Fundamentak

of clinical

Cor pulmonale (pulmonary present-day status M. Ire&

cardiology

heart disease):

Ferrer, M.D.

New York, N. Y.

Thirty years ago, reporting on data from our group at Bellevue Hospital, Richards’ announced that there was a difference in the cardiac performance (referring here only to cardiac output) of patients with heart disease secondary to chronic obstructive pulmonary disease (COPD) (then designated as emphysema or as chronic emphysema and bronchitis) as compared to those with degenerative forms of cardiac disease. In January, 1949, four years later, Dr. Harvey and I discovered, after studying a patient (who turned out to be characteristic of a larger group with COPD) for a second and then a third time following intensive cardiopulmonary treatment, that the pulmonary hypertension which was the keystone of car pulmonale (today also called pulmonary heart disease) in contradistinction to a long-held tenet was not fixed, immutable and hence eventually lethal, but rather, was a reversible hemodynamic complication in COPD.2 Prior to World War II, the mechanism for pulmonary hypertension leading to car pulmonale in chronic emphysema was stated unequivocally as being due to lung destruction, an anatomic unchangeable relentlessly hopeless process. Indeed, in the early forties, and before the work just cited was done, patients with car pulmonale and “emphysema” were kept in the same hopeless corner of our Bellevue wards as the advanced carcinomatoses and generally they all succumbed, quietly, in carbon dioxide narcosis and right-heart failure. Thus in the mid and late forties a new era From the Department of Medicine, College of Surgeons, Columbia University, New York, and diographic Laboratory of the Columbia-Presbyterian New York. Received for publication July 30, 1974. Reprint requests Dr. M. I. Ferrer, 962 Park Ave., 10023.

May, 1975, Vol. 89, No. 5, pp. 657-664

Physicians and the ElectrocarMedical Center,

New York,

N. Y.

began for the patients with car pulmonale, as the abnormal physiology responsible for right-heart involvement became the focus of intensive research by our own and other groups. The pulmonary hypertension of COPD was found to be reversed or obliterated by improvement in respiratory gas exchange,2 the degree of pulmonary hypertension was first closely related to the diminished systemic arterial blood oxyhemoglobin saturation and elevated carbon dioxide tension and acidosis that went with it by ourselves3 and conllrmed by others,4*8 and then this relationship was solidified by the demonstration of a pulmonary arterial pressor response to an acute hypoxic stimulus. s-11Enlarging the study to include the effects of acute alterations in hydrogen ion concentration,12J3 we have now been able to show that in COPD, by far the most common cause of car pulmonale, pulmonary hypertension (the direct inciting event that challenges the right heart) stems from two interacting stimuli, the vasoconstrictive effect of alveolar hypoxia on the small pulmonary arteries which are in contact with alveolar gas tensions, and from a similar effect of an increased hydrogen ion concentrations of the blood perfusing these vessels. These two variables can be graphically displayed (Fig. 1) or an equation used to express the relationship.12*13J5* Thus, without requiring a measurement by cardiac catheterization, the values for pulmonary arterial pressure can now be obtained using arterial blood-gas analysis only.15 Clearly, from the above brief summary, our present day knowledge of the causes of pulmonary hypertension in COPD has greatly expanded (Fig. 2 and Table I), and this has changed *The equation ia found on page 906 of Reference 16 and is based on the work originally published in References 12 and 13.

American

Heart Journal

657

Ferrer

60%

70 %

60 t-

PULMONARY ARTERY MEAN

40

PRESSURE mmHg

0)

[HI+ wEqlL" PH

A,

I

I

I

I

20

30

40

50

60

7.70

7.53

7.40

7.30

7.22

Graphic representation of the relationship between pulmonary artery mean pressure and blood hydrogen ion concentration, considering arterial blood oxyhemoglobin saturation as a fixed parameter in 43 patients with chronic obstructive lung disease.14 Fig. 1.

