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THE EFFECT OF ON THE ELECTROCARDIOGRAM OF ANIMALS AND RELATION OF THIS EFFECT TO THE RATIO OF THE INTRACELLULAR AND EXTRACELLULAR CONCENTRATIONS OF POTASSIUM

Victor A. McKusick

J Clin Invest. 1954;33(4):598-610. https://doi.org/10.1172/JCI102931.

Research Article

Find the latest version: https://jci.me/102931/pdf THE EFFECT OF LITHIUM ON THE ELECTROCARDIOGRAM OF ANIMALS AND RELATION OF THIS EFFECT TO THE RA- TIO OF THE INTRACELLULAR AND EXTRACELLULAR CONCENTRATIONS OF POTASSIUNI By VICTOR A. McKUSICK 1 (From the Clinic of Genieral Medicine anid Experimental Therapeutics of the Nationial Hcart Institute [Cardiovascular Cliniic, U.S.P.H.S. Hospital, Baltinmore, Md.] and the De- partnent of Mledicine, Johnis Hopkinis Untiversity and Hospital, Baltimore, Md.) (Submitted for publication July 16, 1953; accepted December 30, 1953)

The cardiac toxicity of the potassium is fa- three larger species it was given by continuous intrave- miliar from observations both in animals and in nous infusion. The intravenous were adminis- man. With elevation of the serum potassium a vir- tered at rates which delivered 300 mEq. of lithium in a varying from 15 to 90 minutes in individual ex- tually pathognomonic sequence of electrocardio- periments. In the guinea pigs 20 cc. of isotonic LiCl solu- graphic changes occurs. Of interest is the effect tion was administered intraperitoneally at intervals of on the of elements from the same periodic 15 to 20 minutes. Electrocardiograms were recorded at , e.g., lithium, , and cesium. With frequent intervals by means of a Sanborn direct-writinig the reporting (1-5) of patients with severe un- electrocardiograph. In dogs, contact electrodes with con- ductant jelly were used, whereas in the smaller ani- toward reactions from lithium salts taken as a so- mals wires piercing the limbs and attached to dium substitute, it became of practical signifi- "Fahnstock" clips established contacts with the lead cance to evaluate the role of the cardiac toxicity cables. In the case of the dogs, blood samples were taken (if any) in the total picture of lithium intoxication. as the successive electrocardiographic changes developed. Unexpectedly these studies of the effects of lithium In the smaller species, the blood was sampled only at . All animals were anesthetized at the be- disclosed interesting features of potassium me- ginning of the experiments with 65 mg. of pentobarbital tabolism. Because of ramifications of possible for each 5 lbs. of body wxeight administered theoretical significance in this connection, a miiore intraperitoneally. detailed report than that of four years ago (6) was Concentrations of sodium, potassium and lithium in the deemed desirable. serum were estimated by means of the Beckman DU In Hesse Spectrophotometer with flame attachment. In the case 1875, (7) demonstrated that lithium of lithium, observations were made at a wave length of chloride administered intravenously caused dia- 671 millimicrons. stolic stoppage of the heart while nerves and mus- For purposes of estimating lithium and inuliii spaces cles were still irritable. Krumhoff (8, 9) con- three dogs were subjected to bilateral nephrectomy. Im- firmed this finding in 1884 and made the significant mediately thereafter in two animals 50 cc. of 0.65 per additional observation that much more lithium than cent of LiCl and 10 cc. (1 Gm.) of inulin were administered intravenously to each animal. In a third potassium is necessary to produce cardiac arrest. animal only inulin space was determined. The blood was From neuromuscular experiments, MAilheiro (10) sampled one hour after administration of the inulin and concluded that the effect of lithium is an additive lithium solutions and daily thereafter until death. one with potassium. and were withheld in these animals. Estimations of the concentration of inulin in plasma were made by Har- rison's modification (12) of the method of Alving, Rubin, METHODS and Miller (13). In acute experiments modeled after those of Winkler, The effect of lithium on the loss of potassium from in- Hoff, and Smith (11) wvith potassium, lithium chloride, cubated suspensions of human red blood cells was exam- usually in isotonic 0.65 per cent solution, was administered ined in the following manner: suspenisions of red cells (as parenterally to six dogs, one cat, two rabbits and six whole blood) were prepared in various proportions of guinea pigs (cf. Table I A, B, C, D). In the case of the isotonic LiCl (0.65 per cent) solution and of isotonic guinea pigs the solution of lithium chloride was given by NaCl (0.85 per cent) solution, as indicated in Figure 6. intermittent intraperitoneal injection, whereas in the Each suspension was prepared in triplicate and incubated at 370 C. for 24 hours. At 1, 8, and 24 hours one of each 'Present address: The Johns Hopkins Hospital, Balti- set of three was removed from incubation and the super- more 5, Maryland. natant analyzed for potassium, sodium, and lithium. 598 EFFECTS OF LITHIUM ON THE ELECTROCARDIOGRAM 599

