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253 Clinical Scfence (1983) 64,253-258 I EDITORIAL REVIEW I Digitalis intoxication J. K. A R O N S O N MRC Unit and University Department of Clinical Pharmacology, Radclge Iqfirmary. Oflord, UX. Epidemiology Symptoms and signs William Withering’s Account of the Foxglove is sufficiently detailed for one to be able to hazard an estimate of the incidence of digitalis toxicity which occurred at this hands [l]. In the early years of his use of extracts of Digitalis purpurea (from 1775) he met with a very high incidence of toxicity, probably because he used an alcoholic extract, but in later years, with the use of an aqueous extract and with increasing experience, the incidenceof toxicity in his patients dropped. In the years 1782-1785 it was probably about 2&25%. We have failed in modem times to do much better than Withering. The prevalence of digitalis intoxication among patients admitted to hospital has been found to vary very widely and in large prospective studies has been recorded as high as 29% [2l. Less information is available on out-patients (attending either hospital clinics or general practitioners’ surgeries). One might expect a lower prevalence of digitalis toxicity among patients studied outside hospital than in those studied on admission to hospital since digitalis toxicity will not infrequently be the reason for admission. Nonetheless, the prevalence of toxicity in out-patients may still be quite high. Unpublished data collected retrospectively in our laboratory from 3297 patients in the Oxford Area suggest that the incidence of digoxin toxicity in out-patients may be as high as 16%. The published figures from in-patient studies suggest that the mortality rate in untreated digitalis intoxication varies widely and depends on the particular arrhythmias which occur. For example, there are reports of mortality rates varying between 4% and 36% [3, 41 but in patients with particular arrhythmias the mortality rate may be higher, e.g. 50% in patients with paroxysmal supraventricular tachycardia with block ([51 see also reference 131). The symptoms and signs of digitalis intoxication may be non-cardiac or cardiac and are on the whole well known. For a thorough review and references see reference 161. Non-cardiac evidence of toxicity Gastro-intestinal tract disorders (nausea, vomiting, anorexia and diarrhoea) are very common effects of digitalis toxicity but completely non-specific. Rarely digitalis may cause intestinal ischaemia [71. Toxic effects of digitalis on the nervous system occur more frequently than is generally recognized and in severe toxicity occur in up to 65% of patients 181. The effects may result in confusion, dizziness, drowsiness, bad dreams, restlessness, nervousness, agitation and rarely seizures. Acute psychoses and delirium may occur, particularly in the elderly, and rarely digitalis may cause trigeminal neuralgia [9, 101. There is also evidence that cardiac arrhythmias may be caused by the effects of digitalis on the nervous system as well as by direct effects on the cardiac conducting tissues [ 111. Digitalis affects the eyes, occasionally causing photophobia and blurred vision, and, more commonly, colour visual disturbances. Any colour visual abnormality may occur but yellow vision (xanthopsia) is the commonest. So unusual are other causes of an acute colour visual disturbance of this kind in the geneial population that it is almost pathognomonic of digitalis intoxication. Symptoms of colour visual disturbance may occur in up to 15% of patients with digitalis toxicity [121 but have been recorded in much higher incidence in cases of severe intoxication [81. Clinical measurement of colour vision defects is discussed below. 0143-5221/83/030253-0652.00 @ 1983 The Biochemical Society and the Medical Research Society 254 J. K . Aronson Cardiac evidence of toxicity The effects of digitalis intoxication on the heart are manifested in three different ways: arrhythmias, conduction block and worsening heart failure. The commonest arrhythmias, none of which is specific, are ventricular extrasystoles (54%), often coupled (25%), and supraventricular tachycardia (33%). The percentage incidence figures given in parentheses are those given by Chung in his review of 726 patients [ 131. Atrioventricular conduction block is also common (42%) and may be of first degree (14%), second degree (1 7%) or complete (1 1%). Prolongation of the PR interval, without higher degrees of atrioventricular block, may occur in the absence of digitalis toxicity. Although none