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Postgrad Med J: first published as 10.1136/pgmj.27.308.296 on 1 June 1951. Downloaded from 296 ANNOTATION guria is present, in untreated Addison's disease and conditions associated with excessive , The Efect of Potassium and on haemoconcentration and . Although the body stores of potassium are reduced in diabetic The Electrocardiogram acidosis and coma, high serum levels are found The force and general behaviour of cardiac con- frequently before treatment is begun because of traction can be altered in striking fashion under the mechanisms mentioned above. experimental conditions by varying the physical muscle is susceptible in some way to and chemical composition of the fluid bathing the potassium not shared by skeletal muscle. This heart muscle. Slight increases in alkalinity or fact has been demonstrated convincingly in dogs acidity bring about a lengthening or shortening of whose limb muscles continue to twitch vigorously systole respectively and influence the transmission at serum concentrations of potassium sufficient to of the impulse in the conduction system. The ionic cause (Winkler et al., 1939). content of , its historical deriva- Clinical experience tends to support this observa- tion from its primitive forerunner , and tion. With excessive or increasing concentration the importance of changes in its composition to of potassium in the serum, rapid and dramatic the economy of the individual have been portrayed changes in cardiac rhythm, for example, transition lucidly by Gamble (I942). from sinus rhythm to a state resembling ven- The three cations potassium, calcium and tricular flutter, may be recorded graphically must be present in fairly inflexible con- without apparent change in the state of the somatic centrations if the heart is to beat normally; muscle (Levine et al., I951). and the anion content of extracellular The earliest electrocardiographic signs of fluid may be important also but they are beyond potassium intoxication are an increase in ampli-copyright. the scope of this review. As might be expected tude and pointing of the T waves and a shortening from their effect on cardiac muscle, potassium and of the QT interval.* The changes may be subtle calcium when present in abnormal amounts, pro- and inconspicuous and their first appearance may duce changes in the electrocardiogram, the former be overlooked unless especially sought for or unless dramatic and specific, the latter less ostentatious a control electrocardiogram is available for com- but none the less characteristic. The individual parison. The sequential changes may be sum- contribution of sodium to electrocardiographic marized as follows (Merrill et al., 1950):- http://pmj.bmj.com/ changes is less well understood but, as will be ex- i. Changes in ventricular activation: Tall plained later, a low sodium content (hypo- pointed T waves and first shortening and later natraemia) appears to potentiate the abnormalities lengthening of QT interval. R waves become caused by excessive potassium. Significant changes lower and S waves deeper across the precordium. in the serum concentration of one are ST segment is depressed in characteristic fashion. 2. Intra-auricular : Low, wide P waves unlikely to occur alone; whether variations in on October 2, 2021 by guest. Protected other serum can be detected or not, progressing to auricular fibrillation or standstill. they are likely to be present, in addition to 3. Auriculo-ventricular block: Prolonged PR fluctuations in intracellular not measurable by interval, possibly progressing to higher grades of ordinary laboratory methods. The electro- auriculo-ventricular block. cardiogram reflects the summation of the changes 4. Intra-ventricular block: Bundle branch in the ionic environment of the heart, and in this block or diffuse intra-ventricular block progressing lies its chief application in the management of to ventricular standstill. (Merrill et al., 1950)V 5. Ectopic rhythms: Ventricular premature or escape beats progressing to ventricular tachy- Potassium-Hyperkalaemia (hyperpotassaemia) cardia and an undulating ventricular pattern re- Abnormally high serum potassium levels are * In this paper the symbol QT implies a correction for found in renal insufficiency especially when oli- heart rate. Postgrad Med J: first published as 10.1136/pgmj.27.308.296 on 1 June 1951. Downloaded from Yune 1951 Annotation 297 sembling flutter, and finally ventricular fibrillation. mEq./L. and cardiac arrest at I4 to I5 mEq./L. Fig. i illustrates the typical electrocardiographic (Winkler et al., 1938). changes of severe potassium intoxication in a man In man the correlation is much less exact be- aged 65 with uraemia resulting from chronic cause of simultaneous variation in concentration glomerulonephritis. At the time of this tracing of other electrolytes, chiefly sodium and calcium. (Fig. ia) the serum potassium was II.5 milli- There is adequate experimental evidence that some equivalents per litre (mEq./L.)