Drugs 13: 142-151 (1977) © ADIS Press 1977
Digitalis in Pulmonary Heart Disease (Cor Pulmonale) 1 J.£ Doherty, J.J. Kane, J.R. Phillips and J.S. Adamson Univers ity of Arkansas College of Medicine, Division of Cardiology, Veterans Adm inistration Hosp ital anf University of Arkansas College of Medicine, Heart Station, Veterans Administration Hospital, Pulmonary Diseases Section , Veterans Administration Hosp ital, Little Rock, Arkansas
The use of digitalis in pulmonary heart disease has been a topic of great interest for a number of years. The physician's decision to use or not to use digitalis in pulmonary disease has often been an emotional rather than a reasoned one. The diagnostic difficulties from a clinical point of view in separation of'pulmonary from cardiac symtpoms and findings have also been confusing. The fact that small doses of digitalis may have an inotropic effect on the cardiac muscle has been a difficult concept for many physicians to adopt. On the other hand, the larger doses of digitalis that are often necessary to control the ventricular response in supraventricular arrhythmias sometimes gives rise to confusion. We shall attempt to review the subject in detail and examine indications, contraindications , toxicity, dosage, assessment of benefit, and role of'digitalis serum levels in patient management.
1. Indications for Digitalis in Cor Pulmonale
in assessment of possible toxic manifestations. The presence of dyspnoea, pulmonary rales, oedema, tachycardia, and arrhythmia as common findings to pulmonary disease, heart failure and digitalis intoxication serve to illustrate part or this dilemma and will be discussed more fully in a later section. 1.1.1 Arguments Against Digitalis Mounsey et al. (1952) reported only minimal changes in cardiac output and right ventricular enddiastolic pressure in 4 patients with cor pulmonale. Further, acute and chronic haemodynamic studies of Berglund et al. (1963) failed to demonstrate significant improvement in 8 patients (some were not in congestive heart failure) and in only one could improved cardiac performance be demonstrated . 1.1.2 Arguments for Digitalis Many years ago, White (1945) advised that 'usual' management of heart failure accompanying chronic cor pulmonale should include digitalis, rest and diuretics as needed. Ferrer et al. (1950) reported
1.1 Congestive Heart Failure The effectiveness of digitalis in cor pulmonale has long been questioned in congestive heart failure because of doubtful clinical benefit and the difficulty
I Supported in part by the Veterans Administration Medical Research Information System. Grant Number 1887-01. USPHS NIH Grant No.06642·12 and Burroughs Wellcome Co.• Research Triangle Park. N.C . 27709 .
Digitalis in Pulmonary Heart Disease
favourable haemodynamic and clinical effectiveness of digoxin used acutely and chronically in patients with heart failure and cor pulmonale. Attention was also given to basic management of chronic obstructive pulmonary disease (COPD) as well. Henshaw (J 969) advises full digitalisation for heart failure which accompanies lung disease and states it may be the only medication necessary to restore function. Our own view is that digitalis alone will rarely solve the problem. Bates et al. (J 97 J) stress th difficulty of accurate diagnosis (pulmonary oedema - cor pulmonale respiratory failure) and stress the value of blood gases in evaluation. Digitalis and diuretics were employed in an illustrative case with good effect. Piemme (J 972) states that the balance of evidence favours in use of digitalis in patients with right ventricular failure and pulmonary heart disease. The fact that their use may elevate further pulmonary vascular resistance appears to be counter balanced by a favorable effect on right ventricular performance . He advises caution because of the propensity to ventricular arrhythmia exhibited by patients with right ventricular overload. Robin and Gaudio (J 970) and Robin (J 973), in classic references on cor pulmonale and pulmonary oedema, recommended digitalis to increase myocardial contractility in left ventricular failure. J.J.3 Current Views of CHF Indications Ingram and Grossman (J 974) recommend digitalis and diuretics when right heart failure intervenes in chronic cor pulmonale and a similar view is expressed by Fowler (1975). Ferrer (J 975) states that use of digitalis is no longer controversial and there is a consensus that digitalis is indicated for management of congestive heart failure in the presence of cor pulmonale .
1.2 Arrhythmia 1.2 .1 Frequency of Arrhythmia Decreased The frequency of arrhythmia in respiratory failure was felt to be rare by Harvey et al. (J 953). Hecht
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(J 956) also held the view that arrhythmia was
unusual with cor pulmonale. J.2.2 Frequency of Arrhythmia Increased The bulk of investigators today, however, comment upon increased, rather than decreased, frequency of rhythm disturbances. (Corroza and Pastor , 1958; Kirby et al. , 1970). Goldberg et al. (1960) described a series of 37 patients with chronic respiratory disease who exhibited paroxysmal atrial tachycardia with atrioventricular block, all but one of whom were receiving digitalis. Cor pulmonale was present in 10 patients - more than any other aetiological diagnosis of pulmonary disease.
1.2.3 Dangers of Digitalis Toxicity Hunter (J 965) cited the frequent danger of digitalis intoxication and felt that digitalis toxicity contributed to the death of 5 patients in a retrospective chart analysis. He also cited the frequent presence of supraventricular arrhythmias in patients with COPD and did not use this type of rhythm disturbance as an index of digitalis toxicity - only ventricular arrhythmias and heart block, a perfectly valid approach at that time. Hecht (J 967) advised that digitalis be used in the 'rare' patient with cor pulmonale who manifests atrial fibrillation or other atrial arrhythmia, but did urge caution . Kirby et al. (1970) noted a high incidence of arrhythmias in both digitalis treated (61 % ) as well as non-digitalis treated patients (50 % ) with cor pulmonale. They noted that in patients who had been treated with digitalis, atrial tachycardia and atrial tachycardia with block occurred in the presence of less severe hypoxia and hypercarbia than in patients who had not receivedthe drug. They further cited this as evidence that the hypoxaemia of respiratory failure sensitises the myocardium to digitalis. That hypoxia alone is probably not responsible appears to be borne out partially by the fact that arrhythmia is not particularly common in patients with cyanotic congenital heart disease, many of whom exhibit greater degrees of hypoxia than patients with cor
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Digitalis in Pulmonary Heart Disease
pulmonale. It is admitted, of course, that factors other than hypoxia distinguish these diseases.
1.2.4 Current Views of Arrhythmia Indications Arrhythmia, particularly atrial arrhythmia atrial fibrillation, atrial flutter , atrial tachycardia appear to be legitimate indications for digitalis therapy in pulmonary heart disease. Junctional rhythms are also considered to be in this category, particularly if accompanied by heart failure. The familiar rule often cited clinically in the United States in paroxysmal atrial tachycardia with block: 'If the patient is taking digitalis, stop it; if he is not on the drug , then digitalise,' may be applied here. Electrical cardioversion may be used, too, but digoxin should be discontinued 24 hours before; digitoxin several days before .
2. Contraindications to Digitalis in Cor Pulmonale The absolute contraindication is the presence of definite toxicity due to digitalis. Relative contraindications include ventricular arrhythmias (premature ventricular contractions which are frequent and not associated with congestive heart failure; ventricular tachycardia), hypokalemia, and hypomagnesemia and hypercalcemia.
to inappropriate treatment, but also the reverse - left heart failure may be treated as pneumonia. Physical signs of neck venous distention are of little value because of laboured respiration and increased expiratory effort . Upright posture gives mechanical advantage to breathing in COPD with or without heart failure . Apparent liver enlargement because of low and flattened diaphragms and point of maximum impulse near the xyphoid process may also be misleading . Cardiac enlargement, usually seen on chest X-ray, is less apparent because of increased volume of the thoracic cage and is sometimes a problem if no comparison films are available. Finally, ankle oedema is frequently present in COPD due to stasis alone . These patients are very inactive and usually just 'sit' all day leading to puffy ankles , similar to that seen in right heart failure . The auscultatory findings are sometimes very helpful if the heart tones can be heard over the noisy lungs. A third heart sound or protodiastolic gallop rhythm is quite loud in congestive failure and may be best heard in the tricuspid area . The pulmonary component of the second heart sound is invariably accentuated, but is difficult to hear in the usual area because of pulmonary noise. Sometimes one may palpate the right ventricular impulse directly in the epigastric area by introducing one's fingers under the xyphoid and palpating superiorly - a palpable gallop sound is often felt in failure as well as the forcible right ventricular impulse. Sometimes a systolic murmur of tricuspid insufficiency is heard .
