Digitalis toxicity

Digitalis

toxicity

II. The effect of metabolic

alkalosis

IKerritt C. Warren, M.D.* Ralph E. Gianelly, M.D.** Sherilyn L. Cutler, M.A.*** Donald C. Hawison, M.D.**** Palo Alto, Calif.

D

igitalis glycosides remain the most widely used therapeutic agents in the treatment of congestive heart failure. In recent years the effects of metabolic abnormalities on susceptibility to digitalis intoxication have been emphasized.lp” Major stress has been placed on serum and total body electrolytes. Studies on the effects of aberrations in ~02, pCOZ, and pH on the amount of digitalis necessary to produce toxicity have been performed. These have primarily tested the effects of acidosis induced by breathing gas mixtures containing high concentrations of carbon dioxide.3 The effect of metabolic alkalosis on the amount of digitalis necessary to produce toxicity has been investigated.4s5 The duration of toxicity, however, has not been studied. In addition, the experimental conditions were not optimal because blood gases were incompletely monitored and the animals were not used as their own controls. Accordingly, the influence of

metabolic alkalosis on susceptibility to digitalis toxicity and duration of such toxicity in dogs has been studied in this investigation. Methods Studies were performed in 19 dogs (12.3 to 23.4 kilograms) anesthetized with pentobarbital. The initial dose was 30 mg. per kilogram and small supplemental doses were given as necessary to maintain a light plane of anesthesia. Arterial pressure was measured with a P23Db Statham pressure transducer connected to a PE No. 260 cannula in the femoral artery. Standard Lead II of the ECG and arterial pressure were recorded by means of a multichannel Beckman model R direct-writing oscillograph. Ventilation was maintained through a cuffed endotracheal tube with a Harvard respirator. Samples from the femoral arterial cannula were analyzed for ~02, pCOz, pH, K+ and Mgt+. These were collected

From the Departments of Medicine and Pediatrics, Stanford University School of Medicine, Palo Alto, Calif. 94304. Supported in part by Grants HE09058-03, HE-5709.01 and 8.Tl-HD 49-07 from the National Heart Institute and a grant from the Hartford Foundation. Received for publication April 12, 1967. *Assistant Professor, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, Calif. (present address). *“Research Fellow, Cardiology Division, Staniord University School of Medicine, Palo .41to, Calif. ***Research Assistant, Cardiology Division, Stanford University School of Medicine, Palo Alto, Calif. ****Chief, Cardiology Division, Department of Medicine, Stanford University School of Medicine, Palo Alto, Calif. (Address communications to Dr. Harrison.)

358

Digitalis

three times during the control (lactated Ringer’s infusion) experiments; initially, after infusion of a volume of Ringer’s solution which was approximately equal to the volume of sodium hydroxide calculated to produce the desired level of alkalosis, and at the onset of digitalis toxicity. During the alkalosis (sodium hydroxide infusion) experiments, five or six blood samples were obtained for analysis; at the beginning, at intervals during the infusion of sodium hydroxide until the desired degree of alkalosis was obtained, and at the time digitalis toxicity developed. The volumes of sodium hydroxide and Ringer’s solution infused in these experiments were approximately equal, averaging 29.5 f 78 and 243 & 84 ml. in each group respectively. These solutions were infused into the jugular veins. The blood pH, pCOe, and ~02 were determined with a model AMEAstrup ultramicro apparatus. The pH and pCOz were determined by the method of Astrup and associates.‘j The pH electrode was calibrated daily with standard solutions and duplicate pH determinations on blood samples were found to vary by no more than f 0.01 pH unit. The p0~ was determined with a modification of the Clark ~02 electrode,’ and duplicate determinations varied by no more than f 2 mm. Hg. The serum potassium and magnesium were determined with an atomic absorption spectrophotometer (Perkin-Elmer model 290). In each experiment two infusions were given ; acetylstrophanthidin and NaOH (alkalosis), or lactated Ringer’s (control). After a volume of NaOH sufficient to elevate the pH above 7.50 or an equivalent volume of lactated Ringer’s was delivered, acetylstrophanthidin (123 pg per minute) was injected into a femoral vein with a Harvard infusion pump until ventricular tachycardia occurred. Identical infusion rates were used in all studies so that this variable could be eliminated in considering the dose to toxicity and the duration of toxicity. The ECG was monitored on a multichannel oscilloscope. Ventricular tachycardia for these experiments was defined as the occurrence of four consecutive ventricular ectopic beats. Recovery from ventricular tachycardia was considered to have occurred when less than six