the whole face of the disease, car pulmonale, as far as therapy is concerned. Indeed, this cardiac disorder has moved from being universally fatal 30 years ago, to being curable and even preventable in adults and in children.1e-21 As seen in Fig. 3, the therapeutic attack can and must occur before cardiac involvement and as soon as pulmonary hypertension appears in COPD. Only in a very small percentage of instances-those in which the primary pulmonary disease is either a restrictive fibrotic or granulomatous process or repetitive pulmonary emboli with chronic pulmonary vascular occlusion-is the pulmonary hypertension intractable and prognosis poor once right-heart failure appears. The regimen employed by our group17 and similar ones including those used in pediatrics,18-22 especially the recent extensive therapeutic planning described by Petty, Hudson, Neff 21and formalized so well by the InterSociety Commission for Heart Disease Resources,22 have yielded good fruit for our patients with car pulmonale due to COPD. It would seem as if all attention now should be turning first to the preventative aspects of cor.pulmonale20 (which really is prevention of pulmonary hypertension), and then to prevention of COPD itself.23-26And yet, the situation is not that salubrious.

658

As one reviews the expressions in the recent literature regarding car pulmonale there are some disquieting features as well as some areas of disagreement. It is useful, therefore, to review some of these, and then to try to envisage the future of the management of car pulmonale. The definition of car pulmonsle (pulmonary heart disease) is now fairly universally accepted as alteration in structure or function of the right ventricle resulting from disease affecting the structure or function of the lung or its vasculature; this specifically excludes the alterationd resulting from disease of the left ventricle or congenital heart disease. 20Clearly, we now know that neither right-heart failure (a criterion used in the past27 nor right ventricular hypertrophyzs (a diagnosis difficult to make clinically) are essential to its definition. Cardiac enlargement due to right ventricular (RV) dilatation alone,% in the presence of this form of pulmonary hypertension, suffices. This RV dilatation often disappears after successful therapy of car pulmonale and lowering of the pulmonary hypertension. Indeed, with modern management of COPD this RV dilatation may be the earliest and only cardiac sign of car pulmonale. Hence, statistics as to prognosis and incidence of car pulmonale in any population will only be valid using this definition of pulmonary

itlay,

1975, Vol. 89, No. 5

Cor pulmonale (pulmonary heart disease)

CHRONIC ----.-.---.~-

PULMONARY

DISEASE

r-l

REDUCTION IN CAPACITY OF PULMONARY VASCULAR BED - by vasoconstriction - or by anatomic obstructive lesions

Pulmonary

Hypertension

repeated Dilatation Riqht Ventricle Hvpertrophy of Right Ventricle

IIYPOXIA and ACIDOSIS

J

PicythemA

of or --

Cardiac

Ou

Dilatation of Right Ventricle

Right

Ventricular

Failure

Fig. 2. Chronic pulmonary disease produces car pulmonale via two basic mechanisms-reduction in the capacity of the pulmonary vascular bed or by anatomic vascular leaions (see Table I for specific disease entities). The commonest pathway (that on the right of the diagram) starts with the altered blood gases and acidosis and moves into polycythemia and hypervolemia with increased cardiac output-these latter acting to increase the pulmonary hypertension already unleashed by the direct vascoconstricting effects of hypoxia and acidosis. Blood volume, possibly blood viscosity, increased output and direct hypoxic and acidemic effects on the myocardium invoke right ventricular dilatation and failure. This form of pulmonary hypertension and car pulmonale is reversible with correction of the hypoxia and acidosis. If the episodes of hypoxia, acidoaie and pulmonary hypertension are repetitive enough, right ventricular hypertrophy also can occur but today usually is a late manifestation of untreated cases. The second (left hand in the diagram) pathway depicts a much rarer form of car pulmonale in which vascular occlusive lesions create the pulmonary hypertension and this situation is not reversible, and eventually progresses to right heart involvement and failure.

heart disease. Unfortunately, this does not always obtain in published studies. The mechanism of the development of car pulmonale in COPD (see Fig. 2 and Table I) appears to rest firmly on physiologic variables and since the outstanding studies of Heath, Brewer, and Hicken30confirmed Cromie’s original work in 1961,86 the old concept that anatomic lung destruction or pulmonary vascular lesions play a role in this right ventricu-

American Heart Journal

lar disease-a point of discussion until this work and unfortunately still published in some text books31 -can now be discarded with confidence. The nofrndcy of the left vaiW* in car pulmonalo has been under study for Borne years and

perhaps seem to be an area of disagreement even today. The problem arose when autopsy studies done years ago, as summarized by Weisse,32 suggested the presence of left ventricu-