3. Assessment of Benefit from Digitalis in Cor Pulmonale 3.2 Management of Pulmonary Problem 3.1 Overlapping Symptoms of Disease Because of the nature of the symptoms in chronic obstructive pulmonary disease and in cor pulmonale and their complications, it is very difficult to determine the need, as well as assess the benefit (if any) accomplished through treatment with digitalis . The ever present dyspnoea and rales are oflittle value . The frequent complication of pneumonia and/or bronchitis may not only mimic heart failure and lead
One can appreciate the problems of determining improvement of the patient's status because of these overlapping cardiac and pulmonary findings, As heart failure is often accompanied or precipitated by a bout of pneumonia or bronchitis it is sometimes doubly difficult. Naturally, meticulous attention must be paid to management of the patient's primary prob lem, COPD, infection, bronchial toilet, bronchodilators, oxygen therapy, polycythemia. In general, good
145
Digitalis in Pulmonary Heart Disease
management in these areas leads to improvement in cardiac status as well. Providing support for the failing heart caused by the failing lungs (nearly a mortal combination) with digitalis may bring about salutary results.
Table I. Clinical manifestations of digitalis toxicity System
Common
Uncommon
Cardiac
Ventricular premature contraction Paroxysmal atrial tachycardia with block Nonparoxysmal A -V nodal tachycardia A-V block Sinus bradycardia Worsening of congestive heart failure
Atrial fibrillation Atrial flutter Ventricular tachycardia Ventricular fibrillation Sinus arrest SA block Atrial premature contraction A-V nodal premature contraction
Gastrointestinal
Anorexia Nausea Vomiting
Abdom inal pain Constipation Diarrhoea Haemorrhage
Visual
Colour vision (green or yellow) with halos Caution: glaucoma
Blurring or shimmering vision: scotoma, micropsia or macropsia, amblyop ia
Neurological
Fatigue Headache Insomnia Malaise Confusion Vertigo Depression
Neuralgia Convulsions Paresthesia Delirium Psychosis
3.3 Additional Treatment of Heart Disease One should use diuretics (watch potassium'), diet, rest and of course, oxygen (controlled concentrations of 24 to 28 % preferred) to prevent too much carbon dioxide retention while decreasing hypoxia (Petty, 1974). Measurement of arterial blood gases is essential for optimum assessment.
3.4 Symptomatic Assessment When one employs all of these measures, assessment of improvement is less of a task. Symptomatically, the patient is less dyspnoeic and feels improved. Moderate weight loss representing loss of oedema is often observed. Rales improve, but often do not disappear. Cyanosis and arterial oxygen saturation are improved. Digitalis serum levels will be discussed in a subsequent section.
4. Digitalis Toxicity in Cor Pulmonale As the view of cardiac rhythm disturbances in pulmonary disease has shifted from rare (Harvey et al., 1953; Hecht, 1956) to common (Hudson et al., 1973; Kleiger and Senior, 1974), assessment of digitalis intoxication has become more difficult.
4.1 Digitalis Versus Other Factors The practice of most cardiologists has been to view rhythm disturbances due to digitalis with alarm, while non-cardiac manifestations of digitalis are only troublesome and signal caution or alertness for the
Other
Allergic reaction Idiosyncrasy Thrombocytopenia Gynaecomastia (digoxin)
more serious problems with arrhythmia. Arrhythmia associated with digitalis in the presence of pulmonary disease are common today and are complicated by the arrhythmogenic potential of hypoxia and hypercarbia, coupled with bronchodilators sich as isoprenaline (isoproterenol) and aminophylline, together with vagal stimulation, resulting from suctioning, infection and acidosis. Digitalis serum levels are helpful, but not decisive (see section 5). . Table I is an outline of the toxic manifestations of digitalis given in any form, oral or parenterally, and
146
Digitalis in Pulmonary Heart Disease
in any preparation. There was once a feeling expressed that the crude leaf preparation resulted in more gastrointestinal side-effects prior to onset of rhythm disturbances. This has never been supported by a scientific study and purified glycosides are now preferred for clinical use. The dangerous manifestation of digitalis excess being rhythm disturbances, and the fact that any change in rhythm may be due to digitalis, forces one to be especially cautious in seriously ill patients. Patients with cor pulmonale are usually in this category, as advanced disease accompanied by pulmonary hypertension is almost invariably present when manifestations of congestive heart failure are present.
4.2 Other Factors Table II lists factors other than digitalis which may be responsible for rhythm disturbances in cor pulmonale in greater detail (Webb-Johnson and Andrews , 1976).
Table II. Factors in arrhythmia induction in chronic obstructive pulmonary disease
Corticosteroids Diuretics (hvpokalaemial Sympathomimetics Digitalis' Atropine Fluorocarbons (aerosol propellants) Methylxanthines (aminophylline) Infection Hypoxia Hypercarbia. hypocarbia Respiratory acidosis Respiratory alkalosis (respirators) Endogenous catecholamines Hypokalaemia Coexisting C-V Disease (coronary artery disease) Tracheal suctioning (vagaO 1 Often prescribed to more seriously ill patient. prone to arrhythmia for many other reasons.
Table III . Types of arrhythmias
Associated with pulmonary disease
Associated with digitalis excess
Paroxysmal atrial tachycardia with and without block
Paroxysmal atrial tachycardia with and without block
Multifocal atrial tachycardia
Multifocal atrial tachycardia (rare)
A-V junctional rhythm
A- V junctional rhythm
Atrial premature beats
Atrial premature beats
Ventricular premature beats
Ventricular premature beats
A-V dissociation
A-V dissociation
Idioventricular rhythm
Idioventricular rhythm
Parasystole (rare)
Parasystole (rare)
Atrial flutter
Atrial flutter (rare)
Atrial fibrillation
Atrial fibrillation (rare)
Cardiac arrest (ventricular fibrillation and/or asystole)
Cardiac arrest (ventricular fibrillation and/or asystole)
It has been noted repeatedly that the more seriously ill the patient with pulmonary disease, the more prone to rhythm disturbances and the more grave the prognosis and mortality in these patients (Kleiger and Senior. 1974). Because of increased evidence of arrhythmia and death in these patients, Hunter (1967) suggested extra caution be employed when digitalis is required for treatment.
4.3 Types of Rhythm in Cor Pulmonale Versus Digitalis Toxicity Table III categorises types of rhythm disturbances seen in COPD and those associated with digitalis excess. Similarities are not surprising when one realises that these are rhythm problems of the diseased heart, with or without digitalis. Recognition that multifocal atrial tachycardia, parasystole, atrial flutter and atrial fibrillation with rapid ventricular response are rather
Digitalis in Pulmonary Heart Disease
uncommon manifestations of digitalis intoxication is at times of some benefit.
5. Role of Digitalis Serum Levels in Managemen! of Cor Pulmonale The advent of digitalis serum levels in 1969 provided a new dimension by which the presence of digitalis glycosides can actually be measured (in billionths of a gram) in the blood and tissues (see Smith and Haber, 1974). Serum digitalis levels are now generally available in most larger hospitals.