* and serum sodium degree of tolerance to potassium is achieved by 112 mEq./L. No evidence of auricular activity can simultaneous administration of calcium (Winkler be seen. There is diffuse intra-ventricular block et al., 1939). The dissociation between the clinical with low R waves and deep, wide S waves in leads and electrocardiographic appearances on the one V2 to V6. The ST pattern is characteristic; the hand and the serum potassium level on the other S wave becomes continuous with the upstroke of appears to be the result more often of depressed T. no ST segment proper being identifiable. The serum sodium levels, for serum calcium values T waves are tall and pointed and the QT interval may be within normal limits. Fig. 3, reproduced prolonged. The standard and unipolar limb leads from an article by Merrill, Levine, Somerville reflect the changes in the chest leads. When the and Smith (I950), illustrates the potentiating electrolyte imbalance was corrected the electro- effect of low serum sodium levels on the electro- cardiogram returned to its original form which, cardiogram of hyperkalaemia. of course, is grossly abnormal from pre-existing If the electrocardiogram was abnormal before disease (Fig. ib). This case has been reported potassium intoxication developed, the signs of fully elsewhere (Merrill et al., I950). both the pre-existing condition and of hyper- No explanation in electrophysical terms is avail- kalaemia will be superimposed. However, the able for the development of deep S waves across inverted T waves of left ventricular enlargement copyright. the precordium in advanced potassium intoxica- may be made upright by potassium, while those tion. Its resemblance to marked clockwise rota- of cardiac infarction may be more deeply inverted tion of the heart is not supported by clinical (Sharpey-Schafer, I943). observation. Ventricular are a feature of severe Hypokalaemia (Hypopotassaemia) cases (Fig. 2). They often present a bizarre Here also exact correlation is lacking betweeft pattern and are identical with many records ob- lowered serum potassium levels and electro- http://pmj.bmj.com/ tained from the dying heart. A detailed analysis cardiographic changes. As Wallace (i949) has of such arrhythmias has been made elsewhere pointed out recently, relative changes from one (Levine et al., 1951). level to another are more important than de- parture from the absolute level of 5 mEq./L. Relation of Serum Potassium Levels to Potassium depletion results from losses in , Electrocardiographic Changes gastric secretion or other body fluids as in pyloric on October 2, 2021 by guest. Protected .When an isotonic of obstruction and excessive vomiting, especially in is injected at a steady rate by vein into dogs, the infants, and in a variety of other gastro-intestinal serum potassium concentration increases in linear diseases. In diabetic coma, hypokalaemia de- fashion with time, and a sequence of electro- velops from such losses and is aggravated by a cardiographic changes develops resembling closely poor intake, by dilution of body water with that outlined above. The earliest abnormalities potassium-free fluids used in treatment and intra- appear at a potassium concentratioo of about 7.8 cellular transfer of potassium following glucose and mEq./L.; intra-auricular block develops at 9 to II insulin . In certain types of chronic glomerulonephritis; where tubular reabsorption of *The normal serum potassium concentration is 5 potassium is deficient while glomerular filtration is mEq.IL. Milliequivalents per litre are obtained by dividing milligrams per litre by atomic weight and unimpaired, hypokalaemia may result (Sherry et multiplying by valency. al., 1948). Intensive desoxycorticosterone ace- Postgrad Med J: first published as 10.1136/pgmj.27.308.296 on 1 June 1951. Downloaded from 298 POSTGRADUATE MEDICAL JOURNAL .7une 195I tate (DOCA) therapy, especially in Addison's Calcium () disease and certain alkalotic states, encourages Elevated blood calcium is met with in hyper- potassium losses. Finally, in familial periodic parathyroidism, or after excessive administration paralysis, transfers of potassium occur from extra- of parathormone or irradiated . Malig- cellular fluid into the cells without loss in the nant metastases in may cause definite but less urine; dramatic and widespread muscular paralyses marked hypercalcaemia. are associated with a fall, often abrupt, in serum When is injected intravenously potassium (Gass et al., 1948). at a steady rate into dogs so that there is a linear The chief electrocardiographic abnormalities increase in serum calcium with time from the nor- occurring with hypokalaemia comprise depression mal of 5 mEq./L, a constant sequence of electro- of the ST segments and lowering or inversion of cardiographic changes is encountered (Hoff et al.,- T waves in all chest leads, with similar changes re- 1939): flected to standard and unipolar limb leads (Fig. At 7.5 to 33 mEq./L. the rate slows, PR is 4); they are generally less specific and more increased, QT decreased and T waves lowered. difficult to recognize than those of hyperkalaemia. At IZ to 45 mEq./L. the rate increases and The QT interval is prolonged and when the rate death may follow ventricular fibrillation. is slow enough to allow them to be seen, prominent If ventricular fibrillation does not supervene a U waves may appear. The significance of the second slowing process may develop at concentra- latter is not clear, but they appear to be related to tion of 35 to 95 mEq./L. wigtenheral depression of the after-potentials of ventricular contraction the cardiac mechanism and cardiac arrest. which in turn are influenced by the potassium In man electrocardiographic changes follow this general pattern although such high concentrations