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Ferrer

OBSTRUCTIVE DISEASE OF THE LUNG (Emphysema, Bronchitis, Bronchiolitis)

Pulmonary Hypeitension, Reversible I /I-

,

Right HeartEnlargement

J I

+ Right Heart Failure Fig. 3. Schema of the serial steps in the development pulmonale in obstructive diseases of the lungJ4

of COT

lar hypertrophy in a few cases of car pulmonale. These studies, however, are open to review and will probably not be acceptable, since necropsy studies in recent times fail, for the most part, to confirm them. Heath, Brewer, and HickenS have discussed the critical details of determining left ventricular mass in necropsy specimens by new methods, and recent measurements of myocardial fiber diameters33 as well as details of myocardial mitochondrial numbers and surface areas,34 indicate sparing bf the left ventricle in car pulmonale. Obviously, more such studies are needed. Functionally, recent studies35-38 have also indicated no left ventricular dysfunction in car pulmonale, and indeed if there were any found it was the result of a separate left ventricular disease.37,3sThe best summary of our present knowledge of the normalcy of the left ventricle in car pulmonale is by Davies and Overy,35 and they point out that the theoretical suggestions concerning deleterious effects of abnormal blood gases, especially hypoxia, on myocardial metabolism3g~40are incorrect and that new methods confirm a normal left heart. The presence

of arrhythmias

in car pulmonsle

deserves review. As stated in 1960,” chronic arrhythmias, i.e., those resulting in the permanent loss of sinus rhythm, are not a part of the over-all picture of pulmonary heart disease, as they are, for instance, in rheumatic or arteriosclerotic disease. Recent general surveys of car pulmonale confirm this statement. In Padmavati and

Raizada’s41 series of 544 patients with car pulmonale, they do not mention any arrhythmias and Zarraby and Ghafour’s42 100 patients had a low incidence of arrhythmias (4 per cent). This does not imply, however, that arrhythmias are not seen in patients with car pulmonale. Rather, they often appear during acute hypoxic episodes and disappear with improvement.17p43 They can be of all types and serve as a warning signal of acute respiratory failure, and as Hudson and coworkers43stress, if they are seen, a check must be made on blood-gas abnormalities, drug excess (digitalis and bronchodilators17 especially), and hypokalemia. It is suggestedM that acute hypoxia produces mesencephalic stimulation with enhancement of autonomic discharge, especially via the sympathetic division, and this provokes cardiac arrhythmias. Thus acute respiratory insufficiency can be and often is accampanied by arrhythmias, and these can be the first clinical evidence of sudden severe deterioration in gas exchange. The situation is likely to be critical on all fronts and therapy must be broad based, i.e., both respiratory and anti-arrhythmic. The prognosis of car pulmonale is a subject on which much has been written. It is crucial, however, to recognize the difference between the prognosis of the underlying lung disease and the prognosis of the cardiac complication of the lung disease. For example, in COPD the long-term prognosis of the lung disease is not very good, as yet, and with the onset of respiratory insu&iency (as defined by severe abnormalities of gas exchange) the outlook can become ominous.451n the same disease, however, right-heart failure and enlargement have been repeatedly shown to be reversible, and even patients with repeated episodes of right ventricular failure remain alive for long periods-five to 17 years in our own series46 as well as 14 years in Padmavati and Raixada’s41 series in India, and 10 to 12 years in Sadoul’s4’ series in France. Indeed, Heath34 has shown that right ventricular hypertrophy itself can be reversible. If therapy is intensive and modernized,17~21@-50 the comparison of mortality rates for patients with car pulmonale resulting from COPD has improved47,50n51 as compared to the mortality figures acquired in the days before intensive therapy was the rule.52Also, the effective treatment of a known adverse complication of COPD (car pulmonale) lowers the mortality of the basic obstructive lung disease.5l Hypoxia and

May, 1975, Vol. 89, No. 5

Cor pulmonale

(pulmonary

heart disease)

Table I. Diseases causing car pulmonale17-lg Adults: Il. 2. 3. 4. II. -1. 2. 3. 4. 5. 6.