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A. Control tracings (2 :30 p.m.).

B. The first change, peaking of T waves, is demonstrated (4:15 p.m.).

C. Auricular fibrillation and pronounced slowing of the ventricular rate have developed (7:45 p.m.). The T waves are markedly peaked.

RESULTS fibrillation in about an equal number of animals. At autopsy all of these animals showed dilated The electrocardiographic effects of acute parenteral suggesting cessation in diastole. (Loud lithium administration in animals systolic murmurs suggesting cardiac dilatation

A consistent series of electrocardiographic events were heard in the later stages.) In some there were in the was observed in all 15 animals of the four species petechial hemorrhages myocardium. Both of these changes were described Krum- studied (Figures 1 and 2). First, the T waves be- by hoff (8). came high, narrow, and peaked. Secondly, atrial Two guinea pigs were given standstill and less frequently atrial fibrillation solution in an exactly comparable manner. These supervened. First, second, and third degree atrio- animals also showed impairment of A-V conduc- ventricular was observed in some guinea pigs tion before the development of atrial standstill or before the development of the abnormality of atrial atrial fibrillation, both of which occurred in these mechanism. In two dog experiments intra-atrial animals. In general, the same sequence of changes electrocardiograms by electrode catheter corrobo- was seen as has been described for potassium in rated the impression of auricular fibrillation fol- the dog ( 1 1). lowed by atrial standstill at this stage. Thirdly, The significant finding was that lithium pro- widening of the QRS appeared and finally there duced the same electrocardiographic sequence as developed a bizarre, biphasic QRS-T pattern at a did potassium. Hitherto the series of changes slow rate, omen of cardiac arrest. The terminal described has been considered unique for hyper- event was ventricular standstill or ventricular kalemia. 602 VICTOR A. MCKUSWcX appeared to antagonize the electro- in serum lithium concentration, progressed through cardiographic effects of lithium to some extent. the characteristic changes to ventricular standstill. Sodium was a more effective antagonist. In one A reciprocal relationship between lithium and so- dog carried to end-stage changes with lithium, (iuum concentrations is demonstrated (Figures 4 striking improvement, including the return of P and 5). (There are suggestions from clinical ex- waves, accompanied saline infusion. perience [14] that exaggerates the electrocardiographic effects of hyperkalemiiia. Such DISCUSSION may have been the case to some extent in this situation.) No data was obtained bearing on the The mechanism of electrocardiographic the changes question of whether the hyponatremia was the re- of hyperlithemia sult of dilution, intracellular shift, or natriuresis, Figures 3, 4, and 5, present charts of three rep- or of some combination of these mechanisms. resentative dog experiments. In all of the dogs, Inasmuch as the serum lithium concentration serum potassium concentration rose steadily in the bore no direct relationship to the stage of electro- presence of hyperlithemia, attaining a level of cardiographic change observed and since the se- about 10 mEq. per liter at the time of cardiac ar- rum potassium concentration did, it is logical to rest. In one animal (Figure 3) serum potassium assume that the electrocardiographic changes are concentration continued to rise steadily even after the result of potassium shifts produced by lithium. the lithium infusion was discontinued, and the elec- It is unlikely that renal retention of potassium con- trocardiogram, rather than improving with the fall tributes to the elevation of the serum concentration