toxicity

359

ectopic beats per minute were recorded for three consecutive minutes. There were two kinds of experiments: Studies to determine toxic dose. A total of 32 infusions of acetylstrophanthidin were made into eight dogs. Each dog was given four infusions-two on the first day and two seven days later. Half of the animals received sodium hydroxide (0.33 molar) until the pH had risen above 7.50. Then the administration of acetylstrophanthidin was begun. Both infusions were stopped at the onset of toxicity. At least three hours were allowed to elapse following recovery from the arrhythmia before a second infusion was given. The second infusion consisted of lactated Ringer’s solution containing the following concentration of ions (in milliequivalents per liter) : sodium, 130; potassium, 4; calcium, 3; chloride, 109; lactate 25. Acetylstrophanthidin was again administered to toxicity. On the day following these infusions all animals were anorexic, but by the second day all were eating normally. During the following six days they were fed a normal animal diet. One week later the same procedure was carried out with one exception; the lactated Ringer’s preceded the sodium hydroxide infusion. The other half of the animals had similar experiments with the order reversed; that is, the lactated Ringer’s preceded the sodium hydroxide infusion the first week and followed it the second. No other experimental condition was changed. It was found that the experimental regime was too rigorous for successful completion of the four-part experiment when digitalis toxicity was allowed to go without interruption, especially when the animal was alkalotic. Consequently, most of the eight dogs were treated with lidoCaine infusions after five minutes of toxicity. Since three hours were allowed to pass before the next study, the effects of lidoCaine were considered to have disappeared before the second study. This regime was followed for two reasons: (1) to permit each dog to act as his own control and (2) to eliminate the length of anesthesia with accompaning manipulation as a variable factor. No dog -which had deteriorated physically in the week between the experiments was used for the second set of experiments.

3 60

Wuvren et ul.

Table

I. Acetylstrophanthidin

to produce

ventriculur

tachycavdiu

I ~

iVO.

Ringer’s,

A.M.

NaOH,

iVaOH,

P.M.

A.M.

Ringer’s,

P.M.

~

54.9” 45.0 69.5 51.4 58.8 84.0 55.5 70.0

7 8 9 10 11 12 14 15 Mean

and

53.3 52.0 53.3 63.0 54.1 62.5 46.5 67.0

45.5 59.0 67.5 65.4 43.8 58.6 39.6 69.0

64.4 46.7 58.8 68.2 24.0 68.6 31.8 56.1

standard 61.1

f3-i-0r

56.0

*6

*St

56.5

13

52.3

+7t

*Dose in micrograms per kilogram of body weight. iSecond dose not significantly different from first dose.

Studies

to

determine

the

dwutiolz

of

toxicity. A total of 16 infusions of acetylstrophanthidin were carried out in 11 dogs and duration of toxicity without treatment was ascertained. In five of these dogs the full sequence of experiments was done. The other six dogs, however, were used only for part of the sequence. Statistical analysis of the data obtained in this study was performed with an IBM 360,&O digital computer. This computer was programmed to calculate mean and standard errors and to perform a paired t test analysis. Results

Studies to determine toxic dose. In eight dogs (each receiving four separate infusions of acetylstrophanthidin) the dose required to produce ventricular tachycardia during alkalosis was not significantly different from the dose required when the pH was normal (Table I). There was a tendency for the dose necessary to produce toxicity to be less in the afternoon than in the morning. This tendency was present for both the normal and the alkalotic states. The results were highly variable, however, and no significant decrease could be demonstrated (p > 0.05) (Table I). Other studies from this laboratory have shown that when the pH is normal, there is no change in the dose of acetylstrophanthidin necessary to produce toxicity if a period of three hours is allowed between recovery and the second infusion.8 The arterial pH in the normal and