Diseases associated with hypoxia, acidosis, and pulmonary vasoconstriction: Chronic obstructive pulmonary diseases: conditions producing chronic severe airway obstruction such as chronic bronchitis, pulmonary emphysema, and bronchiolitis. Neuromuscular diseases affecting either the respiratory center or the respiratory muscles (chest and diaphragm). Deformities of chest cage: kyphoscoliosis and surgical or traumatic alterations of chest cage or diaphragm. Obesity (in some patients). Diseases causing anatomic obstructive lesions of pulmonary vascular bed: Multiple pulmonary emboli. Restrictive pulmonary fibrosis with fibrosing or granulomatous processes and, rarely, the massive fibrosis of healed tuberculosis and radiation fibrosis. Pulmonary arteritides. Sickle cell disease with pulmonary emboli and thrombosis. Schistosomiasis. Metastatic lesions.

Children. I. Diseases associated with hypoxia, acidosis, and pulmonary vasoconstriction: 1. Obstructive airway disease: such as fibrocystic disease (the most common cause of car pulmonale in children); severe bronchitis; bronchiolitis; severe asthma; upper airway obstruction due to hypertrophied tonsils, adenoids, or tongue; pulmonary lymphangiectasis. 2. Neuromuscular diseases (as in adults) affecting the respiratory center or respiratory musculature. 3. Deformities of chest cage: kyphoscoliosis; congenital chest distortions involving ribs and diaphragm. 4. Obesity (a rare cause). K Diseases causing anatomic obstructive lesions of pulmonary vascular bed: 1. Diffuse interstitial fibrosis, causing restrictive lung disease; seen in chronic pneumonia, sarcoidosis, hemosiderosis, Hamman-Rich syndrome, Mikity-Wilson disease. 2. Multiple pulmonary emboli (uncommon) seen in sickle cell anemia, rheumatic fever, bacterial endocarditis, schistosomiasis, in ventriculovenous shunts for treatment of hydrocephalus, pulmonary thrombosis in nephrotic syndrome, severe dehydration or sepsis. 3. “Primary pulmonary hypertension.”

acidosis represent the initial stages leading to car pulmonale (Fig. 2) and so with the now commonplace use of arterial blood-gas analysis (ABG) in most hospitals, we have at hand the means of controlling and even preventing car pulmonale in COPD. This concept and philosophy of the reversibility of the circulatory derangements is essential to the successful treatment of this most common form of car pulmonale.21 The earlier one suspects and documents cardiac involvement the easier it is to treat, and one regrets such statements in the literature as “in clinical practice it is not very important to establish whether a patient with COPD has early chronic car pulmonale. “53 Without this conviction of the reversibility of cardiac complications the herculean task of managing these often difficult, as well as seriously ill, patients will not be shouldered by their physicians and nursing adjuvants. By contrast, the course of car pulmonale in restrictive pulmonary disease and anatomic obstructive lesions of the pulmonary vascular bed

American

Heart

Journal

is much less amenable to therapy or change, and actually the cardiac involvement often marks the terminal phase in such diseases as the diffuse pulmonary fibroses. However, even here, with therapy, the life expectancy can be as long as seven to eight years after car pulmonale is diagnosed.“j In car pulmonale due to multiple pulmonary emboli there also is reason to think that improvement is occurring. This is discussed in an outstanding review by McIntyre, Sasahara, and Sharma64 who point out that the therapy of each individual attack of pulmonary embolism has improved and that the investigations of fibrinolytic agents acting to dissolve clots hold promise. It is logical to extrapolate, therefore, that multiple occlusive episodes may decrease in number and in the degree of occlusion-both factors that would make long-term pulmonary hypertension and eventual car pulmonale less likely. Thus in the present era of more effective therapies and prevention of car pulmonale, prognosis of cardiac complications is better than in the past, but we are still faced with a somewhat