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D. Thentermltainalsiiovntriulapatrpa.mlw.aei)dmntatd(.00pm) 604 VICTOR A. MCKUSICK since the experiments were of only a few hours except the cat, contains relatively little potassium duration, since urinary output was well maintained (16), could hardly explain the potas- until late in each experiment, and since studies of sium alteration observed. my own and of others (15) reveal an increased The possibilities remain that lithium induces a renal clearance of potassium when lithium is given. rise in serum potassium either by displacing the There was little hemolysis in the blood specimens latter ion from the interior of the cell or, less likely, from which the data were accumulated. At any by causing loss of potassium from the cell by in- rate, since the red blood cell of all the animals used, direct means. Both factors may be operative. In-

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1 2 3 4 5 HOURS FIGURE 3 Serum potassium concentration continued to rise and electrocardiographic changes to progress in spite of discontinuation of the lithium chloride infu- sion with resulting fall in serum lithium concentration. Death occurred at the point indicated by the last set of determinations. EFFECTS OF LITHIUM ON THE ELECTROCARDIOGRAM 605

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15 30 4 5 60 75 90 105 MINUTES FIGuRE 4 This chart also demonstrates the steady progression of potassium rise and electro- cardiographic change. It also demonstrates a reciprocal relationship between lithium and sodium. Death occurred at the time indicated by the last set of electrolyte determinations. tracellular distribution of the lithium ion is sup- nephrectomized dogs was observed by Finken- ported by comparison of inulin and lithium spaces. staedt, O'Meara, and Merrill (19). The data, dealing with inulin and lithium spaces Some of the data from the experiments to test in nephrectomized dogs, which are presented in the effect of lithium on the loss of potassium from Table II indicate that the lithium space always incubated red blood cells are graphically presented exceeded the inulin space to a significant degree. in Figure 6. The potassium concentration of the These data suggest considerable intracellular dis- supernatant at the first hour is indicated as "O" tribution of the lithium ion. Similar findings have and the increment in potassium concentration been presented by several groups of workers (15, thereafter charted. All the suspensions in LiCl 17, 18). The low values for inulin space at one showed greater increments in the potassium con- hour probably indicate incomplete distribution in centration of the supernatant than did the suspen- the extracellular compartment. On the other hand, sions in NaCl alone. It is impossible to be certain the high values for lithium space on the later days from the sodium concentrations in the supernatant probably reflect extrarenal losses of lithium in whether the loss of potassium from the red cells stool, saliva, and vomitus. The phenomenon of represented displacement by one of these or steadily rising inulin space (Table II) after a not, since there were no significant changes in the single injection of inulin in anuric patients and concentration of these ions. Ponder (20) was un- 606 VICTOR A. MCKUSICK