alkalotic studies averaged 7.38 and 7.57 respectively at the onset of ventricular tachycardia. The average ~02 was greater than 90 mm. Hg during all infusions of acetylstrophanthidin and the pCOz was less than 45 mm. Hg during all infusions (Table II). The heart rates slowed significantly (p < 0.05) during the infusion of acetylstrophanthidin prior to the onset of ventricular tachycardia in all except those which received Ringer’s solution in the afternoon. The rate of the ectopic ventricular tachycardia observed one minute after its onset varied widely (Table II). The mean arterial blood pressures increased significantly (p < 0.05) during digitalization in those animals in which the pH was normal (Table II). No significant change in pressure, however, was observed during digitalization after alkalosis had been induced (Table II). Serum potassium increased significantly during the infusion of acetylstrophanthidin in normal and alkalotic animals (p < 0.05). In every study the serum potassium was decreased significantly by the infusion of sodium hydroxide (p < 0.05). The serum magnesium values were not significantly altered by either alkalosis or acetylstrophanthidin infusion (Table II). Studies to determine the duration of toxicity. The average duration of toxicity was greatly prolonged when the animals were alkalotic (Table III). Five of these animals were their own controls and the duration of toxicity was prolonged during alkalosis in all. One animal developed

Digitalis

toxicity

361

l’trblc 11. Blood gases, electrolytes, und hemodynamic vtrkbles 1 Parameter pH

Ringer’s,

Condition

units

C*

(mEq./L.)

Heart pCOe

rate

(mm

pressure

Hg)

(mm.

Hg)

4.6 3.2 3.6

4.2 4.0 4.9

2.3 2.2

2.0 2.0

2.1 2.0

2.0 2.1

0

142 1.56

141 141

136 138

129 160

C 0

169 124

175 151

174 146

181 176

C

43 38

42 38

45 42

45 42

106 106

99 93

101 10.5

90 93

0 p0~

(mm.

:

Hg)

*Abbreviations: C, control; 0, at onset of ventricular acetylstrophanthidin infusion. All values represent the mean of 8 determinations.

Table 111. Duration

PH (units)

Mean

7.42* 7.39* 7.38* 7.28" 7.37 7.36 7.35 7.40 7.36$

tachycardia;

of ventricular tachycardia

Control

Alkalosis

Duration (min.) 7 33 21 14 26 16 18 16 199

Dwntion (min.)

PH (units) 7.59 7.56 7.61 7.62 7.72 7.59 7.52 7.75 7.601

*Paired animals having infusion during conditions. iDied of ventricular fibrillation. ~Difference significant (p < 0.05).

normal

Ringer’s,

3.4 2.5 3.2

C

(beats/min.)

A.M.

3.8 3.1 4.6

C

arterial

NuOH,

7.41 7.41

0 Mean

P.M.

1.34 7.56

C Pd

(mEq./L.)

NaOH, 7.35 1.57

0 Mg++

’

7.35t 7.36

0 Ii+

A.M.

20 43 62 90 42 34 74

18t 521 and

alkalotic

ventricular fibrillation while alkalotic and could not be resuscitated. This was the only animal in the series to develop ventricular fibrillation. Electrocardiografihic changes. The electrocardiographic sequence of events which usually occurred during the administration of acetylstrophanthidin began with ST seg-

Pd, after

infusion

of Ringer’s

or sodium

hydroxide,

but

P.M.

prior

to

ment depression, gradual sinus slowing, and prolongation of the PR interval. This was followed by occasional ventricular premature beats and then the sudden onset of ectopic ventricular tachycardia with AV dissociation (Fig. 1). Some dogs exhibited a different sequence, such as abrupt onset of ventricular tachycardia without occasional premature ventricular contractions. The sequence exhibited by a given dog, however, was usually constant from experiment to experiment. Discussion

In these studies the production of alkalosis did not increase the animals’ sensitivity to acetylstrophanthidin as measured by the amount required to produce ventricular arrhythmia (Table I). These findings are in contrast to findings of other investigators4s5 who reported that the hypokalemia occurring during alkalosis reduced the amount of acetylstrophanthidin necessary to produce ventricular arrhythmias. This discrepancy may be explained by the fact that other investigators4g5 did not use the same animals for control and alkalotic studies and did not measure or control ~02. We observed wide variations

