Battle Casualties in Korea: Studies of the Surgical Research Team, Volume IV
The Electrocardiographic Effects of Alterations inConcentration of Plasma Chemicals*
First Lieutenant Richardson F. Herndon, MC, USAR
Major William H. Meroney, MC, USA
Captain Carl M. Pearson, MC, USAR
The naturally occurring alterations in concentration of plasma chemicals which are known to produce configurational electrocardiographic changes are hypocalcemia,1-3 hyperkalemia1-41 and hypokalemia.2, 3, 12 Experimental evidence suggests that extracellular, not intracellular concentration is the factor producing electrocardiographic abnormality.13, 15, 16 Other electrolytes which may have an electrocardiographic effect are hydrogen ion, sodium, and bicarbonate, but it is not clear whether they have a direct effect upon cell polarization, or whether they influence chemicals which have a direct effect, or whether they are merely associated with changes in concentration of substances with direct effect.1-3, 12
Simultaneous changes in several electrolytes may interact to influencecardiac function. An isolated change in concentration of a single electrolytecannot occur, because chemical equilibrium must be maintained, and variouscombinations of excess and deficiency of electrolyte concentration havebeen observed. Potassium excess, for instance, has been shown to exertexaggerated toxicity in the presence of calcium deficit, and replacementof the calcium deficit instantly modifies the cardiotoxic effects of thehyperkalemia.6, 7, 9-11, 17, 18 The present study is designedto reveal or define further the influence of certain plasma chemicals uponthe electrocardiogram.
Materials and Methods
This is a study of 663 electrocardiograms recorded on 61 patients; atthe same time venous blood was drawn for chemical analyses. The patientswere combat casualties with acute renal insufficiency. The examinationswere performed at the Renal Insufficiency Center, Korea, as an activityof the Surgical Research Team, Army Medical Service Graduate School, Washington,D. C. The electrocardiograms were
*In press: American Heart Journal (Aug. 1955).
286
made at the bedside with the Sanborn Visocardiette. Chemical determinationswere performed by the following methods: nonprotein nitrogen by the methodof Folin and Wu;19 chloride by the method of Sendroy;20carbon dioxide content by the manometric method of Van Slyke;21calcium* by the Clark and Collip modification of the method of Kramer andTisdall;22 inorganic phosphorus by the method of Fiske and Subbarow;23and sodium and potassium by the internal standard flame photometer.24
In the data and discussion to follow, QRS duration is measured in seconds,the QT interval (QTc) in seconds corrected for rate, where normal is 0.39±0.02second,25 and T-wave height in millimeters from the isoelectricline of the tallest precordial T-wave.
Results
Part One: The QTc interval
A. Total plasma calcium is plotted against QTc interval in Figure 1.There is a tendency for the longer intervals to be associated with lowercalcium values; that the relationship is not absolute and would stand littlestatistical tension is evident. The plasmas yielding these calcium valuesshowed considerable variation in their potassium concentration, and themutual antagonism between these ions may have affected the electrocardiographicresponse to variations in the calcium level. In Figure 2 the effect ofvariations of the concentration of plasma calcium is more clearly seenin four individual patients. An association between hypocalcemia and prolongationof the QTc interval has frequently been observed,1, 4, 8, 14 andif ionized calcium had been measured this relationship might have beenmore apparent in the composite chart. The high plasma calcium values wereproduced therapeutically with intravenous infusions of 10 per cent calciumgluconate in distilled water.
B. Inorganic phosphorus is plotted against QTc interval in Figure 3.A determination was not used if the patient had received calcium in theprevious 24 hours. Again a rough correlation is observed. The relationshipis due not to an effect of phosphorus elevation, but to the hypocalcemiawith which it is associated in acute renal insufficiency.4, 17, f8Figure 3 is, thus, a rough mirror image of Figure 1.
C. No consistent relationship was found between the QTc interval andthe plasma levels of sodium, potassium, chloride, bicarbonate or nonproteinnitrogen.
*Ionized calcium was not measured.
287
288
289
Part Two: The QRS complex.
A. Plasma potassium is plotted against QRS duration in Figure 4. Figure5 is a plot of the same relationship in four individuals. Figure 6 is aplot of the relationship in patients who had not received calcium within24 hours prior to the determinations. All charts show QRS duration to benormal until plasma potassium reaches 7.0 mEq./L. As potassium levels exceed7.0 mEq./L. the QRS duration is usually prolonged. This is not constantsince the QRS duration is at times normal even in the presence of a veryhigh potassium level.
B. Potassium concentration was the only factor showing any consistentpattern when plotted against QRS duration. No such relationship was foundbetween QRS duration and calcium, sodium, chloride, bicarbonate, phosphorusor nonprotein nitrogen plasma levels.
Part Three: The T-wave.