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FIGuiE 5 The reciprocal relationship between lithium and sodium is again indicated. Calcium seemed to afford little protection against the effects of lithium on the electrocardiogram and in the amounts used may have contributed to the total toxicity. The last set of electrolyte determinations was derived from blood taken at the time of death. able to demonstrate any effect of lithium on the in low concentrations on aerobic and anaerobic loss of potassium from red cells. glycolysis (23), inasmuch as normal glycolysis Unpublished results of Ling (21 ) in direct appears to be indispensable for the integrity of the skeletal muscle analyses demonstrate that lithium cell membrane, viz., the effects of sodium fluoride can displace 90 per cent or more of the potassium (24) and of iodo-acetate (25) which in skeletal from the interior of the cell. Lithium concentra- muscle produce a gradual fall in tion within the muscles rose in direct proportion to and a loss of potassium from the muscle cell. the fall in potassium concentration. Interesting in this connection are the ingenious The relationship of the physiologic effects of po- older experiments of Odqvist (22) who studied tassium to the ratio of its intracellular and ex- the effect of low concentrations of lithium on the tracellular concentrations penetrability of potassium for the skin of tad- The serum potassium levels at which cardiac ar- poles. Also pertinent may be the effects of lithium rest occurred in these acute experiments was 3 to 6 EFFECTS OF LITHIUM ON THE ELECTROCARDIOGRAM 607 mEq. per liter lower than those which produced in the vicinity of 30. With renal retention of po- cardiac arrest when potassium chloride was in- tassium, a situation roughly comparable to that in fused in acute experiments (11). It is proposed the infusion experiments may result and the ra- that the cardiac effects of the potassium ion are not tio be reduced to about 10 at the extreme with a function of its absolute concentration in the ex- production of characteristic electrocardiographic tracellular fluid. Instead it may be a function of changes. (Concurrent factors which exaggerate the ratio of its concentrations within and without the effects of , such as the cell (KIC/KEC) (see Figure 7). In the nor- and hyponatremia, are disregarded for the purposes mal situation this ratio is assumed to have a value of this exposition.) In hyperlithemia, by reason

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FIG. 6. EFFECT OF LITHIUM ON THE Loss OF POTASSIUM FROM THE HUMAN RED BLOOD CELL WITH INCREMENTS IN POTASSIUM CONCENTRATION OF SUS- PENDING MEDIA OF VARIOUS CONSTITUTIONS (SEE TEXT FOR DETAILS) 608 VICTOR A. MCKUSICK

TABLE II Lithium and inulin spaces in nephrectomized dogs*

Time after nephrectomy Dog Body wt. Inulin space Lithium space Kg. Liters % body wt. Liters %/0 body w'. 1 hour A B 19.6 2.020 10.4 6.700 34.2 C 18.6 2.290 12.3 7.520 40.1

1 day A 16.8 2.150 12.8 B 18.7 2.840 15.2 16.450 88.2 C 17.3 2.965 17.1 12.050 69.6 2 days A 16.4 3.220 19.3 B 17.3 3.270 18.9 15.340 88.7 C 16.8 4.140 24.8 14.700 87.6 3 days A 15.4 3.510 22.8 B 16.4 3.710 22.7 13.290 81.0 C 16.4 14.700 89.7 4 days A 14.5 4.280 29.6 C 15.9 4.160 26.2 20.250 128.7 5 days A 13.6 5.215 38.3 * Dog A. 1 Gm. inulin. Dog B. 1 Gm. inulin and 38.4 mEq. lithium. Dog C. 1 Gm. inUIlin and 23.6 mEq. lithium. of a lowering of intracellular potassiuim concentra- familial periodic paralysis, a fall in serumipotas- tion, KIC/KEC may be lowered, ro& ughly to the sium concentration appears to be the result of shift same value of 10, and the same electro(cardiographic of potassium into cells (26). Because of the re- changes produced without as mark(ed an eleva- sulting increase in the numerator of the ratio, it tion of extracellular potassium. miiight be expected that not so miiarked a fall in se- In diabetic acidosis characteristic hypokalemiiic rum potassium concentration would be necessary electrocardiographic changes may resitilt fromii ele- to produice a given physiologic effect. Analvsis of vation of the KIC/KEC value to 100, 1l et us say. IN reported cases does seem to in(licate that suclh is the case. RATIO OF INTRACELLULAR K+ TO EXTRACELLULAR K+ The values employed in Figure 7 were selectedl KIC for illustrative purposes only It is likely that the K EC fall in intracellular potassium concentration witl hyperlithemia is miiuch less pronounced than indi- NORMAL 15 -=303 5 cated here (27). Assuming that cell water is re- sponsible for 50 per cent of body weight and ex-

RENAL RETENTION 05 HIGH K+ EKG tracellular water for 20 per cent alnd asstuming that the dog excretes a maximum of 200 miiicro-equiva- lents per minute of potassiutm during lithiutmii ad- HYPERLITHEMIA 10 HIGH K+ EKG miiinistration (15), then the estimatedI clhange in intracellular potassiumii concentration wxould not