5.1 Overlap of Therapeutic and Toxic Levels Usual therapeutic and toxic concentrations of digoxin and digitoxin, the two most popular glycosides, reported in the blood serum of human subjects are shown in table IV. Note that there is a relatively wide overlap between therapeutic and toxic levels, and we have already discussed factors that might tend to increase the propensity to develop arrhythmia and either mimic or induce toxicity.
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Table IV. Digitalis serum levels (ng/mll
Glycoside
Underdigitalised
Therapeutic
Definitely toxic
Digoxin
< 0.5
0.5-2.5
> 3.0
Digitoxin
< 10
10-25
> 35
6.1 Renal Function The most important factor with digoxin is adequate renal function. Doherty et al. (J 964) and Marcus et al. (J 966) have shown that functional capacity of the human kidney best determines the amount of drug excretedand thereby, the dosage requirement, as the drug is very little metabolised in the normal human subject. That this principle applies in cor pulmonale is shown well in figure I, where the blood urea nitrogen (BUN) is plotted against per cent of total dose of
5.2 Toxic Serum Levels in Cor Pulmonale Paciaroni et al. (1974) reported that toxicity to digitalis appears at lower serum levels in patients with pulmonary heart disease than is observed with other aetiologies. There is sufficient evidence with other disease states (hypokalaemia, hypothyroidism) to believe that this observation is correct (Doherty, 1973).
6. Dosage of Digixin in Cor Pulmonale Appreciation that toxicity to digoxin may occur at lower than usual serum levels of the drug should lead to more rigid evaluation of determinants of digitalis dosage in cor pulmonale.
Percentage total dose excreted in urine first 24 hours
Fig. 7. Effect of renal function on digoxin excretion. Blood urea nitrogen (BUN) is plotted on a logarithmic scale on the vertical axis ; ·per cent of the total dose of digoxin excreted in the first 24 hours after a single dose on the horizontal axis. Open circles (0) represent cor pulmonale; closed circles Ie) pat ients with heart disease of other aetiology. Note that the higher the BUN, the less digoxin is excreted .
Digitalis in Pulmonary Heart Disease
digoxin excreted 24 hours after administration of a single dose. One can readily see that reduction in renal functional capacity adversely affects digoxin excretion: the higher the BUN, the less digoxin excreted in the urine. The open circles represent patients with cor pulmonale, solid closed circles other aetiology of heart disease. Thus, compromised renal functional capacity suggests a reduction in dosage of digoxin. Digitoxin is seldom used by the author because of prolonged excretion, metabolism and half-life (Lukas, 197 n
6.2 Body Size Another important determinant is body size. Ewy et al. (I 97 I) has shown that digoxin dosage should be based on lean body mass - the obese individual requiring no more digoxin than the normal weight individual. The space of distribution of digoxin is not changed by increased weight. One should remember that many patients with cor pulmonale are quite thin (hypoventilation syndrome of obesity being the striking exception)and smaller doses are suggested for this reason as well.
6.3 Age Another important determinant is age, as most with cor pulmonale are elderly. Again, Ewy et al. (I969) demonstrated diminished renal clearance of digoxin in the elderly patient. This plus their smaller lean body mass are factors in increased digitalis toxicity in the older patient requiring the drug.
6.4 Combined Determinants All of these factors suggest a reduction in digoxin dosage in the patient with cor pulmonale who is often elderly, thin, and sometimes has compromised renal function .
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6.5 Increased Sensitivity to Digoxin in Cor Pulmonale The other major important factor, increased sensitivity to digoxin, is best illustrated by the following brief case study : A 52-year-old male with a long history of chronic bronchopulmonary disease was given O.75mg of tritium labeled digoxin intravenously to study the serum level, turnover t1 /2, and excretion of the drug . At the time of the study his creatinine clearance was 59ml/min, electrolytes were normal, p02 was 79mm, and pC0 2 52mm, pH 7.395 . (His respiratory problem was under reasonable control. The physical examination was not remarkable except for a few coarse rales over both lung fields (with increased resonance), normal sinus tachycardia, point of maximum cardiac impulse in epigastric area with prominent right ventricular gallop sound . The diaphragms were rather low, the liver was palpable 3cm. No oedema was present. Chest X-ray revealed hyperlucent lung fields and heart at upper limits of size as well as flattening of diaphragm . Electrocardiogram (ECG) done the day before the study is reproduced in figure 2. Note it is abnormal , showing non-specific ST-T changes and Pwaves of the pulmonale type. A ventricular ectopic beat is seen in lead AVF. Approximately 2 hours after being given digoxin, the patient complained of palpitation and the ECG shown in figure 3 was obtained. Note the appearance of paroxysmal atrial tachycardia (PAT) with block. About 2 hours later, the rhythm changed again and the ECG shown in figure 4 was recorded. It reveals PAT without block and a faster ventricular response. Shortly after this ECG was obtained, the patient noted spontaneous cessation of arrhythmia and said he felt much better. Fortunately, no further arrhythmia occurred and the patient's study was completed without incident. Figure 5 shows a semilogarithmic plot of serum turnover curve of tritiated digoxin during the first 48 hours of the study. Note the digoxin serum level was 1.7ng/ml at time of appearance of arrhythmia, and 1.2ng/ml when it disappeared spontaneously. It is
Digitalis in Pulmonary Heart Disease
Fig. 2. Electrocardiogram (ECG) on CC 24 Oct . 1966. Abnormal ECG. showing sinus tachycardia. rate 130. 'P' pulmonale and non-specific ST-T changes . A single premature ventricular contraction is seen in lead AVF.
very difficult to analyse these serum levels so soon after an intravenous bolus when the serum level is initially extremely high and falling rapidly. It should be noted that immediately after receiving the bolus injection the cardiac tissues are exposed to potentially toxic amounts of digoxin but require some time to accumulate enough of the drug to result in manifestations of toxicity (Doherty and Perkins, 1966). The half-time of early disappearance for intravenously administered digoxin is about 30 minutes (Doherty and Perkins, 1962) so at 2 hours enough may have accumulated in this patient to account for the arrhythmia which was manifest. This patient did receive a rather modest dose of digoxin, had normal excretion and turnover time (58 hours, tl/2, was only moderately hypercarbic and hypoxic, had normal electrolytes and yet still manifest toxicity to digitalis. A modest degree of right heart failure was present, and ST-T changes present on the electrocardiogram were of non-specific nature .
149
t------------------'1 3
'--- - - - - - - - - - - - - -- - ....... 4 Fig. 3. Electrocardiogram on CC 25 Oct . 1966. Abnormal ECG. showing paroxysmal atrial tachycardia with block. although sometimes without. as in lead AVR. Atrial rate 214. ventricular rate (variable 107-214). Aberrant conduction is seen in leads I. V• . Fig. 4. Electrocardiogram on CC 25 Oct . 1966. Abnormal ECG showing paroxysmal atrial tachycardia without block (1 : 1) conduction) atrial rate 214. ventricular rate 214. This rhythm disturbance spontaneously converted shortly after this electrocardiogram was obtained.'
Digitalis in Pulmonary Heart Disease
150
7. Conclusions Digitalis therapy in cor pulmonale or congestive heart failure and atrial arrhythmia is a well accepted form of management and provides a supplementary means of treatment for the patient with sufficiently prolonged hypoxia to develop pulmonary hypertension and congestive failure. One should recognise that these seriously ill patients are already prone to arrhythmia and this may be more easily provoked by digitalis. Lower serum digoxin levels appear to result in toxic effects. Smaller doses of digoxin are recommended, except when necessary to control the ventricular response with atrial fibrillation.