of these effects (arrhythmias or A-V block) is specific for digitalis intoxication, the concurrence of an ectopic arrhythmia with atrioventricular block greatly increases the likelihood that digitalis is to blame. Sinus bradycardia is not very common (3.4%) and is of very low specificity, particularly in patients who are resting [ 141. Occasionally digitalis intoxication may cause atrial fibrillation (1.7% in Chung’s own series) or atrial flutter (1.8%), and this may afford great difficulty in interpretation. In patients with pre-existing atrial fibrillation the most common arrhythmias are supraventricular tachycardia or escape rhythm, and these arrhythmias are then easily mistaken for uncomplicated atrial fibrillation. In toxic doses digitalis may impair, rather than improve, cardiac contractility and intoxication then appears as worsening heart failure, sometimes in the absence of arrhythmias or heart block. In one series of 148 patients considered to ‘be suffering from digitalis intoxication worsening congestive heart failure occurred in 7.5% [151. Diagnosis The diagnosis of digitalis intoxication is usually made by clinical suspicion based on symptoms and signs directly attributable to the toxic effects of digitalis. Although those symptoms and signs are usually non-specific it is often possible to make the diagnosis by observing the patient’s progress over a few days after the initial suspicion has been raised, particularly if digitalis is withdrawn in the meantime. A set of criteria for the diagnosis of digitalis intoxication in this way [ 161 is given in Table 1. Furthermore, one’s index of suspicion may be increased by the presence of other factors which enhance the toxicity of digitalis. TABLE1. Criteriafor the diagnosis of digitalis intoxication A. One or more of the following, not known to have been present before treatment with digoxin: I . Supraventriculartachycardia with atrioventricular block 2. Ventricular extrasystoles-(a) more than Urnin and/or (b) bigemini andlor (c) multifocal 3. Ventricular tachycardia 4. Atrial fibrillation with ventricular response rate less than 60 beatslmin in the presence of ventricular extrasystoles 5. Second- or third-degree atrioventricularblock B. Any of the following, if resolving on withdrawal of digoxin: I. Symptoms attributable to digitalis toxicity (see the text) 2. Ventricular extrasystoles more than S h i n 3. First-degree heart block 4. Sinus bradycardia (heart rate less than 60 beatshin) 5. Atrial fibrillation with ventricular response rate less than 60 beatshin C. Additional factors increasing the likelihood of toxicity: I. Renal failure 2. Hypokalaemia, hypomagnesaemiaand hypercalcaemia 3. Hypothyroidism 4. Oldage 5. Hypoxia and acidosis 6. Concomitant therapy with quinidine, verapamil, nifedipine, amiodarone or spironolactone Important factors ( a ) Renal impairment. Renal impairment alters both the distribution of digoxin and p-methyl digoxin in the body and impairs their excretion 1171. Thus for a given loading dose or maintenance dose, higher plasma concentrations occur than would do if renal function were normal. Although the relationship between plasma digoxin concentrations in these circumstances and the occurrence of digitalis toxicity has not been fully worked out, there is no doubt that patients with renal impairment are at a greater risk of digitalis toxicity than patients with normal renal function. This does not apply to patients taking digitoxin. (b) Hypokalaemia. The effects of all digitalis glycosides on the tissues are enhanced by hypokalaemia (or total body potassium depletion even when the plasma potassium concentration remains within the normal range) [321. This is especially important to consider in patients taking diuretics in addition to digitalis. (c) Other electrolyte abnormalities. Magnesium deficiency and hypercalcaemia probably also enhance the effects of all digitalis glycosides. (d) Hypothyroidism. In hypothyroidism there are several effects which may enhance tissue responsiveness to all digitalis glycosides. Firstly their distribution is altered and higher plasma concentrations result. Secondly, there may be concurrent impairment of renal function. Thirdly, there seems to be a direct effect on the tissues Digitalis intoxication themselves, resulting in increased sensitivity. For a review of these effects see 1181. (e) Age. The elderly are more susceptible to the effects of digitalis, partly because of impairment of renal function but also perhaps because of increased sensitivity of Na+,K+-activated ATPase to the inhibitory effects