120 exceed 10 per cent of the normiial value in Dogs 2. DIABETIC ACIDOSIS 100 LOW K~EKG 5, and 6 reported above. Several hours may be necessary (28, 29) for the 2 FAMILIAL PERIODIC LOW K* EKG restoration of intracellular concentra- PARALYSIS 1.6 potassium tion in a situation of intracellular depletion such as FIG. 7. A THEORETICAI EXPOSITION OF I diabetic acidosis or severe . Particularly SHIP OF THE RATIO OF THE INTRACELLULAIRTHENANDREXATRA-EXTRA- CELLULAR CONCENTRATIONS OF POTASSIU-I I TO ELECTRO- is this true of muscular tissues. Patients have CARDIOGRAPHIC FINDINGS been observed in whom hyperkalemic electrocardio- EFFECTS OF LITHIUM ON THE ELECTROCARDIOGRAM 609 graphic changes developed with lower serum con- REFERENCES centrations of potassium than usual when potas- 1. Salt substitutes-a warning. J. A. M. A., 1949, 139, sium was administered more rapidly than the in- 588. tracellular restoration could be accomplished. For 2. Corcoran, A. C., Taylor, R. D., and Page, I. H., instance, one patient with diabetic acidosis died of Lithium poisoning from the use of salt substitutes. hyperkalemia from the intravenous administra- J. A. M. A., 1949, 139, 685. tion (over a period of a very few minutes) of only 3. Hanlon, F. W., Romaine, M., III, Gilroy, F. J., and Deitrick, J. E., Lithium chloride as -a substitute 0.9 gram of KCl from a syringe. Such experiences for in the diet. Observations on are explicable on the basis of the physiologic sig- its toxicity. J. A. M. A., 1949, 139, 688. nificance of the potassium ratio, or "membrane po- 4. Stern, R. L., Severe lithium chloride poisoning with tassium gradient" as it may be called (30). This complete recovery. Report of case. J. A. M. A., concept is essentially that of Bernstein (31) who 1949, 139, 710. related muscular excitability and the resting mem- 5. Waldron, A. M., Lithium intoxication occurring with the use of a table in the low sodium brane potential to the potassium ratio. dietary treatment of and congestive The increase in amplitude of the T wave in spite . Univ. Hosp. Bull., Ann Arbor, 1949, of presumed reduction in may 15, 9. be the result of increased excitability which hyper- 6. McKusick, V. A., Effect of lithium on the electro- kalemia produces. Events in all parts of the heart cardiogram of animals.- Federation Proc., 1950, 9, may be transpiring more rapidly and with greater 84. 7. Hesse, A., Lithion. Inaugural Dissertation Dieterich, synchronization, to result in a higher but narrower Gottingen, 1876. Quoted by Good (9). T wave in the case of . In the case 8. Krumhoff, E., Experimentelle Beitrage zur Wirkung of the QRS complex, explanation for the changes des Lithium. Inaugural Dissertation, Gottingen, observed is not so simple, it would seem, since fre- Eisenach, 1884. Quoted by Good (9). quently widening and amplification of the QRS 9. Good, C. A., An experimental study of lithium. Am. seem to occur simultaneously. J. M. Sc., 1903, n.s., 125, 273. It is obvious that the above observations in no 10. Milheiro, E., Action des associations lithium-potas- sium et lithium-calcium sur la contracture vera- way exclude the possibility of a more direct action trinique du muscle strie. Compt. rend. Soc. de of the lithium ion in the production of the electro- biol., 1927, 97, 872. cardiographic changes observed. 11. Winkler, A. W., Hoff, H. E., and Smith, P. K., Fac- tors affecting the toxicity of potassium. Am. J. SUMMARY AND CONCLUSIONS Physiol., 1939, 127, 430. 1. Elevation of serum lithium concentration is 12. Harrison, H. E., A modification of the diphenylamine method for determination of inulin. Proc. Soc. accompanied by a consistent series of electro- Exper. Biol. & Med., 1942, 49, 111. cardiographic changes indistinguishable from those 13. Alving, A. S., Rubin, J., and Miller, B. F., A direct of hyperkalemia. colorimetric method for the determination of inulin 2. Lithium causes elevation of serum potassium, in blood and . J. Biol. Chem., 1939, 127, 609. probably mainly through direct displacement from 14. Finch, C. A., Sawyer, C. G., and Flynn, J. M., Clinical the cell. syndrome of potassium intoxication. Am. J. Med., 3. Although direct effects of the lithium ion can- 1946, 1, 337. not be excluded on the basis of these data, the elec- 15. Foulks, J., Mudge, G. H., and Gilman, A., Renal ex- cretion of cation in the dog during infusion of iso- trocardiographic changes of hyperlithemia may be tonic solutions of lithium chloride. Am. J. Physiol., secondary to changes in the ratio of intracellular 1952, 168, 642. potassium to extracellular potassium, as may the 16. Hoeber, R., Physical Chemistry of Cells and Tissues. electrocardiographic changes in other states of al- Philadelphia, The Blakiston Co., 1945, p. 249. tered body potassium concentrations. 17. Radomski, J. L., Fuyat, H. N., Nelson, A. A., and Smith, P. K., The toxic effects, excretion and dis- ACKNOWLEDGMENTS tribution of lithium chloride. J. Pharmacol. & Mr. Alfred Casper and Miss Catharine DeLea assisted Exper. Therap., 1950, 100, 429. in the conduct of these experiments. Dr. Nathan W. 18. Davenport, V. D., Distribution of parenterally ad- gave advice and assistance in performance of part ministered lithium in plasma, brain and muscle of of the electrolyte determinations. rats. Am. J. Physiol., 1950, 163, 633. 610 VICTOR A. MCKUSICK

