurin was injected in the same dose as before and the ouput was 300 cc. on that day; on the followiJtg day, the aminopyrine was continued and the output fell to less than 200 cc. When aminopyrine was discontinued the output rose to its original level.
The above examples are unselected except in the sense that the writers avoid this type of sedation as far as possible prior to or coincident with diuretic therapy and these experiments were conducted simply to exemplify an important point. It would be expected from the start that diuresis would be influenced by narcotics. There is an extremely rich nerve supply to the kidneys; ,the action of drugs affecting the autonomic nervous systems upon diuresis has been established. There is clinical and experimental evidence which indicates that diuresis is influenced by the central' nervous system. Moreover, drugs acting upon the nervous system can also affect the blood supply of the kidney and modify its secretory func-
THE EFFECT OF SEDATIVES ON DIURESIS
87 I
tion by an alteration of vasomotor tonus; they can also influence the production of hormonal substances which promote and depress diuresis. Finally, drugs can also influence the processes of fluid exchange between tissue and blood, in the tissues, and can act particularly upon the renal tissue itself .. The very multiplicity of these possible modes of action makes it comprehensible why an exact analysis of them soon , encounters difficulties. Two factors may act in the same direction, complement or antagonize each other, so that very complex situations, difficult to unravel, are presented. Although medicine is only imperfectly informed about the diuretic and antidiuretic action of somnifacients, clinical and experimental investigations are available concerning the extent and frequency of this effect and provide, to some extent, quite uniform results: Effect of Hypnotics on Diuresis.-The first animal experiments on the effect of hypnotics upon diuresis extend quite far into the past. In 1888, v. Schroeder found that the diuretic effect of caffeine was partly abolished by the stimUlating action of this drug upon the vasomotor nerves and the diminution of the blood supply of the kidney resulting from this. For this reason the author attempted to abolish the vasoconstriction produced by caffeine in rabbits by combining caffeine with chloral or paraldehyde; he found that diuresis was actually augmented by this. Earlier, Langgaard had studied caffeine diuresis in chloralized rabbits and subsequently Huchard warned against using morphine since it "paralyzes the kidneys." A series of investigations concerning the influence of hypnotics on diuresis were published by E. P. Pick and his pupils. They emerged from studies on pituitrin antidiuresis and its influence by narcotics. These studies not only prove that diuresis is altered by hypnotics and sedatives, but also indicate that the individual narcotics do not act uniformly. Narcotics can be divided into two large groups in respect to their action on diuresis. The so-called mesencephalic group (phenobarbital,' chloretone) depress diuresis, an action ascribed to depression of the diuresis centers. Drugs acting upon the cortex (chloral, paraldehyde) augment spontaneous diuresis as well as the diuresis provoked by caffeine and theobromine, since
LINN
J.
BOYD, DAVlD SCHERF
they abolish the normal depressant action of the cerebral centers. Water and salt diuresis are not affected in a parallel manner but in entirely different ways. Subsequently, many contradictory results were obtained. Contradictions chiefly arose owing to the fact that animal experiments were not always performed under identical conditions: For example, various species as well as various races of animals were employed, and this is not without significance in rabbit experiments. The nutriment of the animal was not always the same; the administration, of fluid in an experiment at times was accomplished through an esophageal or duodenal sound, but at other times intravenously; likewise, the amount of liquid varied and the experiments extended over various lengths of time and the intervals elapsing between the individual experiments on the same animal were not always identical. Finally, different doses of the narcotic led to entirely different results. In this manner, to mention but one example, Epstein found that luminal, which otherwise depresses diuresis, increases diuresis when the intravenous introduction of water is employed in an experiment. He explains this as an abnormal central regulatory event which is produced by the sudden hydremia; thus the centers react differently to various narcotics.
If the least alteration of the experimental arrangement suffices to modify the results even in the animal kingdom, naturally this situation prevails to a vastly greater extent in the human, and especially in the sick, individual. In patients, both the tissues and centers may react in an entirely different manner than in the healthy individual, so that "paradoxical" reactions appear just as they are encountered in animal experiments when the animal has received preliminary treatment with certain poisons. Not rarely the extent and manner of response varies from day to day since the individual factors regUlating diuresis undergo frequent alterations in cardiac patients. Thus it happens that even brief experiments in man cannot be compared with one another. Despite these difficulties a large amount of data has also been assembled in the clinic. Effect of Morphine on Diuresis.-Many years ago morphine and its derivatives were recommended as important agents for supporting digitalis therapy in patients with cardiac decompensation. Obligatory indications for morphine are cardiac asthma and pulmonary edema. After the administration of moderate amounts of morphine one may observe not only an amelioration of the dyspnea, but also a decrease of
THE EFFECT OF SEDATIVES ON DIURESIS
873
hepatic enlargement and an increase of diuresis. These therapeutic actions may be explained as indirect effects on the circulation through the reduction of dyspnea and the subsequent improvement of the heart. In older literature morphine was designated as a cardiac tonic: "Morphine is a second digitalis!" Accordingly cases of myocardial disease may be observed in which massive diuresis and decisive improvement appear without any other therapy save one injection of morphine. On the basis of abundant clinical material it has been demonstrated that a definite increase of urinary output occurs after morphine, pantopon, and chloral hydrate. On the other hand, phenobarbital and veronal were without effect, according to Hopmann. This observer believes that the promotion of diuresis by means of morphine is the result of a decrease of motor unrest rather than a consequence of lessened dyspnea. According to the same investigator, the increase of diuresis after the administration of morphine often is not distinct in dyspneic individuals and, on the contrary, may be very apparent in patients without dyspnea. Hopmann also believes that an influence on renal blood supply (effect on vasomotor centers) by morphine can be eliminated. He stresses the observation that morphine particularly increases nocturnal but not diurnal diuresis, so that morphine effects recall, to some extent, nycturia. According to Macrez, chloral is preferable to the barbiturates in decompensated cardiac patients. On the other hand, if renal function is tested by the administration of 1500 cc. of water given within a period of thirty minutes while the patient is under the influence of morphine, an unequivocal depression of diuresis is found in normal individuals; the same results were obtained in renal diseases of various types. The addition of atropine or epinephrine to morphine did not abolish the depression. The results of these investigations, performed on healthy individuals, do not contradict those obtained in decompensated cardiac patients. The effect of morphine is complex and the indirect diuretic effect in cardiac patients has other points of attack than the inhibitory effect on tbe normal kidney. Morphine assumes an intermediate position between the cerebral and mesencephalic narcotics.