of digitalis [331, and because of changes in the tissue distribution of digoxin 1341. (f)Hypoxia and acidosis. For reasons which are not understood there is increased tissue responsiveness to digitalis in the presence of hypoxia or acidosis. (g) Drug interactions. (These are reviewed in reference [191.) Several different drugs may cause an increase in plasma digoxin concentrations at constant doses of digitalis. These include quinidine (which inhibits digoxin renal and non-renal elimination and alters its tissue distribution), verapamil (which inhibits digoxin renal elimination), nifedipine and amiodarone (which cause an increase in plasma digoxin concentrations by unknown mechanisms), and spironolactone (which has a small effect in inhibiting digoxin renal elimination). In the presence of one or more of these additional factors, digitalis intoxication should be strongly suspected in any patient in whom there are also suggestive symptoms or signs. In general it is then better to assume that toxicity has occurred and to withdraw treatment than to continue. The use of some of these factors in the interpretation of the plasma digoxin concentration is discussed below. Confirmatory diagnosis When one’s clinical suspicion has been aroused, it is common to apply diagnostic tests in the hope of confirming the diagnosis. Often, however, such confirmation may be dimcult to achieve. The following tests may be used: (a) Electrocardiogram. In the absence of arrhythmias the routine ECG is not helpful. Not only are the effects of digitalis on the ECG non-specific (prolongation of the PR interval, narrowing of the QRS complex, inversion of the T-wave), but they may occur in the presence or absence of toxicity. The most typical effect, depression of the ST segment, virtually always occurs in a properly digitalized patient. Occasionally digitalis causes electrical alternans, but that too is non-specific. Evidence of hypokalaemia on the ECG should lead one to suspect toxicity. Careful measurement of various intervals of the ECG from recordings made at 100 mm/s 255 have been shown to correlate well with plasma digitalis concentrations in individuals, and the so-called ‘PTQ score’ (which combines PR and QT intervals and an assessment of the T-wave) may prove useful in distinguishing toxic from non-toxic individuals 1201. The technique has not yet been proven to be valuable in routine clinical use, although it has a place in research. (b) Plasma potassium concentration. The plasma potassium concentration should be measured in all patients with suspected digitalis intoxication. If there is a low plasma potassium concentration (or other evidence of total body potassium depletion, e.g. a metabolic alkalosis), then digitalis intoxication should be assumed. This is the case even when the plasma digitalis concentration is low [161. This is because the effect of digitalis in inhibiting Na+,K+-ATPaseis enhanced in the absence of potassium. (c) Plasma digitalis concentration. So-called ‘therapeutic ranges’ have been established for digoxin and digitoxin. At values above those ranges (>3 ng/ml for digoxin, and >30 ng/ml for digitoxin) there is a very high incidence of toxicity. However, toxicity may also occur in patients with plasma digitalis concentrations below those values and in such cases other evidence must be sought. If there is evidence of potassium depletion toxicity should be assumed to be present (see above). Paradoxically the presence of hyperkalaemia, if otherwise unexplained, is also associated with an increased incidence of digitalis toxicity. That is because hyperkalaemia may occur as a result of excessive inhibition of Na+,K+-ATPase in intoxication. Indeed, in overdose hyperkalaemia is a bad prognostic sign 1211. Other patients in whom one’s suspicion of digitalis intoxication should be increased are those with the factors discussed above (e.g. renal impairment, hypothyroidism). In patients taking digoxin those with a plasma digoxin concentration inappropriately low for the dose they are taking may also be at increased risk of toxicity because of the presence of cardioactive metabolites not detected by the routine digoxin assay. We have suggested [161 that in patients with plasma digoxin concentrations below 3.0 ng/ml a diagnosis of digoxin toxicity should be seriously considered if there is hypokalaemia or if there are any two of the following: (a) plasma potassium >5-0 mmol/l without a clear explanation; (b) plasma creatinine > 150 pmol/l; (c) age > 60 years; (d) daily maintenance dose > 6 pg/kg. Although this approach should