100
10
t I
E
--
I I
Cl
S c ·x o Cl
is O. '-t-:c:-;:-- ::-- -- ---:!".: - - - -- -- ----, 0 2 4 6
12
24
48
Hours
References Fig. 5.
Tritiated digoxin serum turnover in cor pulmonale. Digoxin concentration in nanograms /ml on hor izontal axis (logarithmic scale) and time in hours on the vertical axis. An intravenous dose of O.75mg tritiated digoxin was given at zero time and concentration in the serum is plotted thereafter. PAT with block appeared at 2 hours after drug was given at a serum concentration of 1.7ng /ml and disappeared when concentration was 1.2ng/ml at 4 hours the onset and offset of arrhythmia after drug was given. Dominant serum t1/2 was 58 hours (normal range usually 17 to 48 hours) . Arrows indicate onset and offset of arrhythmia.
Serum levels of digoxin were normal with appearance of toxicity, but are difficult to assess because of the recent intravenous bolus of digoxin. Of additional interest is the fact that at the time of a post mortem examination some 3 years later, the patient had widespread coronary artery disease in addition to cor pulmonale and had experienced at least one unrecognised myocardial infarction. This serves to illustrate that the additional effects of concomitant or associated disease may also playa part in increased sensitivity to digitalis.
Ayers. S.M. and Mueller. H.: Hypoxia. hypercapnia and cardiac arrhythmias: The importance of regional abnormalities of vascular distensibility . Chest 63: 981-985 (1973) . Bates, D.V .; Macklem , P.T.; Christie , R.V. Case 59: Pulmonary edema ; in Bates, Macklem , Christie (Eds) Cor Pulmonale In Respiratory Function in Disease, 2nd Ed., p. 454 -455 (Saunders, Philadelphia 1971). Berglund, E.; Widimsky, J . and Malmberg, R.: Lack of effect of digitalis in patients with pulmonary disease with and without heart failure. American Journal of Cardiology 11: 477-482 (1963). Doherty, J .E. and Perkins, W .H.: Studies with tritiated digoxin in human subjects after intravenous administration. American Heart Journal 63: 528-536 (1962) . Doherty, J .E.; Perkins , W .H. and Wilson, M.e. : Studies with tritiated digoxin in renal failure. American Journal of Medicine 37: 536-544, (1964) . Doherty, J.E . and Perkins, W .H.: Tissue concentration and turn over of tritiated digoxin in dogs. Amer ican Journal of Cardiology 17: 47-52 (1966) . Doherty, J .E.: Clinical pharmacology and therapeutic use of digitalis glycosides. Drugs 6: 182-221 (1973) . Ewy, G .A.; Kapadia, G .G.; Yao, LV. : Lullin, M. and Marcus , F.I.: Digoxin metabolism in the elderly . Circulation 39: 449-453 (1969) . Ewy , G .A.; Grover, B.M.; Ball, M.F .; Nimmo, L.; Jackson , B. and Marcus , F.: Digoxin metabolism in obesity. Circulation 44 : 810-814 (l97t). Ferrer, M.I.; Harvey, R.M.; Cathcart, R.T.; Webster, C.A.; Richards , C .W ., Jr . and Cournand, A. Some effects of digoxin
Digitalis in Pulmonary Heart Disease
upon the heart and circulation in man - digoxin in chronic cor pulmonale. Circulation I: 161-186 (1950 ). Ferrer. M.l.: Cor pulmonale - present day status. American Heart Journal 89: 657 -664 (1975) . Fowler. N.O.: Cor pulmonale caused by disease: in Fowler (Ed) Cardia c Diagnosis and Treatment. 2nd Ed.• p.801-815 (Harper and Row . Hagerstown 1972). Goldberg. L.M.; Bristow. J .D.; Parker . BMM. and Ritzmann. L.W .: Paro xysmal atrial tachycardia with block - its frequent association with chroni c pulmonary disease. Circulation 21: 499-504 (1960) . Harvey. R.M.; Ferrer . M.1. and Cournand, A.: The treatment of chronic cor pulmonale . Circulation 7: 932-940 (1953). Hecht . H .H.: Heart failure and lung disease. Circulation 14: 265-290 (1956) . Hinshaw . H .C.: Pulmonary heart disease. pulmonary congestion and edema ; in Hinshaw (Ed) Diseases of the Chest . 3rd Ed.• p.445 -463 (Saunders . Philadelphia 1969). Hudson. L.D .; Kurt. T.L.; Petty. T.L. and Genton , E.: Arrhythmias associated with acute respiratory failure in patients with chronic airway obstruction. Chest 63: 661-665 (1973 ). Hunter. C.C .• Jr .: Errors in the management of patients dying of chroni c obstructive lung disease. Journal of the Ame rican Medical Association 199: 488-491 (1967) . Ingram . R.H .•Jr. and Grossman. G .D.: Chronic cor pulmonal e; in Hurst . Logue. Schlant and Wagner (Eds) The Heart. 3rd Ed.• p.1278-1289 (McGraw-Hill. New York 1974). Kleiger, R.E. and Senior. R.M.: Long term electrocardiographic monitoring of ambulatory patients with chroni c airway obstru ction . Chest 65: 483-4 87 (1974) . Lukas. D.S.: Some aspects of distribution and disposition of digitoxin in man . Annal s of New York Academy of Sciences 179: 338-359 (1971) . Marcus. F.l.; Peterson . A .S.; Salel, A.F .; Scully. J . and Kapadia. G .G.: The metabolism of tritiated digoxin in renal insufficiency in dogs and man . Journal of Pharmacolog y and Experimental Therapeutics 153: 372-382 (1966) .
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Mounsey . J .P.O.; Ritzman. L.W .; Silverstone. N.J .; Briscoe. U.A. and Mcl.emert , G .A.: Circulatory changes in severe pulmonary emphysema . British Heart Journal 14: 153-172 (1952 ). Paciaron i, E.; Foschi, F.; Victori, N.; Saccomanno . G . and Raspa, E.G.: La Digoxinemia nei sogetti con cnore pulmononose cronico. Giornale Gerontolog y 22: 832-836 (1974) . Petty. T.L.: Management of acute and chronic respiratory insufficiency in chronic airway s obstruction ; in Baum (Ed) Textbook of Pulmonary Diseases. 2nd Ed.• p.665-685 (Little Brown . Boston 1974). Piemme , T.E.: Secondary pulmonary hyperten sion; in Holman . Cranston (Eds) Bronchopulmonary Diseases and Related Disorders. p.548-560 (Harper and Row. Hagerstown 1972). Robin . E.D.; Cross , C.E . and Zelis, R.: Pulmonary edema (two parts) New England Journal of Medicine 288: 239-246 , 292-304 (1973) . Robin , E.D . and Gaudio . R.: Cor pulmonale. Disease-a-Mouth . p.I -38 (May 1970). Rogers. R.M.; Spear. J .F.; Moore . C.V.M.; Horowitz , L.H. and Soone, J.E. : Vulnerability of canine ventricle to fibrillation during hypoxia and respiratory acidosis. Chest 63: 986-994 (1973 ). Smith , T.W. and Haber. E.: Serum or plasma concentra tion of digitalis glycosides: Principles and Approa ches in Digitalis. p.61-71 (Little Brown . Boston 1974). Webb-Johnson . D. and Andrew s. J.L. , Jr.: Arrh ythm ias in pulmonary disease implications for drug therapy . Lahey Clinic Foundation Bulletin 25: 30-42 (1976) . Wh ite. P.D.: Chronic cor pulmonale (pulmonary heart disease); in White (Ed) Heart Disease. p.464-473 (Macmillan. New York 1945).
Author's address: Prof. James E. Doherty , Division of Cardiology. Veterans Administration Hospital and University of Arkansas College of Medicine, Little Rock, AR 72206 (USA).
