Download Digitalis Intoxication

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 Unpublished data collected retrospectively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.