content of the serum. The point is discussed copyright. elsewhere (Somerville et al., 195I). of calcium are not recorded. Clarke (I941) pro- duced bradycardia in normals by intravenous in- Hypokalaemia is found often with concomitant jection to Z.5 to 5 gm. of calcium chloride. This changes in concentration of other cations, es- was followed by sinus , shifting pace- pecially calcium. Additional electrocardiographic maker, auriculo-ventricular block and extra sy- abnormalities may be introduced thereby. Low stoles. Similar changes, with the addition of potassium may accompany a high serum calcium shortened QT interval were recorded in two

level; the QT interval may then be prolonged or patients with hyperparathyroidism, when the http://pmj.bmj.com/ shortened respectively depending on which abnor- serum calcium level was 9 meq./l. (Kellogg and mality dominates the picture. In the hypokalaemia Kerr, 1936). of diabetic acidosis, Martin and Wertman (I947) found the QT interval prolonged whether the Hypocalcaemia total calcium or ionized calcium fraction was low i Depression of the serum calcium follows re- or normal. moval or injury to the parathyroid glands, an on October 2, 2021 by guest. Protected The lack of parallelism between the depression infrequent complication of partial thyroidectomy. of serum potassium concentration and electro- Similar reduction with or without tetany is found cardiographic changes is emphasized again. The with rickets, osteomalacia, pregnancy, coeliac numerous and complex variables involved in disease, sprue and other causes of steatorrhoea, and hypokalaemic states such as fluctuations in pH and with certain cases of renal insufficiency with phos- in blood volume and intracellular electrolyte im- phate retention. When tetany is produced by balance secondary to extracellular changes, pro- hyperventilation, no reduction in serum calcium vide a ready explanation. The electrocardiogram, may be noted although the ionized calcium fraction however, as in hyperkalaemia, reflects the summa- is depressed. tion effects of these factors influencing cardiac The dominant change in the electrocardiogram muscle and is a useful guide to clinical progress ini hypocalcaemia is prolongation of the QT in- and management. terval (Fig. 5). Other abnormalities are incon- Postgrad Med J: first published as 10.1136/pgmj.27.308.296 on 1 June 1951. Downloaded from 3fune 1951 Annotation 299

FIG. I.-Electrocardiograms of a case of potassium intoxication with uraemia. Fig. ia shows the typical changes of severe hyper- kalaemia (serum potassium: I I.5 mEq./L.). When the electrolyte imbalancewas corrected, the tracing returned to its original form which is abnormal from pre-existing disease (Fig. Ib).

G.E.&e68 LEAD V5. JUNE 30, 1949 copyright. *

No 121 K 9.0 255 o.m http://pmj.bmj.com/ FIG. 2.-.Electrocardiogram showing b) ventricular arrhythmia occurring with hyperkalaemia. The pointed T waves. and ST segments are characteristic. The rhythm be- came irregular with a lowering of 4-10 c.m serum potassium (Fig. 2C). In I 2d, the tracing has improved, but I'. the T waves are still pointed and on October 2, 2021 by guest. Protected QT is abnormally long (0.46). C)

Na 127.5 K 8.2 7:30 a.m.

d)

Na 127.5 K 5.0 ;3 p 1:3.0 P.M. Postgrad Med J: first published as 10.1136/pgmj.27.308.296 on 1 June 1951. Downloaded from 300 POSTGRADUATE MEDICAL JOURNAL g7une 1951

FIG. 3.-Electroqardiograms obtained from four patients with serum potassium elevated to copyright. about the same degree. The changes are more pronounced when the serum sodium is also depressed than when it is normal. http://pmj.bmj.com/

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FIG. 4.-Electrocardiogram of hypokalaemia obtained from a woman aged 50 with Addison's disease treated for six years with DOCA. The ST segments are slightly depressed in V4-6; T waves are low or flat, and upright U waves are present in all chest leads. The QT interval is prolonged (0.48). Postgrad Med J: first published as 10.1136/pgmj.27.308.296 on 1 June 1951. Downloaded from ,7une I951 Annotation 301

FIG. 5 (Courtesy of Prof. A. Kekwick and Mr. R. Vaughan Hudson).-Electrocardiogram (chest leads) of hypocalcaemia obtained from a man with Riedel's disease of the thyroid and hypo- parathyroidism. A few minutes later he de- veloped tetany. The QT interval is prolonged (0.46) and the T waves flat or widened, especially in V4-6. While this pattern is indistinguishable from that of hypokalaemia, certain cases of hypocalcaemia can be recognized by a prolonged ST segment rather than a widened T wave. copyright.

