Clinical evaluation of a "diuretic cocktail"

LAWRENCE J. GALLA, A.B., D.O., and WIL- acetazoleamide depressing hydration of carbon LIAM BALDWIN, JR., D.O., F.A.C.0.1., York, dioxide, exchange resins drawing salt from food Pennsylvania in the intestinal tract, or water diuresis. Therefore, diuretic therapy should be planned to permit daily salt and water balance. The treatment should take into account the particular type of fluid or electro- The characteristics of an ideal diuretic can be lyte to be removed, the need for speed in its re- easily enumerated; it should be effective without moval, and the setting in which it will be done. producing electrolyte disturbance, nephrotoxicity, Oral diuretics, for example, are desirable; however, sensitivity, refractoriness, or cardiac toxicity. How- they are often not powerful enough for acute or ever, in practice, a compound encompassing these emergency problems, or they may irritate the pa- properties remains to be found. Furthermore, be- tient's stomach. It may be said that oral diuretics cause of the many factors involved in the patho- are useful in cases where a modest diuretic action logic states that result in abnormal water retention, is satisfactory. Other clinical situations are met by a universal diuretic—that is, one that will work in other means. every situation—has yet to to be made available. Diet is rather important. Patients with edema In recent years a number of new diuretic drugs will probably have to accept a low-salt diet sooner utilizing various physiologic principles have ap- or later; the sooner they start, the sooner better peared. From time to time chemical modifications results can be expected. But even marked sodium of these drugs are elaborated, to improve on the restriction is a powerful tool and has inherent established modalities.1,2 dangers. Sodium depletion and electrolyte imbal- The purpose of this paper is to review briefly ance have led to the development of weakness, some of the advantages and disadvantages of cer- anuria, and azotemia, and when the cause was tain types of established diuretics, and to report unrecognized and untreated, death has resulted. a clinical study comparing the diuretic response of The danger is particularly great in patients with what we shall call a "diuretic cocktail" with that renal disease. of oral diuretics in comparable clinical entities. Although there is no such thing as an ideal diuretic, several are useful for different situations. Basis and means for diuretic therapy Some classes of these agents will now be reviewed.

Diuretics are almost always used for removal of Acid formers • Ammonium chloride and other acid extracellular fluid. Regardless of their site of action, formers have been used in the treatment of edema diuretics must accomplish this by increasing the both for their own diuretic action and because excretion of sodium. Because their action is never they enhance the action of the mercurials and the specific for sodium alone, but involves other ions xanthines. It has been demonstrated that ammo- as well, it could be said that diuretics always nium chloride, given over a period of 2 or 3 days, threaten electrolyte homeostasis. may double the effect of the mercurial agents.' Electrolyte imbalance can be induced, then, by However, within a few days of continuous admin- restriction of sodium in the diet, mercurial agents istration, ammonium chloride become ineffective inhibiting salt reabsorption in the renal tubule, as a diuretic. Moreover, in spite of this self-limiting Dr. Calla is in the third year of a residency in osteopathic medicine at protective device to conserve base, ammonium West Side Osteopathic Hospital, York, Pennsylvania, where Dr. Bald- chloride sometimes causes acidosis. The drug is win is chairman of the Department of Osteopathic Medicine. 207 JOURNAL A.O.A., VOL 61, NOV. 1961 especially dangerous in elderly persons, in whom Excretion of sodium and chloride is increased; so, the ability of the kidneys to excrete acid urine and to a lesser degree, is excretion of potassium. Occa- urea is diminished. sionally bicarbonate is excreted, and there is a Toxic symptoms include weakness, nausea, and compensatory reduction in excretion of ammonia. vomiting. Two of the commonest members of this group are hydrochlorothiazide and chlorothiazide. Osmotic agents • The use of urea as a diuretic has Toxic reactions include dehydration, hypochlo- decreased since the introduction of the newer, more remic alkalosis, and hypokalemia. Thirst, weakness, dependable agents. lethargy, drowsiness, and tachycardia may appear; While the osmotic diuretics may induce a degree occasional vertigo and paresthesia have been re- of salt loss, this loss is usually not very great. How- ported. ever, these drugs can still be considered a physio- Benzydroflumethiazide ( Naturetin) and hydro- logic approach to diuresis. flumethiazide (Saluron ) have recently gained prom- inence and have shown promise in the field of Xanthines • These agents act by decreasing the diuretic therapy. For added protection in conditions absorption of water in the proximal tubules. They predisposing to hyponatremia, and for patients on are considered secondary to the mercurials; the long-term therapy, potassium has been added to use of aminophylline as a supplement to the mer- benzydroflumethiazide. curial agents in the treatment of intractable con- gestive heart failure has been recommended.' The Spironolactones • These agents bear a close struc- xanthines are not considered as effective or de- tural similarity to one of the sodium-retaining hor- pendable as the mercurials in the treatment of mones of adrenal cortex, aldosterone. They act by edema. a competitive inhibition to block the action of Fatalities and less serious manifestations such as aldosterone on the distal tubules. They are effec- gastrointestinal distress have been reported when tive only when edema is caused by liberation of aminophylline is given intravenously, especially at aldosterone, a condition which exists when the a rapid rate. If given intramuscularly, local discom- aldosterone-stimulating hormone is liberated from fort is common. the anterior pituitary as a result of stimulation of osmolar or volume receptors. Mercurials • These are the most effective diuretics. Because the loss of fluid from the intravascular They act by inhibiting succinic dehydrogenase in or interstitial compartments may result in a com- the distal tubule of the kidney. This prevents re- pensatory increase in secretion of aldosterone, spiro- absorption of sodium and chloride and causes loss nolactone (Aldactone) can be used to block the of these two ions and water. There is no significant "rebound" that usually follows an effective diuresis alteration in potassium excretion. During the period produced by other agents given for treatment of of greatest sodium loss ( 2 to 6 hours after adminis- congestive heart failure. tration) ammonium excretion is slightly depressed. Aldactone is by no means a panacea for the The onset of drug action is within 2 hours after treatment of congestive heart failure, but it is use- administration, and the effect lasts 12 to 18 hours. ful. It also seems to be effective in edema caused Two of the most commonly used parenteral agents by cirrhosis of the liver. in this class are meralluride ( Mercuhydrin ) and mercaptomerin ( Thiomerin). Carbonic anhydrase inhibitors • Acetazoleamide Toxic reactions to the mercurials include, besides (Diamox) acts by inhibiting carbonic anhydrase symptoms attributable to electrolytic imbalance, activity in the renal tubules. When this occurs, the chills, fever, malaise, muscular aching, nausea, production of hydrogen to be exchanged for sodium erythema, chest pain, vomiting, dyspnea, and al- is impaired. The result is a loss of chloride, sodium, lergic reaction.' bicarbonate, and water. The effect diminishes rapid- ly within 48 hours, in spite of continued adminis- Isocytosines • Diuretics in this group are interest- tration. ing, but they have limited usefulness. 3 One agent Because of the loss of bicarbonate in the urine, is amisometradine (Rolicton). The excretion of the effective action may produce a hyperchloremic sodium and chloride reaches a peak in 12 hours acidosis, because the chloride ion is retained at the with these agents. Potassium excretion is increased, expense of the bicarbonate. However, this may be and bicarbonate excretion is decreased. turned to advantage, because the hyperchloremic Toxic factors include the production of such acidosis thus produced will potentiate the effect gastrointestinal symptoms as nausea and diarrhea. of a mercurial diuretic. The refractory property of this type of diuretic causes it to lose effectiveness if it is used daily. Clinical study