A. Figure 7 shows the relation of potassium to the height of the T-wave.Figure 8 shows the same in four patients. T-wave abnormality was rarelyseen at potassium levels of less than 6.5 mEq./L., but became marked ashyperkalemia progressed. A comparison of patients in Figure 8 shows widepatient-to-patient variation.
B. A plot of T-wave height against the plasma concentration of eithercalcium, sodium, chloride, bicarbonate, phosphorus or nonprotein nitrogendid not show a consistent pattern.
Part Four: The composite electrocardiographic effects of progressivehyperkalemia.
There is a step-wise evolution of electrocardiographic abnormality inprogressive hyperkalemia when calcium concentration is normal. This isshown in Figures 9 and 10. At plasma levels of less than 6.5 mEq./L. thereis no effect on the electrocardiogram. The earliest electrocardiographicchange is elevation and peaking of the T-waves, especially in the precordialleads, first seen at a plasma potassium level of about 6.5 mEq./L. As plasmapotassium rises, this becomes more marked until the T-waves are very high,narrow and peaked.
The next change is a widening of the "S-ST" angle. The terminal portionof the QRS complex becomes wider and deeper. The initial portion of theQRS complex is unchanged. Overlapping this is a gradual loss of the STsegment. The end point of this effect is the most advanced hyperkalemicalteration. ST segment loss begins with a slight angulation of the ST segmentfrom the iso-electric line. Angulation becomes more severe until the STsegment completely disappears.
As hyperkalemia progresses, a late electrocardiographic abnormalityis gradual QRS broadening. This begins with S-ST angle widen-
290
291
292
ing and is a prolongation only to the upper limits of normal. This increaseappears to be largely a delay in the activation of the base of the rightventricle and is reminiscent of what is traditionally known as "right bundle-branchblock." Later the initial vector of the QRS complex is also prolonged andthe QRS resembles a rather indeterminate ventricular conduction defect.Here there may be rhythm disturbances, especially nodal rhythm. The PRinterval may become prolonged, so much so that the P-wave is lost in thepreceding T-wave.
Lastly, the lethal result of uninterrupted progressive hyperkalemiais the "sine" wave of ventricular fibrillation.
293
Comment
These data show wide variation in the relationships between the concentrationof plasma chemicals and the pattern of the simultaneously recorded electrocardiograms.We believe the explanation for this lies in the multiplicity of chemicalabnormalities measured (and we did not measure them all), rather than inthe factors embodied in the term "individual variation."
The electrocardiogram is an accurate, sensitive instrument for measurementof depolarization and repolarization of myocardial muscle cells. It isaffected by various plasma electrolytes. The vari-
294
ation in concentration of a single electrolyte may be reflected withconsiderable precision by the electrocardiogram. However, it is impossibleto vary a single electrolyte even experimentally for chemical equilibriummust be maintained.
Clinical situations are even more complicated. We have shown that ifcalcium concentration is normal, the electrocardiogram reflects the potassiumlevel with considerable accuracy. The electrocardiographic changes producedby progressive increments of plasma potassium are rather predictable andconsistent provided the additive effects of hypocalcemia are not superimposed.In our cases other concomitant changes in electrolyte concentration havenot shown an appreciable effect. Our inability to show a consistent electrocardiographicreflection of alternations in concentration of plasma sodium has been especiallydisappointing.
The electrocardiogram does not lend itself well to the comparison ofduration and amplitude measurements in different patients. Positional variationsare difficult to eliminate; QRS duration and QT interval vary in normalpersons. In addition, there are variations from the normal in our patientsthat defy measurement, such as the peaking of T-waves in hyperkalemia.
Often a changing pattern in serial tracings has been of more significancethan a single tracing. We have observed several episodes of severe potassiumintoxication interrupted by artificial dialysis in the same patient. Electrocardiogramsserially taken in separate episodes recorded similar patterns at similarlevels of hyperkalemia when other abnormalities had been corrected.26Others have made like observations, finding the electrocardiogram to bean index of the level of hyperkalemia,8, 14 and that the electrocardiogramshows definite evidence of hyperkalemia when serum potassium exceeds 7.4mEq./L.13 Other observers1, 8, 14 have found QT durationto be prolonged in hyperkalemia. We have been unable to do so. Hypocalcemiaassociated with hyperphosphatemia may account for the discrepancy.
Summary and Conclusions
1. Data from 663 electrocardiograms and blood chemical determinationsin 61 patients are presented.
2. The relationships between the configuration of the electrocardiogramand the plasma concentration of potassium, calcium, sodium, phosphorus,chloride, bicarbonate and nonprotein nitrogen are discussed. Only potassiumand calcium are demonstrated to have potent effect on the electrocardiogramin our series.
295
3. QTc interval is prolonged in hypocalcemia, and hyperphosphatemia.QRS duration is prolonged in hyperkalemia. T-wave amplitude is increasedin hyperkalemia.
4. These data show wide variation in the electrocardiographic reflectionof multiple electrolyte abnormalities. However, there is a step-wise evolutionof electrocardiographic abnormality in progressive hyperkalemia when calciumconcentration is normal.