result in a low incidence of false negative diagnoses (i.e. small type I error) there is a relatively high incidence J. K . Aronson 256 TABLE2. Likelihood ratios for the diagnosis of digoxin intoxication at speclfied values of plasma digoxin concentration (from [221) ~ ~~ ~ ~~ Plasma digoxin concentrationrange Likelihood ratio (ndml) 04.99 1.c1.99 24-2.99 >2.0 >3*0 0.14 0.35 5.18 7.55 11.73 (41%) of false positive diagnoses (i.e. large type I1 error). There is currently no guidance to the interpretation of the plasma digoxin concentration in patients with thyroid disease, hypoxia or acidosis. There is little information on the probability of digitalis intoxication at given plasma digitalis concentrations. Eraker & Sasse 1221 have published likelihood ratios for diagnosis of toxicity at given plasma digoxin concentrations, calculated from pooled data published in five different studies. Their calculations are most easily interpreted as suggesting that a given plasma digoxin concentration in a patient with suspected digoxin intoxication increases or decreases the probability of intoxication. Thus a plasma digoxin concentration of less than 1 ng/ml decreases the likelihood of toxicity seven-fold (likelihood ratio 0.14), while a concentration of more than 3 ng/ml increases the likelihood by about 12-fold (likelihood ratio 11073). The full set of likelihood ratios is given in Table 2. Any of the factors which enhance the response to digoxin will increase the values of these ratios (i.e. make toxicity more likely). (d) Provocative and therapeutic tests. Various tests have been devised in which an attempt is made either to provoke or cure arrhythmias, thus providing presumptive evidence of digitalis intoxication. Provocative tests include the infusion of acetylstrophanthidin, the administration of a d.c. shock, carotid sinus massage and calcium infusion. Although such tests may be of value in research [231, they are hazardous and should be avoided in routine practice. Tests which depend on their apparent therapeutic efficacy include the administration of antiarrhythmics such as phenytoin, of cations such as potassium and magnesium, and of compounds which lower circulating calcium concentrations such as EDTA or sodium citrate. However, none of these manoeuvres, even if successful in abolishing arrhythmias, is specific for digitalis intoxication. (e) Salivary electrolytes. It has been claimed by several investigators that the measurement of salivary potassium and calcium concentrations, particularly in combination, is useful in discriminating toxic from non-toxic individuals. The individual results of some studies certainly seem to suggest that that is so, but there is too much divergence of results between studies to suggest that these measurements are of routine value clinically (compare, for example, [241 with [251). (f)Intraerythrocytic cation concentrations. Because digitalis inhibits transmembrane cation transport it has been suggested that digitalis intoxication may be accompanied by an increase in intracellular sodium concentration and a decrease in intracellular potassium concentration. Some studies have demonstrated such changes but alterations in cation transport may occur in other common conditions, such as hypertension and obesity, and it is too soon to say whether these measurements will be of routine value in the diagnosis of digitalis intoxication [ 101. (g) Colour vision testing. Although complaints of visual symptoms are relatively uncommon in digitalis intoxication, it has been shown that there are abnormalities of colour vision detectable in toxic patients, even in the absence of visual symptoms, by the use of sensitive colour vision measurement techniques 126, 271 such as the Farnsworth-Munsell 100-Hue test. In this test patients are required to set in order a graduated series of different hues, matched for saturation and brightness. This test provides a qualitative differentiation of colour vision abnormalities between acquired defects and the usual forms of congenital defect and in addition allows one to quantify the extent of the defect. In selected patients with digoxin intoxication diagnosed by the criteria mentioned above, the colour vision score was found to be significantly higher than in non-toxic patients [261. After withdrawal of digoxin the colour vision scores fell to non-toxic values. Furthermore colour vision scores correlated well both with plasma digoxin concentrations [26, 271 and with measures of erythrocytic cation transport receptor numbers and activity, including intraerythrocytic sodium