661

Ferrer

discouraging. outlook as far as some of the basic lung diseases themselves, especially COPD, are concerned In considering present-day therapy in car pulmonale, there is no controversy about the need to

attack the pulmonary insufficiency in COPD (as defined by a PO, of less than 50 mm. Hg and a PO, of more than 50 mm. Hg), and since it has been shown that circulatory disturbances are the rule below arterial oxyhemoglobin saturation levels of 85 per cent14,55(Fig. 11, the emphasis is upon control of the arterial blood gases (ABG). Indeed, it is probably true that the two greatest advances in the modern handling of patients with car pulmonale due to COPD are (1) the ready and now commonplace use of arterial blood-gas analysis in most hospitals today, allowing for appraisal of respiratory insufficiency much as diabetic control is followed by metabolic measurements, and (2) the successful use of artificial respiratory ventilatory aids both in and out of the hospital by these patients. The repeated monitoring of ABG is a basic and absolute necessity in following patients with COPD. There should be at least a monthly test until it is proved that stability is achieved. During attacks of acute respiratory insufficiency the therapeutic effects can only be gauged by ABG values. It is likely that, in the modern era of car pulmonale, the onset of the cardiac complications of COPD is best diagnosed from hypoxia and acidosis in the ABG, change in heart size by x-ray, and the appearance in the electrocardiogram of transitory negative T-waves in Leads Vi-V, (right V-leads),15 since edema of the legs is seldom seen in this age of powerful diuretics and since the liver size is deceptive in COPD patients with a low diaphragm. The use of oxygen in treating patients with COPD and car pulmonale has been carefully considered throughout the recent past. It is clear that high-flow 0, therapy without the assistance of a mechanical ventilatory aid such as is provided by intermittent positive pressure breathing (IPPB) devices, or the self-regulatory volume respirators or tank or suit respirators, can induce carbon dioxide narcosis and coma. With mechanical ventilatory aids56v57normalization of ABG is achieved and if the aid can be used at home in a regular fashion, i.e., for 30 minutes, three to five times a day, control of hypoxia and its consequences is fairly good. A new and recent therapy,

662

the use of continuous nasal low-flow oxygen (1 to 3 L. per minute) without mechanical ventilation has brought new improvements in heart and lung function in COPD.22,58-60This therapy is best used as near to 24 hours a day as possible and is indicated when IPPB at home is difficult. It should be maintained at least 15 to 18 hours per day.6gCareful checking with serial arterial blood determinations has shown that respiratory depression due to increase in carbon dioxide tension appears to be unusual, but must be watched for.5gThe goal of such therapy is to keep the arterial oxygen tension between 55 and 60 mm. Hg at rest. The use of digitalis in car pulmonale is no longer controversial and is clearly recommended by several groups .2J7Jg,22,61 Certain practical problems remain, however. Both digitalis and diuretics are important agents in the management and rehabilitation of patients with car pulmonale in heart failure and yet it must be stressed that arrhythmias will easily appear with over use of digitalis bodies in these hypoxic patients, and hypokalemia after diuresis can also bring ectopic activity. Thus, only careful and balanced appraisal of dosage of these two agents will result in proper handling of digitalis in car pulmonale. The value of respiratory stimulants remains a topic of debate,‘j2 and has not been accepted as part of most respiratory care programs. The resultant increased work of breathing on already fatigued respiratory muscles is a limiting feature in this concept. The problem of fatigued musculature has only recently been studied quantitatively63 and yet the understanding of the importance of diaphragmatic weakness has led to its treatment by resting the diaphragm and other inspiratory muscles with a tank respiratory for extended periods of time. By thus supplying the breathing energy on a long-term basis with the use of tank respirators at home, the muscles can recover and permit only intermittent use of assisted breathing later on. Sleeping in tank or suit respirators can be of great value in these instances. Summary

In reviewing the present-day status of car pulmonale, it is clear that considerable progress has been made in almost all instances of the disease. It is clearly a preventable form of heart disease in most cases and it is treatable and curable

May, 1975, Vol. 89, No. 5

Cor pulmonale

in its most common form, i.e., in COPD. One must agree with Petty,64 that today we have effective means of caring for the majority of respiratory cripples. Therapy for lung disease now appears even to have reduced the expected rate of pulmonary function deterioration in some patients. Surely with improved gas exchange and early detection of respiratory insufficiency the outlook for patients with respiratory diseases leading to car pulmonale is better today than it was 30 years ago.65 REFERENCES

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American

Heart Journal

(pulmonary

heart disease)

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May, 1975, Vol. 89, No. 5