Chlorothiazide • This agent and its congeners are The "diuretic cocktail" used in this study consists probably the most potent oral diuretics. Their mode of 500 cc. of 5 per cent dextrose in water, 2 cc. of action resembles that of the carbonic anhydrase of meralluride, and 500 mg. of aminophylline. It inhibitors; they also act directly on the renal tubules. is given intravenously over a period of 3 to 4 hours.

208 TABLE I-WEIGHT LOSS IN FIRST 24 HOURS Total No. No. pounds Average Group and description No. patients patients lost loss

Group I: Results with diuretic cocktail 10 2 5 3 4 4 2 5 1 6 1 9 2 Refractory 25 3.04 Group II: Results with oral diuretics and digitalis 30 1 5 2 35 1.14

TABLE II-AVERAGE WEIGHT LOSS ON FIRST 5 DAYS Electrolytes • There was no great alteration in the level of sodium, potassium, or chloride ions in Group II Group I (oral diuretics patients treated with the diuretic cocktail. As can Day of ( diuretic cocktail): and digitalis): be seen in Table III, the sodium fraction dropped treatment average pounds lost average pounds lost 2.0 mEq. in 5 days of treatment; potassium dropped 1 2.7 1.0 0.1 mEq., and chloride dropped 6.0 mEq. This 2 4.0 1.5 shows that it is possible to administer diuretics 3 5.0 2.5 without appreciable impairment of electrolyte bal- 4 6.0 3.5 ance. 5 7.0 3.5 Clinical failures • Two patients were refractory to This therapeutic method was first reported in the diuretic cocktail. One patient had an allergic 1959.2 In the present study, we used it in 25 reaction, developing pruritus at the injection site. patients (Group I) with congestive heart failure The other developed a dilution syndrome. Treat- who were treated at West Side Osteopathic Hos- ment was discontinued in both cases. pital. Ten of these patients had previously become refractory to treatment with oral diuretics and digi- TABLE III-AVERAGE DAILY ELECTROLYTE FRACTIONS OF talis. PATIENTS GIVEN DIURETIC COCKTAIL For purposes of comparison, another group of Day of Sodium Potassium Chloride 35 patients (Group II) with congestive heart failure treatment (mEq.) (mEq.) ( mEq. ) was treated with oral diuretics ( 30 with benzydro- flumethazine, and 5 with mercurial agents) and 1 140 4.6 104 2 138 4.5 101 digitalis. 3 138 4.5 99 Because of the great number of clinical variables 4 138 4.5 99 in this condition, only some general observations 5 138 4.5 98 about results can be offered.