Digitalis in Pulmonary Heart Disease (Cor Pulmonale) 1 J.£ Doherty, J.J. Kane, J.R. Phillips and J.S. Adamson Univers ity of Arkansas College of Medicine, Division of Cardiology, Veterans Adm inistration Hosp ital anf University of Arkansas College of Medicine, Heart Station, Veterans Administration Hospital, Pulmonary Diseases Section , Veterans Administration Hosp ital, Little Rock, Arkansas
The use of digitalis in pulmonary heart disease has been a topic of great interest for a number of years. The physician's decision to use or not to use digitalis in pulmonary disease has often been an emotional rather than a reasoned one. The diagnostic difficulties from a clinical point of view in separation of'pulmonary from cardiac symtpoms and findings have also been confusing. The fact that small doses of digitalis may have an inotropic effect on the cardiac muscle has been a difficult concept for many physicians to adopt. On the other hand, the larger doses of digitalis that are often necessary to control the ventricular response in supraventricular arrhythmias sometimes gives rise to confusion. We shall attempt to review the subject in detail and examine indications, contraindications , toxicity, dosage, assessment of benefit, and role of'digitalis serum levels in patient management.
1. Indications for Digitalis in Cor Pulmonale
in assessment of possible toxic manifestations. The presence of dyspnoea, pulmonary rales, oedema, tachycardia, and arrhythmia as common findings to pulmonary disease, heart failure and digitalis intoxication serve to illustrate part or this dilemma and will be discussed more fully in a later section. 1.1.1 Arguments Against Digitalis Mounsey et al. (1952) reported only minimal changes in cardiac output and right ventricular enddiastolic pressure in 4 patients with cor pulmonale. Further, acute and chronic haemodynamic studies of Berglund et al. (1963) failed to demonstrate significant improvement in 8 patients (some were not in congestive heart failure) and in only one could improved cardiac performance be demonstrated . 1.1.2 Arguments for Digitalis Many years ago, White (1945) advised that 'usual' management of heart failure accompanying chronic cor pulmonale should include digitalis, rest and diuretics as needed. Ferrer et al. (1950) reported
1.1 Congestive Heart Failure The effectiveness of digitalis in cor pulmonale has long been questioned in congestive heart failure because of doubtful clinical benefit and the difficulty
I Supported in part by the Veterans Administration Medical Research Information System. Grant Number 1887-01. USPHS NIH Grant No.06642·12 and Burroughs Wellcome Co.• Research Triangle Park. N.C . 27709 .
Digitalis in Pulmonary Heart Disease
favourable haemodynamic and clinical effectiveness of digoxin used acutely and chronically in patients with heart failure and cor pulmonale. Attention was also given to basic management of chronic obstructive pulmonary disease (COPD) as well. Henshaw (J 969) advises full digitalisation for heart failure which accompanies lung disease and states it may be the only medication necessary to restore function. Our own view is that digitalis alone will rarely solve the problem. Bates et al. (J 97 J) stress th difficulty of accurate diagnosis (pulmonary oedema - cor pulmonale respiratory failure) and stress the value of blood gases in evaluation. Digitalis and diuretics were employed in an illustrative case with good effect. Piemme (J 972) states that the balance of evidence favours in use of digitalis in patients with right ventricular failure and pulmonary heart disease. The fact that their use may elevate further pulmonary vascular resistance appears to be counter balanced by a favorable effect on right ventricular performance . He advises caution because of the propensity to ventricular arrhythmia exhibited by patients with right ventricular overload. Robin and Gaudio (J 970) and Robin (J 973), in classic references on cor pulmonale and pulmonary oedema, recommended digitalis to increase myocardial contractility in left ventricular failure. J.J.3 Current Views of CHF Indications Ingram and Grossman (J 974) recommend digitalis and diuretics when right heart failure intervenes in chronic cor pulmonale and a similar view is expressed by Fowler (1975). Ferrer (J 975) states that use of digitalis is no longer controversial and there is a consensus that digitalis is indicated for management of congestive heart failure in the presence of cor pulmonale .
1.2 Arrhythmia 1.2 .1 Frequency of Arrhythmia Decreased The frequency of arrhythmia in respiratory failure was felt to be rare by Harvey et al. (J 953). Hecht
143
(J 956) also held the view that arrhythmia was
unusual with cor pulmonale. J.2.2 Frequency of Arrhythmia Increased The bulk of investigators today, however, comment upon increased, rather than decreased, frequency of rhythm disturbances. (Corroza and Pastor , 1958; Kirby et al. , 1970). Goldberg et al. (1960) described a series of 37 patients with chronic respiratory disease who exhibited paroxysmal atrial tachycardia with atrioventricular block, all but one of whom were receiving digitalis. Cor pulmonale was present in 10 patients - more than any other aetiological diagnosis of pulmonary disease.
1.2.3 Dangers of Digitalis Toxicity Hunter (J 965) cited the frequent danger of digitalis intoxication and felt that digitalis toxicity contributed to the death of 5 patients in a retrospective chart analysis. He also cited the frequent presence of supraventricular arrhythmias in patients with COPD and did not use this type of rhythm disturbance as an index of digitalis toxicity - only ventricular arrhythmias and heart block, a perfectly valid approach at that time. Hecht (J 967) advised that digitalis be used in the 'rare' patient with cor pulmonale who manifests atrial fibrillation or other atrial arrhythmia, but did urge caution . Kirby et al. (1970) noted a high incidence of arrhythmias in both digitalis treated (61 % ) as well as non-digitalis treated patients (50 % ) with cor pulmonale. They noted that in patients who had been treated with digitalis, atrial tachycardia and atrial tachycardia with block occurred in the presence of less severe hypoxia and hypercarbia than in patients who had not receivedthe drug. They further cited this as evidence that the hypoxaemia of respiratory failure sensitises the myocardium to digitalis. That hypoxia alone is probably not responsible appears to be borne out partially by the fact that arrhythmia is not particularly common in patients with cyanotic congenital heart disease, many of whom exhibit greater degrees of hypoxia than patients with cor
144
Digitalis in Pulmonary Heart Disease
pulmonale. It is admitted, of course, that factors other than hypoxia distinguish these diseases.
1.2.4 Current Views of Arrhythmia Indications Arrhythmia, particularly atrial arrhythmia atrial fibrillation, atrial flutter , atrial tachycardia appear to be legitimate indications for digitalis therapy in pulmonary heart disease. Junctional rhythms are also considered to be in this category, particularly if accompanied by heart failure. The familiar rule often cited clinically in the United States in paroxysmal atrial tachycardia with block: 'If the patient is taking digitalis, stop it; if he is not on the drug , then digitalise,' may be applied here. Electrical cardioversion may be used, too, but digoxin should be discontinued 24 hours before; digitoxin several days before .
2. Contraindications to Digitalis in Cor Pulmonale The absolute contraindication is the presence of definite toxicity due to digitalis. Relative contraindications include ventricular arrhythmias (premature ventricular contractions which are frequent and not associated with congestive heart failure; ventricular tachycardia), hypokalemia, and hypomagnesemia and hypercalcemia.
to inappropriate treatment, but also the reverse - left heart failure may be treated as pneumonia. Physical signs of neck venous distention are of little value because of laboured respiration and increased expiratory effort . Upright posture gives mechanical advantage to breathing in COPD with or without heart failure . Apparent liver enlargement because of low and flattened diaphragms and point of maximum impulse near the xyphoid process may also be misleading . Cardiac enlargement, usually seen on chest X-ray, is less apparent because of increased volume of the thoracic cage and is sometimes a problem if no comparison films are available. Finally, ankle oedema is frequently present in COPD due to stasis alone . These patients are very inactive and usually just 'sit' all day leading to puffy ankles , similar to that seen in right heart failure . The auscultatory findings are sometimes very helpful if the heart tones can be heard over the noisy lungs. A third heart sound or protodiastolic gallop rhythm is quite loud in congestive failure and may be best heard in the tricuspid area . The pulmonary component of the second heart sound is invariably accentuated, but is difficult to hear in the usual area because of pulmonary noise. Sometimes one may palpate the right ventricular impulse directly in the epigastric area by introducing one's fingers under the xyphoid and palpating superiorly - a palpable gallop sound is often felt in failure as well as the forcible right ventricular impulse. Sometimes a systolic murmur of tricuspid insufficiency is heard .