LINN
J.
BOYD, DAVID SCHERF
Effect of Analgesics on Diuresis.-The following. observation possesses greater practical significance and is illustrated by the clinical excerpts presented earlier: not only'outspoken narcotics, but also analgesic agents such as antipyrine and aminopyrine, which are more frequently employed, can influence diuresis: On the occasion of his observations on the antipyretic effect of aminopyrine, Gessler noted that in addition to numerous other metabolic effects, this agent also depresses water and salt diuresis. Averbuck also found a depression of water excretion but not of salt diuresis after the administration of this drug to rabbits. At the same time Scherf studied the effect of aminopyrine on the diuresis of man. In a patient suffering from endocarditis it was striking that a marked decrease in the output of urine occurred simultaneously with the fall of temperature after the administration of 1.5 gm. of aminopyrine per day. When the drug was discontinued, the fever rose again and a copious outflow of urine followed. Systematic investigation of the effect of aminopyrine on fifty individuals (healthy, compensated, or decompensated cardiac patients and those with various other illnesses) revealed that 84 per cent of those studied showed a distinct increase of weight produced by water and salt retention after the administration of 1.5-2.0 gm. of aminopyrine daily for five days. In many instances the increase of weight amounted to more than 2 kg. Those with normal circulations also showed decreased diuresis, but the reduction of urinary output was more evident in patients with edema or those tending to manifest it. No explanation was offered for the fact that 16 per cent of the group failed to react to aminopyrine. Not only spontaneous diuresis, but also the effect of the purine or mercury diuretics is completely abolished by aminopyrine in a majority of patients. Patients who lose 6 to 8 pounds within twenty-four hours as the result of marked diuresis following the injection of a mercurial diuretic, do not react at all if the same diuretic is administered in the same dose while they are under the influence of 1.5-2.0 gm. of aminopyrine daily; as a matter of fact the weight may be even increased on the following day. In the same manner aminopyrine diminishes the thirst and thereby the ingestion of water
THE EFFECT OF SEDATIVES ON DIURESIS
875
in diabetes insipidus. Here also the excretion of chlorides is depressed in a parallel manner to the excretion of water. Aug. mentation of diuresis by aminopyrine was not encountered. If a dog in which a bladder fistula has been produced is given a 5 per cent aminopyrine solution intramuscularly and, simultaneously, 200 cc. of water is introduced into the stomach by means of a tube, a complete depression of diuresis is observed (Fig. 111). This persists for several hours. If the same experiment is repeated and 8 gm. of urea are administered in addition, the urea being administered by mouth, then
/
10 C.c. I-+-+-t-t- t--+-+-+-+--{----+-I +.-H-+--H
/
.; c.c.
I-+-+-r-+-+-+--+-h/'-:-+--+-+-+-+-+-+-+-1
/
Ic.c.
I
--10'
I HOUR
+
Z HOu"
- - - I GRAM AMINOP ... jIlN~ + 200c.c. H.O ------1 'RAM AMINOPVRINE+200c.c.H.O+ 8 GRAMS UREA
Fig. lll.-Complete depression of diuresis by aminopyrine.
the decrease in urinary output is interrupted after forty to sixty minutes. Hypertonic glucose solution administered intravenously acts similarly. Accordingly, "renal diuretics" unfold their action despite the simultaneous administration of aminopyrine. The effect of hypnotics and sedatives on diuresis of patients with diabetes insipidus has been carefully studied. But it should be anticipated that the results of observations upon healthy individuals, compensated and decompensated patients cannot be compared with those observed in diabetes insipidus;
LINN
J.
BOYD, DAVlD SCHERF
this peculiarly obvious fact often has not received adequate consideration. More recently Kahn confirmed the beneficial effect of aminopyrine in diabetes insipidus and recommended it in combination with pituitary preparations. Comment and Summary.-In general the clinical and experimental investigations described above teach that agents which act upon the central nervous system influence diuresis even when they are administered in the usual therapeutic doses. This influence is exerted in the healthy individual, but it can also be demonstrated in patients suffering from renal diseases and in some individuals with cardiac disease and is expressed predominantly as a depression. Accordingly, care should be observed in the employment of the compounds mentioned in treating patients with edema or those exhibiting a tendency to it. But while aminopyrine and related preparations depress spontaneous diuresis, in some circulatory patients an increase of urinary output is observed after the use of morphine and chloral hydrate and, under definite conditions also, after phenobarbital. To some extent, at least, this depends upon the action of the agent on the inhibiting cortical centers. Exact details on the point of attack and concerning the working mechanism of these agents are unknown. If their employment should be necessary over a long period of time, then serial determination of the body weight is absolutely indicated in order to detect latent edema or to follow the course of manifest water retention.