concentrations 1261. These data suggest that bedside colour vision testing may be of value in the immediate diagnosis of digitalis intoxication, but this suggestion needs formal prospective evaluation in an unselected population. Treatment 135,361 In all cases of toxicity digitalis should be withdrawn. Potassium should be given if there is evidence of potassium depletion and usually oral Digitalis intoxication administration of about 48 mmol daily will be sufficient. In the majority of cases no further measures will be required. Arrhythmias generally do not require specific treatment, but if there is a life-threatening ventricular arrhythmia phenytoin is the antiarrhythmic of choice and should be given under cardiographic monitoring. Unlike most other effective antiarrhythmics phenytoin increases the rate of conduction through the atrioventricular node and thus does not potentiate the effects of digitalis on the node. It does, however, depress ventricular automaticity and should not be given if there is second- or third-degree atrioventricular block. If phenytoin fails then a kadrenoceptor antagonist (such as practolol or propranolol) or lignocaine should be used. The most difficult digitalisinduced arrhythmia to treat is paroxysmal supraventricular tachycardia with atrioventricular block. Propranolol or practolol are probably the treatments of choice, but there is a risk of worsening heart block and a temporary pacemaker is advisable when they are used. If they fail, phenytoin should be used cautiously. Verapamil and amiodarone are better avoided in these circumstances because of their interactions with digoxin (see above). Sinus bradycardia and heart block sometimes respond to atropine but in the latter case a temporary pacemaker may be required. In the case of digitoxin the administration of activated charcoal or of a resin such as cholestyramine or colestipol helps reduce the body load of digitoxin by reducing the reabsorption of bile-excreted drug [281. Specific antibodies to digoxin rapidly reverse the toxic effects of digoxin and digitoxin but are at present reserved for severe intoxication, particularly in overdose [291. The role of d.c. shock in treating arrhythmias in patients taking digitalis is not clear. If the arrhythmia is not attributable to digitalis then d.c. shock is not contra-indicated, but very low energies should be used, at least to start with, e.g. 10 J initially, increasing gradually as required [ 301. For digitalis-induced arrhythmias it is probably better not to use d.c. shock (except for life-threatening ventricular arrhythmias) since one is unable to remove the cause of the arrhythmia and the use of even low energies carries a risk of life-threatening arrhythmias. Prevention Digitalis toxicity may in part be prevented by carefully tailoring initial dosages to the needs of the individual, by avoiding hypokalaemia, and by adjusting dosages in patients whose renal function is deteriorating and in whom interacting 257 drugs such as quinidine are used. A method for tailoring initial dosages of digoxin to individual needs has been described [311 and evaluated. Only occasionally should it be necessary to check plasma concentrations with this method. Several different nomograms and equations have been published as guides to therapy but none is ideal [311 and there is no substitute for careful observation of the patient. Acknowledgments I am grateful to the Wellcome Trust and the British Heart Foundation for financial support. References 1 11 ESTES, W.J. & WHITE,P.D. (1965)William Withering and the purple foxglove. ScientiJFeAmerican, 212 (6), 110-1 19. 121 BBLLER,G.A., SMITH, T.W.,ABELMANN, W.H., HABER,E. & HOOD, W.B. (1971) Digitalis intoxication: a prospective clinical study with serum level correlations. New England Journal of Medicine, 284,989-997. I31 DWIFUS,L.S., MCKNIOHT,E.H., KAIZ, M. & Lmom, W. (1963)Digitalis intolerance. Geriatrics, 18,494-502. 141 FRIEND,D.G. (1962) Current concepts in therapy. Cardiac glycosides. New England Journal of Medicine, 266,8849. 151 L o w , B. & LEVIN& H.D. (1958) Current Concepts in Digitalis Therapy. Little, Brown and Co., Boston. I61 ROBINSON, B.F. (1975) In: Meyler's Side m e c t s of Drugs, chapter 17. Ed. Dukes, M.N.G. Excerpta Medica, Amsterdam. 171 ARONSON, J.K. (1978) In: Side Effects of Drugs, Annual 2, chapter 17A. Ed. Dukes, M.N.G. Excerpta Medica, Amsterdam. I81 LELY,A.H. & VAN ENTER,C.H.J. (1970)Large-scaledigitoxin intoxication.British Medical Journal, Ui, 737-740. 