3. Assessment of Benefit from Digitalis in Cor Pulmonale 3.2 Management of Pulmonary Problem 3.1 Overlapping Symptoms of Disease Because of the nature of the symptoms in chronic obstructive pulmonary disease and in cor pulmonale and their complications, it is very difficult to determine the need, as well as assess the benefit (if any) accomplished through treatment with digitalis . The ever present dyspnoea and rales are oflittle value . The frequent complication of pneumonia and/or bronchitis may not only mimic heart failure and lead
One can appreciate the problems of determining improvement of the patient's status because of these overlapping cardiac and pulmonary findings, As heart failure is often accompanied or precipitated by a bout of pneumonia or bronchitis it is sometimes doubly difficult. Naturally, meticulous attention must be paid to management of the patient's primary prob lem, COPD, infection, bronchial toilet, bronchodilators, oxygen therapy, polycythemia. In general, good
145
Digitalis in Pulmonary Heart Disease
management in these areas leads to improvement in cardiac status as well. Providing support for the failing heart caused by the failing lungs (nearly a mortal combination) with digitalis may bring about salutary results.
Table I. Clinical manifestations of digitalis toxicity System
Common
Uncommon
Cardiac
Ventricular premature contraction Paroxysmal atrial tachycardia with block Nonparoxysmal A -V nodal tachycardia A-V block Sinus bradycardia Worsening of congestive heart failure
Atrial fibrillation Atrial flutter Ventricular tachycardia Ventricular fibrillation Sinus arrest SA block Atrial premature contraction A-V nodal premature contraction
Gastrointestinal
Anorexia Nausea Vomiting
Abdom inal pain Constipation Diarrhoea Haemorrhage
Visual
Colour vision (green or yellow) with halos Caution: glaucoma
Blurring or shimmering vision: scotoma, micropsia or macropsia, amblyop ia
Neurological
Fatigue Headache Insomnia Malaise Confusion Vertigo Depression
Neuralgia Convulsions Paresthesia Delirium Psychosis
3.3 Additional Treatment of Heart Disease One should use diuretics (watch potassium'), diet, rest and of course, oxygen (controlled concentrations of 24 to 28 % preferred) to prevent too much carbon dioxide retention while decreasing hypoxia (Petty, 1974). Measurement of arterial blood gases is essential for optimum assessment.
3.4 Symptomatic Assessment When one employs all of these measures, assessment of improvement is less of a task. Symptomatically, the patient is less dyspnoeic and feels improved. Moderate weight loss representing loss of oedema is often observed. Rales improve, but often do not disappear. Cyanosis and arterial oxygen saturation are improved. Digitalis serum levels will be discussed in a subsequent section.
4. Digitalis Toxicity in Cor Pulmonale As the view of cardiac rhythm disturbances in pulmonary disease has shifted from rare (Harvey et al., 1953; Hecht, 1956) to common (Hudson et al., 1973; Kleiger and Senior, 1974), assessment of digitalis intoxication has become more difficult.
4.1 Digitalis Versus Other Factors The practice of most cardiologists has been to view rhythm disturbances due to digitalis with alarm, while non-cardiac manifestations of digitalis are only troublesome and signal caution or alertness for the
Other
Allergic reaction Idiosyncrasy Thrombocytopenia Gynaecomastia (digoxin)
more serious problems with arrhythmia. Arrhythmia associated with digitalis in the presence of pulmonary disease are common today and are complicated by the arrhythmogenic potential of hypoxia and hypercarbia, coupled with bronchodilators sich as isoprenaline (isoproterenol) and aminophylline, together with vagal stimulation, resulting from suctioning, infection and acidosis. Digitalis serum levels are helpful, but not decisive (see section 5). . Table I is an outline of the toxic manifestations of digitalis given in any form, oral or parenterally, and
146
Digitalis in Pulmonary Heart Disease
in any preparation. There was once a feeling expressed that the crude leaf preparation resulted in more gastrointestinal side-effects prior to onset of rhythm disturbances. This has never been supported by a scientific study and purified glycosides are now preferred for clinical use. The dangerous manifestation of digitalis excess being rhythm disturbances, and the fact that any change in rhythm may be due to digitalis, forces one to be especially cautious in seriously ill patients. Patients with cor pulmonale are usually in this category, as advanced disease accompanied by pulmonary hypertension is almost invariably present when manifestations of congestive heart failure are present.
4.2 Other Factors Table II lists factors other than digitalis which may be responsible for rhythm disturbances in cor pulmonale in greater detail (Webb-Johnson and Andrews , 1976).
Table II. Factors in arrhythmia induction in chronic obstructive pulmonary disease
Corticosteroids Diuretics (hvpokalaemial Sympathomimetics Digitalis' Atropine Fluorocarbons (aerosol propellants) Methylxanthines (aminophylline) Infection Hypoxia Hypercarbia. hypocarbia Respiratory acidosis Respiratory alkalosis (respirators) Endogenous catecholamines Hypokalaemia Coexisting C-V Disease (coronary artery disease) Tracheal suctioning (vagaO 1 Often prescribed to more seriously ill patient. prone to arrhythmia for many other reasons.
Table III . Types of arrhythmias
Associated with pulmonary disease
Associated with digitalis excess
Paroxysmal atrial tachycardia with and without block
Paroxysmal atrial tachycardia with and without block
Multifocal atrial tachycardia
Multifocal atrial tachycardia (rare)
A-V junctional rhythm
A- V junctional rhythm
Atrial premature beats
Atrial premature beats
Ventricular premature beats
Ventricular premature beats
A-V dissociation
A-V dissociation
Idioventricular rhythm
Idioventricular rhythm
Parasystole (rare)
Parasystole (rare)
Atrial flutter
Atrial flutter (rare)
Atrial fibrillation
Atrial fibrillation (rare)
Cardiac arrest (ventricular fibrillation and/or asystole)
Cardiac arrest (ventricular fibrillation and/or asystole)
It has been noted repeatedly that the more seriously ill the patient with pulmonary disease, the more prone to rhythm disturbances and the more grave the prognosis and mortality in these patients (Kleiger and Senior. 1974). Because of increased evidence of arrhythmia and death in these patients, Hunter (1967) suggested extra caution be employed when digitalis is required for treatment.
4.3 Types of Rhythm in Cor Pulmonale Versus Digitalis Toxicity Table III categorises types of rhythm disturbances seen in COPD and those associated with digitalis excess. Similarities are not surprising when one realises that these are rhythm problems of the diseased heart, with or without digitalis. Recognition that multifocal atrial tachycardia, parasystole, atrial flutter and atrial fibrillation with rapid ventricular response are rather
Digitalis in Pulmonary Heart Disease
uncommon manifestations of digitalis intoxication is at times of some benefit.
5. Role of Digitalis Serum Levels in Managemen! of Cor Pulmonale The advent of digitalis serum levels in 1969 provided a new dimension by which the presence of digitalis glycosides can actually be measured (in billionths of a gram) in the blood and tissues (see Smith and Haber, 1974). Serum digitalis levels are now generally available in most larger hospitals.