19. Finkenstaedt, J. T., O'Meara, M. P., and Merrill, McElroy and B. Glass, eds., Baltimore, The Johns J. P., Observations on the volume of distribution of Hopkins Press, 1952, vol. 2, p. 748. inulin in anuric subjects. J. Clin. Invest., 1953, 32, 26. Talbott, J. H., Periodic paralysis; a clinical syndrome. 209. Medicine, 1941, 20, 85.. 20. Ponder, E., The tonicity-volume relations for systems 27. Berliner, R. W., Personal communication. containing human red cells and the chlorides of 28. Levitt, M. F., and Gaudino, M., Use of radio-active monovalent cations. J. Gien. Physiol., 1949, 32, 391. to measure intracellular cation concentra- 21. Ling, G. N., Personal communication. tions in the normal dog. Am. J. Physiol., 1949, 159, 22. Odqvist, G., PermeabilitHitsstudien bei kaulguappen. 67. Archiv. for Zoologi., 1925, 17A, No. 30. 29. Moore, F. D., Adaptation of supportive to 23. MacLeod, J., Swan, R. C., and Aitken, (G. A., Jr., the needs of the surgical patient. J. A. M. A., 1949, Lithium: its effect on hulmnan spermatozoa, rat 141, 646. testicular tissue and upon rats in vivo. Am. J. 30. Lenzi, F., and Caniggia, A., Intoxication par le Physiol., 1949, 157, 177. chlorure de potassium chez un diabetique en coma; 24. Hoeber, R., Loc. cit., p. 250. importance du "gradient potassique de surface" sur 25. Ling, G. N., The role of phosphate in the maintenance l'origine des modifications ecg. par K+. Cardio- of the resisting potential and selective ionlic ac- logia, 1951, 19, 265. cumulation in frog muscle cells in Phosphorus 31. Bernstein, J., Untersuchungeni zur Thermodynamik , a symposium on the role of phosphorus der bioelektrischen Strome. Pfluger's Arch. f. d. in the metabolism of and animals. WV. D. ges. Physiol., 1902, 92, 521.