References
1. White, P. D., and Mudd, S. G.: Observations on theEffect of Various Factors on the Duration of Electrical Systole of theHeart as Indicated by the Length of the QT Interval of the Electrocardiogram.J. Clin. Investigation 7: 387, 1929.
2. Katz, L. N.: Electrocardiography. Lea and Febiger,Philadelphia, 1946.
3. Spealman, C. R.: Action of Ions on the Mammalian Heart.Am. J. Physiol. 136: 332, 1942.
4. Merrill, J. P., Levine, H. D., Sommerville, W., andSmith, S., III: Clinical Recognition and Treatment of Acute Potassium Intoxication.Ann. Int. Med. 33: 797, 1950.
5. Levine, H. D., and Merrill, J. P.: Advanced Disturbancesof the Cardiac Mechanism in Potassium Intoxication. Circulation 3:889, 1951.
6. Winkler, A. W., Hoff, H. E., and Smith, P. K.: FactorsAffecting the Toxicity of Potassium. Am. J. Physiol. 127: 430, 1939.
7. Govan, C. D., Jr., and Weiseth, W. M.: Potassium Intoxication:Report of an Infant Surviving a Serum Potassium Level of 12.27 Millimolesper Liter. J. Pediat. 28: 550, 1946.
8. Keith, N. M., Burchell, H. B., and Baggenstoss, A.H.: Electrocardiographic Changes in Uremia Associated with a High Concentrationof Serum Potassium. Am. Heart J. 28: 817, 1944.
9. Marchand, J. F., and Finch, C. A.: Fatal SpontaneousPotassium Intoxication in Uremia. Arch. Int. Med. 73: 384, 1944.
10. Finch, C. A., Sawyer, C. G., and Flynn, J. M.: TheClinical Syndrome of Potassium Intoxication. Am. J. Med. 1: 337,1946.
11. Winkler, A. W., Hoff, H. E., and Smith, P. K.: ElectrocardiographicChanges and Concentration of Potassium in Serum Following Intravenous Injectionof Potassium Chloride. Am. J. Physiol. 124: 478, 1938.
12. Darrow, D. C.: Body Fluid Physiology: The Role ofPotassium in Clinical Disturbances of Body Water and Electrolytes. NewEng. J. Med. 242: 978, 1950; 242: 1014, 1950.
13. Elkinton, J. R., Tarail, R., and Peters, J. P.: Transfersof Potassium in Renal Insufficiency. J. Clin. Investigation. 28:378, 1949.
14. Keith, N. W., and Burchell, H. B.: Clinical Intoxicationwith Potassium: Its Role in Severe Renal Insufficiency. Am. J. Med. Sc.217:1, 1949.
15. Crismon, J. M., Crismon, C. S., Calabresi, M., andDarrow, D. C.: Electrolyte Redistribution in Cat Heart and Skeletal Musclein Potassium Poisoning. Am. J. Physiol. 139: 667, 1943.
16. Elkinton, J. R., Winkler, A. W., and Danowski, J.S.: The Importance of Volume and of Toxicity of Body Fluids in Salt DepletionShock. J. Clin. Investigation 26: 1002, 1947.
296
17. Meroney, W. H., and Herndon, R. F.: The Managementof Acute Renal Insufficiency. J. A. M. A. 155: 877, 1954.
18. Meroney, W. H., and Herndon, R. F.: The Treatmentof Potassium Intoxication with Calcium. (To be published.)
19. Folin, O. K. O., and Wu, H.: A System of Blood Analysis.J. Biol. Chem. 38: 81, 1919.
20. Sendroy, J., Jr.: A Note on the Photoelectric Microdeterminationof Chloride in Biological Fluids. J. Biol. Chem. 142: 171, 1942.
21. Peters, J. P., and Van Slyke, D. D.: QuantitativeClinical Chemistry, Vol. 2. Williams and Wilkins, Baltimore, 1932.
22. Clark, E. P., and Collip, J. B.: A Study of the TisdallMethod for the Determination of Blood Serum Calcium with a Suggested Modification.J. Biol. Chem. 63: 461, 1925.
23. Fiske, C. H., and Subbarow, Y.: The Colorimetric Determinationof Phosphorus. J. Biol. Chem. 66: 375, 1925.
24. Wallace, W. M., Holliday, M., Cushman, M., and Elkinton,J. R.: Application of Internal Standard Flame Photometer to Analysis ofBiologic Material. J. Lab. and Clin. Med. 37: 621, 1951.
25. Taran, L. M., and Szilagyi, N.: The Duration of ElectricalSystole (QT) in Acute Rheumatic Carditis in Children. Am. Heart J. 33:14, 1947.
26. Pearson, C. M., and O'Meara, P. M.: An ElectrocardiographicStudy of Recurrent Hyperkalemia: Report of a Case. (To be published.)