spicuous and inconstant. Barker et al. (1937) from calcium deficiency involves the ST segment, investigated nine patients with hypocalcaemia, while in hypokalaemia wide flat T waves are three with hypoparathyroidism following thyroid- responsible (Nadler et al., I948). ectomy and six with renal insufficiency and Table i summarizes the chief effects of calcium uraemia. They found the QT interval prolonged and potassium on the electrocardiogram. As in all instances, and by comparing the latter with pointed out above, what the electrocardiogram http://pmj.bmj.com/ mechanical systole (the interval between the first records is the summation of effects of electrolyte and second heart sounds) showed disproportionate imbalance involving intra- and extra-cellular con- lengthening of electrical systole (QT interval). centrations of different ions. Changes produced The increased QT interval of hypocalcaemia thereby may reflect a combination of two abnormal may be indistinguishable from that of hypo- patterns, for example those of hyperkalaemia and kalaemia; in certain cases they may be differ- hypocalcaemia. Pre-existing abnormalities will on October 2, 2021 by guest. Protected entiated by the fact that lengthening resulting persist or may be modified further. TABLE I SUMMARY OF EFFECTS OF POTASSIUM AND CALCIUM ON THE ELECTROCARDIOGRAM Potassium Calcium High Low High Low PR Lengthened - Lengthened - QRS I Lengthened - ST Depressed Depressed - Lengthened T Tall, pointed Low or inverted Low or unchanged - U Prominent - QT At first, shortened, later Lengthened Shortened Lengthened lengthened Arrhythmias Frequent - May occur 302 POSTGRADUATE MEDICAL JOURNAL J7une 1951 Postgrad Med J: first published as 10.1136/pgmj.27.308.296 on 1 June 1951. Downloaded from Summary 4. The main feature of hypocalcaemia is i. The main electrocardiographic changes found lengthening of the QT interval. with hyperkalaemia are tall pointed T waves; 5. Abnormal serum concentrations of potassium characteristic ST segment depression; intra- and calcium may be present at the same time and auricular, intra-ventricular and auriculo-ventricular both may influence the electrocardiogram. block and prolonged QT interval. In the early 6. The electrocardiogram is valuable in the stages the- latter may be shortened. In advanced diagnosis and management of electrolyte im- potassium intoxication, various forms of. ventricu- balance since it represents the summation of effects lar arrhythmia may supervene. of ionic disturbances affecting the heart. 2. In hypokalaemia the QT is prolonged, Certain observations mentioned above were prominent U waves appear, ST segments are made possible by a grant from the National Heart depressed and T waves are low or inverted. Institute, Public Health Service 3. Hypercalcaemia causes auricular-ventricular (Grant No. H-446). block, shortening of the QT interval and low T waves. Bradycardia and sinus arrhythmia may WALTER SOMERVILLE, M.D., M.R.C.P., occur. Cardiac Department, The Middlesex Hospital.

BIBLIOGRAPHY BARKER, P. S., JOHNSTONE, F. D., and WILSON, W., and SMITH, S., 3rd (I9g5o), Ann. intern. F. N. (I937), Amer. Heart Y., I4, 82. Med., 33, 797. CLARKE, N. E. (I94I), Ibid., 22, 376. NADLER, C. S., BELLET, S., and LANNING, M. GASS, H., CHERKASKY, M., and SAVITSKY, N. (I948), Amer. Y'. Med., 5, 838. (I948), Medicine, 27, Io5. SHARPEY-SCHAFER, E. P. (I943), Brit. Heart Y., GAMBLE, J. L. (I942), 'Chemical Anatomy, Physiology 5, 8o. copyright. and Pathology of Extracellular Fluid,' Boston. SHERRY, S., EICHNA, L. W., and EARLE, D. P. HOFF, H. E., SMITHI, P. K., and WINKLER, A. W. JUN. (I948), Y. Clin. Invest., 27, 556. (1939), Amer. J. Physiol., I25, I62. SOMERVILLE, W., LEVINE, H. D., and THORN, KELLOGG, F., and KERR, W. J. (1936), Amer. G. W. (I951), Medicine, 30, 43. Heart J., 12, 346. WALLACE, W. M., and MOLL, F. C. (I949) LEVINE, H. D., MERRILL, J. P., and SOMER- Pediatrics, 4, 287. VILLE, W. (I95I), Circulation, in press. WINKLER, A. W., HOFF, H. E., and SMITH, P. K. MARTIN, H. E., and WERTMAN, M. (I947), Amer. (1938), Amer. Y'. Physiol., I24, 478. Heart3J., 34, 646. WINKLER, A. W., HOFF, H. E., and SMITH, P. K. MERRILL, J. P., LEVINE, H. D., SOMERVILLE, (I1939), Ibid., 127, 430. http://pmj.bmj.com/ on October 2, 2021 by guest. Protected

ERRATUM The Editors'regret that in our April number the illustrations to Mr. D. R. K. Reid's article on Hashimoto's Disease appear in wrong order. Figure i should be-figure 4, figure 2 should be figure i and figure 4, figure 2.