362

Warren

et al.

t-l

sec.-l

Fig. 1. ECG’s illustrating typical changes during an infusion of acetylstrophanthidin are shown. A, Control tracing: B. earlv ST-T changes with slight prolongation of the PR interval and> slowing of The heart rate; C, beginning digitalis toxicity with further slowing, greatly prolonged PR interval and marked ST-T changes (two couoled ventricular oremature beats occurred at this hme); D, ventricular tachycardia which developed abruptly.

in the amount of acetylstrophanthidin necessary to produce ventricular tachycardia in normal and hypoxic dogs.8 The use of each dog as his own control was considered to be necessary to overcome the wide individual variations in the amounts of acetylstrophanthidin required to produce toxicity. It is our conclusion that alkalosis acutely induced by an infusion of sodium hydroxide did not alter the animals’ susceptibility to arrhythmias induced by acetylstrophanthidin. The induction of alkalosis produced a fall in serum potassium in all studies, a finding which is similar to that observed by others.4J0 Normal serum potassium values in dogs have been reported as 4.6 + 0.8 mEq. per liter.Q It is likely that intracellular potassium increased slightly although this was not measured in these

studies. Alkalosis with its accompanying hypokalemia did not alter the expected elevation in the serum potassium occurring during the infusion of acetylstrophanthidin. The magnitude of this increase was similar in both normal and alkalotic conditions and is comparable to the rise noted by other observers.gJ1-13 This increase has been attributed to an increase in the loss of potassium from the cell resulting from blockage of the re-entry of potassium by the acetylstrophanthidin.13J4 The failure of the serum magnesium to change significantly during digitalization is in contrast to the decreases reported by Kleiger and associates.Q No explanation for these differences is apparent. The rise in arterial pressure produced by the infusion of acetylstrophanthidin in the animals with normal pH’s has been observed by other investigators.r5J6 This has been attributed to the peripheral vasoconstrictive action of digitalis glycosides. In our studies no significant increase in arterial pressure was observed during acetylstrophanthidin infusion in alkalotic animals (Table II). It is possible that the alteration in pH prevented the vasoconstrictive action of acetylstrophanthidin. The duration of ventricular arrhythmias induced by acetylstrophanthidin was prolonged by alkaiosis in all five dogs in which studies in both the normal and alkalotic states were made. The average duration of toxicity during alkalosis was almost three times that observed at a normal pH. One animal developed ventricular fibrillation after infusion with acetylstrophanthidin during alkalosis. These studies do not provide for speculation regarding the role of the alkalosis separate from the hypokalemia since these occurred concomitantly and no independent studies were carried out. Although the mechanism by which the toxic effect of digitalis w-as prolonged is not defined by this study, the following hypotheses are suggested. Alkalosis clearly causes hypokalemia, and the transport of acetylstrophanthidin out of cardiac cells may be impaired by the hypokalemia. It is known that the transport mechanisms for potassium and digitalis are closely interrelated.r2-14 In the presence of metabolic alkalosis there is a shift of hydrogen and

Digitalis

sodium from the cell to the extracellular fluid and a concomitant movement of potassium into the cell. Given a constant total body potassium, maintenance of a low concentration of potassium in the extracellular fluid requires that the influx of potassium and the efflux of sodium and hydrogen all remain at high levels. The presence of increased potassium transport during alkalosis may impair the egress of acetylstrophanthidin and therefore prolong toxicity. Another possible explanation is that the altered intracellular electrolyte concentration results in a reduced metabolism of acetylstrophanthidin or an altered binding of the intracellular digitalis glycoside. The present study does not confirm or deny these speculations. We conclude, then, that metabolic alkalosis prolonged the duration of toxic ectopic ventricular arrhythmias induced by acetylstrophanthidin and that the mechanism for this action is not understood at this time. There are two clinical conditions to which these data may be applied. First, cardiac arrest frequently occurs in patients who are taking digitalis glycosides or who have toxic arrhythmias due to digitalis. In the resuscitation attempts, these patients are administered large volumes of sodium bicarbonate and occasionally develop alkalosis. Our studies would suggest that the toxicity to digitalis might be enhanced. Secondly, respiratory alkalosis frequently develops in patients with obstructive pulmonary vascular disease due to hyperin digitalis ventilation and alteration toxicity may develop.