5.1 Overlap of Therapeutic and Toxic Levels Usual therapeutic and toxic concentrations of digoxin and digitoxin, the two most popular glycosides, reported in the blood serum of human subjects are shown in table IV. Note that there is a relatively wide overlap between therapeutic and toxic levels, and we have already discussed factors that might tend to increase the propensity to develop arrhythmia and either mimic or induce toxicity.
147
Table IV. Digitalis serum levels (ng/mll
Glycoside
Underdigitalised
Therapeutic
Definitely toxic
Digoxin
< 0.5
0.5-2.5
> 3.0
Digitoxin
< 10
10-25
> 35
6.1 Renal Function The most important factor with digoxin is adequate renal function. Doherty et al. (J 964) and Marcus et al. (J 966) have shown that functional capacity of the human kidney best determines the amount of drug excretedand thereby, the dosage requirement, as the drug is very little metabolised in the normal human subject. That this principle applies in cor pulmonale is shown well in figure I, where the blood urea nitrogen (BUN) is plotted against per cent of total dose of
5.2 Toxic Serum Levels in Cor Pulmonale Paciaroni et al. (1974) reported that toxicity to digitalis appears at lower serum levels in patients with pulmonary heart disease than is observed with other aetiologies. There is sufficient evidence with other disease states (hypokalaemia, hypothyroidism) to believe that this observation is correct (Doherty, 1973).
6. Dosage of Digixin in Cor Pulmonale Appreciation that toxicity to digoxin may occur at lower than usual serum levels of the drug should lead to more rigid evaluation of determinants of digitalis dosage in cor pulmonale.
Percentage total dose excreted in urine first 24 hours
Fig. 7. Effect of renal function on digoxin excretion. Blood urea nitrogen (BUN) is plotted on a logarithmic scale on the vertical axis ; ·per cent of the total dose of digoxin excreted in the first 24 hours after a single dose on the horizontal axis. Open circles (0) represent cor pulmonale; closed circles Ie) pat ients with heart disease of other aetiology. Note that the higher the BUN, the less digoxin is excreted .
Digitalis in Pulmonary Heart Disease
digoxin excreted 24 hours after administration of a single dose. One can readily see that reduction in renal functional capacity adversely affects digoxin excretion: the higher the BUN, the less digoxin excreted in the urine. The open circles represent patients with cor pulmonale, solid closed circles other aetiology of heart disease. Thus, compromised renal functional capacity suggests a reduction in dosage of digoxin. Digitoxin is seldom used by the author because of prolonged excretion, metabolism and half-life (Lukas, 197 n
6.2 Body Size Another important determinant is body size. Ewy et al. (I 97 I) has shown that digoxin dosage should be based on lean body mass - the obese individual requiring no more digoxin than the normal weight individual. The space of distribution of digoxin is not changed by increased weight. One should remember that many patients with cor pulmonale are quite thin (hypoventilation syndrome of obesity being the striking exception)and smaller doses are suggested for this reason as well.
6.3 Age Another important determinant is age, as most with cor pulmonale are elderly. Again, Ewy et al. (I969) demonstrated diminished renal clearance of digoxin in the elderly patient. This plus their smaller lean body mass are factors in increased digitalis toxicity in the older patient requiring the drug.
6.4 Combined Determinants All of these factors suggest a reduction in digoxin dosage in the patient with cor pulmonale who is often elderly, thin, and sometimes has compromised renal function .
148
6.5 Increased Sensitivity to Digoxin in Cor Pulmonale The other major important factor, increased sensitivity to digoxin, is best illustrated by the following brief case study : A 52-year-old male with a long history of chronic bronchopulmonary disease was given O.75mg of tritium labeled digoxin intravenously to study the serum level, turnover t1 /2, and excretion of the drug . At the time of the study his creatinine clearance was 59ml/min, electrolytes were normal, p02 was 79mm, and pC0 2 52mm, pH 7.395 . (His respiratory problem was under reasonable control. The physical examination was not remarkable except for a few coarse rales over both lung fields (with increased resonance), normal sinus tachycardia, point of maximum cardiac impulse in epigastric area with prominent right ventricular gallop sound . The diaphragms were rather low, the liver was palpable 3cm. No oedema was present. Chest X-ray revealed hyperlucent lung fields and heart at upper limits of size as well as flattening of diaphragm . Electrocardiogram (ECG) done the day before the study is reproduced in figure 2. Note it is abnormal , showing non-specific ST-T changes and Pwaves of the pulmonale type. A ventricular ectopic beat is seen in lead AVF. Approximately 2 hours after being given digoxin, the patient complained of palpitation and the ECG shown in figure 3 was obtained. Note the appearance of paroxysmal atrial tachycardia (PAT) with block. About 2 hours later, the rhythm changed again and the ECG shown in figure 4 was recorded. It reveals PAT without block and a faster ventricular response. Shortly after this ECG was obtained, the patient noted spontaneous cessation of arrhythmia and said he felt much better. Fortunately, no further arrhythmia occurred and the patient's study was completed without incident. Figure 5 shows a semilogarithmic plot of serum turnover curve of tritiated digoxin during the first 48 hours of the study. Note the digoxin serum level was 1.7ng/ml at time of appearance of arrhythmia, and 1.2ng/ml when it disappeared spontaneously. It is
Digitalis in Pulmonary Heart Disease
Fig. 2. Electrocardiogram (ECG) on CC 24 Oct . 1966. Abnormal ECG. showing sinus tachycardia. rate 130. 'P' pulmonale and non-specific ST-T changes . A single premature ventricular contraction is seen in lead AVF.
very difficult to analyse these serum levels so soon after an intravenous bolus when the serum level is initially extremely high and falling rapidly. It should be noted that immediately after receiving the bolus injection the cardiac tissues are exposed to potentially toxic amounts of digoxin but require some time to accumulate enough of the drug to result in manifestations of toxicity (Doherty and Perkins, 1966). The half-time of early disappearance for intravenously administered digoxin is about 30 minutes (Doherty and Perkins, 1962) so at 2 hours enough may have accumulated in this patient to account for the arrhythmia which was manifest. This patient did receive a rather modest dose of digoxin, had normal excretion and turnover time (58 hours, tl/2, was only moderately hypercarbic and hypoxic, had normal electrolytes and yet still manifest toxicity to digitalis. A modest degree of right heart failure was present, and ST-T changes present on the electrocardiogram were of non-specific nature .
149
t------------------'1 3
'--- - - - - - - - - - - - - -- - ....... 4 Fig. 3. Electrocardiogram on CC 25 Oct . 1966. Abnormal ECG. showing paroxysmal atrial tachycardia with block. although sometimes without. as in lead AVR. Atrial rate 214. ventricular rate (variable 107-214). Aberrant conduction is seen in leads I. V• . Fig. 4. Electrocardiogram on CC 25 Oct . 1966. Abnormal ECG showing paroxysmal atrial tachycardia without block (1 : 1) conduction) atrial rate 214. ventricular rate 214. This rhythm disturbance spontaneously converted shortly after this electrocardiogram was obtained.'
Digitalis in Pulmonary Heart Disease
150
7. Conclusions Digitalis therapy in cor pulmonale or congestive heart failure and atrial arrhythmia is a well accepted form of management and provides a supplementary means of treatment for the patient with sufficiently prolonged hypoxia to develop pulmonary hypertension and congestive failure. One should recognise that these seriously ill patients are already prone to arrhythmia and this may be more easily provoked by digitalis. Lower serum digoxin levels appear to result in toxic effects. Smaller doses of digoxin are recommended, except when necessary to control the ventricular response with atrial fibrillation.