Weight loss • The average weight loss in the first Summary 24 hours of treatment was just over 1 pound in patients treated with oral diuretics and digitalis, Effective diuretic administration presupposes that and just over 3 pounds in patients treated with the the physician possesses some knowledge of the diuretic cocktail. The group treated with the di- renal mechanism for sodium reabsorption and of uretic cocktail includes two patients who proved the inhibition of this process. Various diuretics act refractory to the treatment; if they are excluded at various stages to prevent sodium retention, with from the average, the loss for the 23 remaining varying degrees of efficacy and safety. In a clinical patients was 3.3 pounds. The distribution and range study of patients with congestive heart failure, we of loss are reported in Table I. found that a "diuretic cocktail" consisting of 500 cc. Table II records the average total weight loss for of 5 per cent dextrose in water, 2 cc. of meralluride, the two groups for each of the first 5 days of and 500 mg. of aminophylline, given intravenously diuretic therapy. As can be seen, patients treated in 3 to 4 hours, was more efficacious than oral with the diuretic cocktail lost an average of twice diuretics and digitalis, as demonstrated by loss of as much weight during the 5-day period as those weight. Two of the 25 patients treated with the treated by other means. cocktail were refractory; one had an allergic re-

JOURNAL A.O.A., VOL. 61, NOV. 1961 209 action (pruritus at the injection site) and the other sium on edema, conducted by Hahnemann Hospital, Philadelphia, Sept. 1959. developed a dilution syndrome. 3. Merrill, J. P.: Use and abuse of diuretics. M. Clin. North We feel that the synergistic and potentiating America 44:1155-1166, Sept. 1960. action of a combination of diuretics has been Beckman, H.: Drugs; their nature, action and use. W. B. Saunders demonstrated by this study. The diuretic cocktail Co., Philadelphia, 1958. accomplished clinically significant diuresis in most Bland, J. H.: Clinical recognition and management of disturbances of body fluids. Ed. 2. W. B. Saunders Co., Philadelphia, 1956. instances, even in cases where other diuretic agents Blumgart, H.: Symposium on congestive heart failure. American had failed. Heart Association, 1960. Duncan, G. C.: Diseases of metabolism. Ed. 2. W. B. Saunders Co., Philadelphia, 1959. Friedberg, C. K.: Diseases of heart. Ed. 2. W. B. Saunders Co., 1. Modell, W.: Drugs of choice: 1958-1959. C. V. Mosby Co., Philadelphia, 1956. St. Louis, 1958. Hoffman, \V. S.: Biochemistry of clinical medicine. Ed. 2. Year 2. Urrichio, J.: Use of diuretics in severe heart failure, in Sympo- Book Publishers, Chicago, 1959.

Osteogenesis imperfecta: Case report

DONALD W. KETNER, D.O.,* Detroit, Michigan Case report

A 14-year-old girl was first seen on the orthopedic service at the Detroit Osteopathic Hospital on Osteogenesis imperfecta is a hereditary, often con- August 5, 1957. Her chief complaint was inability genital and familial disease which is manifested by to walk for the past 3 years, and marked deformities an inability to produce adequate and normal inter- of the lower extremities. She had had 43 recognized cellular substances of certain mesenchymal deriva- fractures since birth. The birth was described as tives, particularly osteoblasts and fibroblasts, in atraumatic, although there was a fracture of the various body areas. The result is a young patient proximal left femur at that time. There is now a with a fragile skeleton, thin skin and sclera, poor pseudoarthrosis at that site. teeth, a tendency to macular bleeding, and hyper- The family history was negative and the child's mobility of joints. system history was within normal limits for the age There are two forms of the disease. Osteogenesis group. imperfecta congenita is noted at birth and has ob- Physical examination revealed a 14-year-old white viously developed in utero. It is often fatal. Oste- female of normal mental development, who was 3 ogenesis imperfecta tarda starts its course sometime feet 6 inches tall and 57 pounds in weight. She in childhood. It may produce symptoms of disturb- was unable to stand or walk. There was a marked ance in only one or two systems, and its effects are dorsolumbar scoliosos and distortion of both lower much less severe than those of the congenital form. extremities. Laboratory examination revealed nor- The disease is quite rare, but it has been rec- mal serum calcium and phosphorus; other hema- ognized for nearly 200 years. It apparently occurs tologic findings were also normal. as a spontaneous mutation and, once established Various projections of the dorsal spine, chest, in the hereditary apparatus, it persists as a domi- and pelvis (Figs. 1, 2, and 3) showed a marked nant characteristic. dorsolumbar scoliosis with the convexity of the Presented at the annual meeting of the American Osteopathic Acade- lower curve to the right. The pelvis was flattened my of Orthopedics, Los Angeles, October 28, 1959. This paper was in the anteroposterior as well as the lateral plane. prepared during a residency in the Department of Orthopedics, Detroit Osteopathic Hospital, on the service of Dr. John P. Wood, senior The fourth, fifth, sixth, and seventh ribs showed attending surgeon. pseudofractures in the posterior lateral margins on °Address, 2673 W. Grand Blvd. the right.

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