363

was greatly prolonged in the alkalotic animals. Possible mechanisms to explain this observation were discussed. The acetylstrophanthidin used to produce digitalis toxicity in these studies was kindly supplied by Dr G. C. Chiu, Eli Lilly & Co., Indianapolis 6, Ind. REFERENCES 1.

2.

3.

4.

5.

Lown, B., and Levine, S. A.: Current concepts in digitalis therapy, Boston, 1954, Little, Brown & Company. Rodensky, P. L., and Wasserman, F.: Observations on digitalis intoxication, Arch. Int. Med. 108:171, 1961. Baum, G. L., Dick, M. M., Blum, A., Kaupe, A., and Carballo, J.: Factors involved in digitalis sensitivity in chronic pulmonary insufficiency, AM. HEART J. 57:460, 1959. Bliss, H. A., Fishman, W. E., and Smith, P. M.: Effect of alterations of blood pH on digitalis toxicity, J. Lab. & Clin. Med. 62:53, 1963. Talso, P. J., Remenchik, A. P., and Cutilletta, A.: Altered myocardial potassium gradients in acute alkalosisand their relationship to acetylstronhanthidin sensitivitv in the dog. Circulation’26:794, 1962. . Astrup, P., Jorgensen, K., Andersen, 0. S., and Engel, K.: The acid-base metabolism: A new approach, Lancet 1:1035, 1960. Tansen, D. 5.: Direct POZ and pC0~ measurement, Laboratorium 3I1, 1963. Harrison. D. C.. Robinson. M. C.. and Kleieer. R. E. : Role of hypoxia in digitalis’ toxicity, Cir: culation 34 (suppi. 111):124, Oct. 1966. Kleiger, R. E., Seta, K., Vitale, J. J., and Lown, B.: Effects of chronic depletion of potassium and magnesium upon the action of acetylstrophanthidin on the heart, Am. J. Cardiol. 17:520, 1966. Tobin, R. B.: Varying role of extracellular electrolytes in metabolic acidosis and alkalosis, Am. J. Physiol. 195:685, 1958. Lown, B., Whipple, G. H., McLemore, G., and Levine, S. A.: Effects of digitalis upon body electrolytes, Circulation Res. 9:522, 1961. Grupp, G., and Charles, A.: Effect of ouabain and 3-acetylstrophanthidin on potassium exchange in the dog heart in situ, J. Pharmacol. & Exper. Therap. 143:356, 1964. Corm, H. L.: Effects of digitalis and hypoxia on potassium transfer and distribution in the dog heart, Am. J. Physiol. 184:548, 1956. Cairns, A. B., Jr., Love, W. D., and Burch, G. E.: The effects of acetylstrophanthidin on the kinetics of potassium and Rb8” in the myocardium of dogs, AM. HEART J. 59:404, 1960. Ross, J., Jr., Waldhausen, J. A., and Braunwald, E.: Studies on digitalis. I. Direct effects on the peripheral vascular resistance, J. Clin. Invest. 39:930, 1960. Dock. W.. and Tainter. M. L.: The circulatorv changes after full therapeutic doses of digitalis with a critical discussion of views on cardiac output, J. Clin. Invest. 8:467, 1930. Y .

6.

7. a.

9.

10.

11.

12.

Summary

The influence of metabolic alkalosis on the amount of acetylstrophanthidin necessary to produce ventricular tachycardia was studied in anesthetized dogs. Although an infusion of sodium hydroxide to produce an average pH of 7.57 resulted in hypokalemia, no significant difference in the amount of acetylstrophanthidin necessary to cause digitalis toxicity during control and metabolic alkalosis was noted. Acute digitalization produced an elevation of serum potassium, a slower heart rate, and an increase in arterial blood pressure. The duration of ventricular arrhythmias caused by acetylstrophanthidin, however,

toxicity

13.

14.

15.

16.