100
10
t I
E
--
I I
Cl
S c ·x o Cl
is O. '-t-:c:-;:-- ::-- -- ---:!".: - - - -- -- ----, 0 2 4 6
12
24
48
Hours
References Fig. 5.
Tritiated digoxin serum turnover in cor pulmonale. Digoxin concentration in nanograms /ml on hor izontal axis (logarithmic scale) and time in hours on the vertical axis. An intravenous dose of O.75mg tritiated digoxin was given at zero time and concentration in the serum is plotted thereafter. PAT with block appeared at 2 hours after drug was given at a serum concentration of 1.7ng /ml and disappeared when concentration was 1.2ng/ml at 4 hours the onset and offset of arrhythmia after drug was given. Dominant serum t1/2 was 58 hours (normal range usually 17 to 48 hours) . Arrows indicate onset and offset of arrhythmia.
Serum levels of digoxin were normal with appearance of toxicity, but are difficult to assess because of the recent intravenous bolus of digoxin. Of additional interest is the fact that at the time of a post mortem examination some 3 years later, the patient had widespread coronary artery disease in addition to cor pulmonale and had experienced at least one unrecognised myocardial infarction. This serves to illustrate that the additional effects of concomitant or associated disease may also playa part in increased sensitivity to digitalis.
Ayers. S.M. and Mueller. H.: Hypoxia. hypercapnia and cardiac arrhythmias: The importance of regional abnormalities of vascular distensibility . Chest 63: 981-985 (1973) . Bates, D.V .; Macklem , P.T.; Christie , R.V. Case 59: Pulmonary edema ; in Bates, Macklem , Christie (Eds) Cor Pulmonale In Respiratory Function in Disease, 2nd Ed., p. 454 -455 (Saunders, Philadelphia 1971). Berglund, E.; Widimsky, J . and Malmberg, R.: Lack of effect of digitalis in patients with pulmonary disease with and without heart failure. American Journal of Cardiology 11: 477-482 (1963). Doherty, J .E. and Perkins, W .H.: Studies with tritiated digoxin in human subjects after intravenous administration. American Heart Journal 63: 528-536 (1962) . Doherty, J .E.; Perkins , W .H. and Wilson, M.e. : Studies with tritiated digoxin in renal failure. American Journal of Medicine 37: 536-544, (1964) . Doherty, J.E . and Perkins, W .H.: Tissue concentration and turn over of tritiated digoxin in dogs. Amer ican Journal of Cardiology 17: 47-52 (1966) . Doherty, J .E.: Clinical pharmacology and therapeutic use of digitalis glycosides. Drugs 6: 182-221 (1973) . Ewy, G .A.; Kapadia, G .G.; Yao, LV. : Lullin, M. and Marcus , F.I.: Digoxin metabolism in the elderly . Circulation 39: 449-453 (1969) . Ewy , G .A.; Grover, B.M.; Ball, M.F .; Nimmo, L.; Jackson , B. and Marcus , F.: Digoxin metabolism in obesity. Circulation 44 : 810-814 (l97t). Ferrer, M.I.; Harvey, R.M.; Cathcart, R.T.; Webster, C.A.; Richards , C .W ., Jr . and Cournand, A. Some effects of digoxin
Digitalis in Pulmonary Heart Disease
upon the heart and circulation in man - digoxin in chronic cor pulmonale. Circulation I: 161-186 (1950 ). Ferrer. M.l.: Cor pulmonale - present day status. American Heart Journal 89: 657 -664 (1975) . Fowler. N.O.: Cor pulmonale caused by disease: in Fowler (Ed) Cardia c Diagnosis and Treatment. 2nd Ed.• p.801-815 (Harper and Row . Hagerstown 1972). Goldberg. L.M.; Bristow. J .D.; Parker . BMM. and Ritzmann. L.W .: Paro xysmal atrial tachycardia with block - its frequent association with chroni c pulmonary disease. Circulation 21: 499-504 (1960) . Harvey. R.M.; Ferrer . M.1. and Cournand, A.: The treatment of chronic cor pulmonale . Circulation 7: 932-940 (1953). Hecht . H .H.: Heart failure and lung disease. Circulation 14: 265-290 (1956) . Hinshaw . H .C.: Pulmonary heart disease. pulmonary congestion and edema ; in Hinshaw (Ed) Diseases of the Chest . 3rd Ed.• p.445 -463 (Saunders . Philadelphia 1969). Hudson. L.D .; Kurt. T.L.; Petty. T.L. and Genton , E.: Arrhythmias associated with acute respiratory failure in patients with chronic airway obstruction. Chest 63: 661-665 (1973 ). Hunter. C.C .• Jr .: Errors in the management of patients dying of chroni c obstructive lung disease. Journal of the Ame rican Medical Association 199: 488-491 (1967) . Ingram . R.H .•Jr. and Grossman. G .D.: Chronic cor pulmonal e; in Hurst . Logue. Schlant and Wagner (Eds) The Heart. 3rd Ed.• p.1278-1289 (McGraw-Hill. New York 1974). Kleiger, R.E. and Senior. R.M.: Long term electrocardiographic monitoring of ambulatory patients with chroni c airway obstru ction . Chest 65: 483-4 87 (1974) . Lukas. D.S.: Some aspects of distribution and disposition of digitoxin in man . Annal s of New York Academy of Sciences 179: 338-359 (1971) . Marcus. F.l.; Peterson . A .S.; Salel, A.F .; Scully. J . and Kapadia. G .G.: The metabolism of tritiated digoxin in renal insufficiency in dogs and man . Journal of Pharmacolog y and Experimental Therapeutics 153: 372-382 (1966) .
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Mounsey . J .P.O.; Ritzman. L.W .; Silverstone. N.J .; Briscoe. U.A. and Mcl.emert , G .A.: Circulatory changes in severe pulmonary emphysema . British Heart Journal 14: 153-172 (1952 ). Paciaron i, E.; Foschi, F.; Victori, N.; Saccomanno . G . and Raspa, E.G.: La Digoxinemia nei sogetti con cnore pulmononose cronico. Giornale Gerontolog y 22: 832-836 (1974) . Petty. T.L.: Management of acute and chronic respiratory insufficiency in chronic airway s obstruction ; in Baum (Ed) Textbook of Pulmonary Diseases. 2nd Ed.• p.665-685 (Little Brown . Boston 1974). Piemme , T.E.: Secondary pulmonary hyperten sion; in Holman . Cranston (Eds) Bronchopulmonary Diseases and Related Disorders. p.548-560 (Harper and Row. Hagerstown 1972). Robin . E.D.; Cross , C.E . and Zelis, R.: Pulmonary edema (two parts) New England Journal of Medicine 288: 239-246 , 292-304 (1973) . Robin , E.D . and Gaudio . R.: Cor pulmonale. Disease-a-Mouth . p.I -38 (May 1970). Rogers. R.M.; Spear. J .F.; Moore . C.V.M.; Horowitz , L.H. and Soone, J.E. : Vulnerability of canine ventricle to fibrillation during hypoxia and respiratory acidosis. Chest 63: 986-994 (1973 ). Smith , T.W. and Haber. E.: Serum or plasma concentra tion of digitalis glycosides: Principles and Approa ches in Digitalis. p.61-71 (Little Brown . Boston 1974). Webb-Johnson . D. and Andrew s. J.L. , Jr.: Arrh ythm ias in pulmonary disease implications for drug therapy . Lahey Clinic Foundation Bulletin 25: 30-42 (1976) . Wh ite. P.D.: Chronic cor pulmonale (pulmonary heart disease); in White (Ed) Heart Disease. p.464-473 (Macmillan. New York 1945).
Author's address: Prof. James E. Doherty , Division of Cardiology. Veterans Administration Hospital and University of Arkansas College of Medicine, Little Rock, AR 72206 (USA).