191 ARONSON, J.K. (1980) In: Side Effects ofDrugs. Annual 4, chapter 18. Ed. Dukes, M.N.G. Excerpta Medica, Amsterdam. I101 ARONSON, J.K. (1981) In: Side Effects of Drugs, Annual 5, chapter 18. Ed. Dukes, M.N.G. Excerpta Medica, Amsterdam. 11 1I Levrrr, B., CAGIN,N. KUID, J., SoMseno, J. & GILLIS,R. (1976) Role of the nervous system in the genesis of cardiac rhythm disorders. American Journal of Cardiology, 37, 1111-1113. I121 STORSTEIN, 0..HANSTEEN, V., HAW, L., HILUSTAD,L. & STORSTEIN, L. (1977)Studies on digitalis. XIII. A prospective study of 649 patients on maintenance treatment with digitoxin. American Heart Journal, 93,434-443. I131 CHUNG,E.K. (1969) Digitalis Intoxication, p. 96. Excerpta Medica, Amsterdam. 1141 WILLIAMS, P., ARONSON. J.K. & SLEIGHT,P. (1978)Is a slow pulse rate a reliable sign of digitalis toxicity? Lancer, U, 1340-1342. CAPELLER, D., COPELAND, G.D. & SIERN,T.N. (1959) Digitalis intoxication: a clinical report of 148 cases. Annals of Internal Medicine, SO, 869-878. 161 ARONSON,J.K., GRAHAME-SMITH,D.G. & WIGLEY,F.M. (1978)Monitoring digoxin therapy. The use of plasma digoxin concentration measurements in the diagnosis of digoxin toxicity. QuarrerlyJournal of Medicine, NS47, I 11-1 22. 171 ARONSON,J.K. (1982) The clinical pharmacokinetics of cardiac glycosides in patients with renal dysfunction. Clinical Pharmacokinerics(In press). 1181 SHENFIBLD, G.M. (1981)Influence of thyroid dysfunction on drug pharmacokinetics. Clinical Pharmacokinetics, 6, 275- 151 VON 297. 1191 ARONSON, J.K.(1982) In: Side Effects of Drugs, Annual 6, chapter 18. Ed. Dukes, M.N.G. Excerpta Medica, Amsterdam. I201 JOUBERT, P.H., MOLLen, F.O., PANSEOROW, D.F. & KLEYNHANS, P.H.T. (1975) A correlative study of serum digoxin levels and electrocardiographic measurements. South A/rcanMedicalJournal, 49,1177-1181. 1211 BISMUTH, C., GAULTIER, M., CONSO, F. & EMYMIOU, M.L. 258 J. K.Aronson (1973) Hyperkalaemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clinical Toxicology, 6, 153-162.. I221 ERAKER, S.A. & SASSE,L. (1981) The serum digoxin test and digoxin toxicity: a Bayesian approach to decision making. Circulation, 64,409-420. 1231 KLEIN, M.D., Low, B., BARR, I., HAGEMEUERF.. P. (1974) Comparison of serum GARRISON. H. & AXELROD, digoxin level measurement with acetyl strophanthidin tolerance testing. Circulation, 49, 1053-1062. 1241 WOWAN, S., BIGGER,J.T., MANDELI.D. & BARTELSTONE, H.J. (1971) Salivary electrolytes in the diagnosis of digitalis toxicity. New England Journal of Medicine, 285,87 1-876. I251 WEISSEL, M., F R ~ S C H E H., & FUCHS,G. (1976) Wertigkeit der Speichelektrolyteund Serumdigoxinspiegel bei der Objektivierung von Digitalisintoxikationen. Wieier Klinische Wochenschrft, 88,455-458. 1261 ARONSON, J.K. & FORD,A.R. (1980) The use of colour vision measurement in the diagnosis of digoxin toxicity. Quorterly Journal of Medicine, NS49,273-282. N. & ALKEN,R.G. (1980) Color vision deficien(271 RIETEROCK, cies: a common sign or intoxication in chronically digoxintreated patients. Journal of Cardiovascular Pharmacology, 2, 93-99. 1281 CARRUTHERS, S.G. & DUJOVNE, C.A. (1980) Cholestyramine and spironolactone and their combination in digitoxin elimination. Clinical Pharmacology and Therapeutics, 27,184-187. 1291 SMITH,T.W., HABER, E., YEATMAN. L. & BUTLER,V.P. (1976) Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. New England Journal of Medicine, 294,797-800. 1301 HAGEMEUER, F. & VAN HOUWE.E. (1975) Titrated energy cardioversion of patients on digitalis. British Heart Journal, 37,1303-1307. I311 ARONSON, J.K.(1978) Monitoring digoxin therapy. 111. How useful are the nomograms? British Journal of Clinical Pharmacology, 5.55-64. H.F. (1977) Digoxin toxicity in 1321 BRATER,D.C. & MORRELLI, patients with normokalaemic potassium depletion. Clinical Pharmacology and Therapeutics, 22,2l-33. 1331 P u r r , D. & SCHOCH,P. (1974) Effect of age and cardiacglycosides on the activity of adenosine triphosphatase (ATPase) (EC 3.6.1.3) of red cell ghost membranes. Mechanisms of Ageing and Development, 3,245-252. D.G. (1977) Monitoring I341 ARONSON, J.K. & GRAHAME-SMITH, digoxin therapy: 11. Determinants of the apparent volume of distribution. British Journal of Clinical Pharmacology, 4, 223-227. I351 ALGARRA,F., CASELLAS,A., COLTART, J., CHILDERS,R., MAITRE,MJ. & RAMON, J.R.(1980) Diagnosis and treatment of digitalis intoxication. In: Diagnosis and Treatment of Cardiac Arrhythmias, 1977, chapter 18. Ed. Bayes, A. & Cosin, J. Pergamon Press, Oxford. 1361 BANKA,V.S. & HELFANT,R.H. (1980) Digitalis. In: Bellet’s Essentials of Cardiac Arrhythmias, pp. 255-275. Ed. Helfant, R.H. W.B. Saunders, Philadelphia.