THE PULMONARY CIRCULATION IN CHRONIC BRONCHITIS AND EMPHYSEMA P, Finnegan Department of Medicine, Regional Hospital, Galway. IN the Croon~an lecture delivered to the Royal College of Physicians of London in 1963. W. M. Arnott recounted the work of the Department of Medicine of Birmingham University and emphasised the importance of the close structural and functional relationship of .the heart and lungs. When I later joined his Department I was able to collaborate with J. M. Bishop and R. D. Stark in the study of the cardiopulmonary function of patients with chronic bronchitis and emphysema. The importance of the scientific analysis of the structure and funcgon of the body was admirably taught by J. F. Donegan. It is a pleasure to acknowledge his formative influence which provided the necessary foundation for a subsequent career in clinical science.
Pulmonary hypertension There is general agreement that pulmonary hypertension is the major factor in the causation of congestive cardiac failure in patients with chronic bronchitis and emphysema. It is noteworthy that not all patients with chronic bronchitis have raised pulmonary artery pressures. Burrows et al. I1972) described different patterns of cardiovascular dysfunction associated w~th chronic obstructive lung disease. The patients with mild ventilatory impairment had normal pulmonary artery pressures at rest but they developed pulmcnary hypertension during exercise, In patients with predominant emphysema the cardiac output was low and the pulmonary artery pressures were only sgghtly above the normal range. The patients with predominant bronchitis and marked bypcxaemia, however, had well maintained cardiac outputs and more
severe pulmonary hypertension. The authors suggested that the pulmonary hypertension was caused by the fact that the cardiac output was well maintained in the presence of an increased pulmonary vascular resistance. This study also showed an inverse correlation between the survival rate and the pulmonary vascular resistance. A similar relationship has been demonstrated in a group of 128 patients studied in Birmingham (Bishop, 1975). The development of pulmonary hypertension is therefore important in terms of morbidity and mortality,
Causes of pulmonary hypertension A number of factors have been implicated in the causation of the pulmonary hypertension including changes in cardiac output and pulmonary blood volume; the abnormal blood viscosity; increased pulmonary venous pressure; acidaemia and hypoxaemia, The evidence relating to these features will be briefly reviewed. Cardiac output When the technique of cardiac catheterisation was first used in patients with chronic bronchitis and emphysema an increased cardiac output was reported by several authors (Howarth et al., 1947; Harvey et al., 1951) and the concept of high output cardiac failure was postulated. Subsequent studies failed to substantiate the earlier findings and in a review of the subject Wade and Bishop (1962) concluded that only a small minority of patients had abnormally large cardiac outputs. The argument that an increased pulmonary blood flow was responsible for the pulmonary hyperten-
234
IRISH JOURNALOF MEDICALSCIENCE
sion must be rejected. However, unlike other patients with heart failure, the cardiac output is not reduced except in a small minority. Pulmonary blood volume Abraham et al. (1967) showed that an acute increase in the pulmonary blood volume raised the pulmonary arterial and venous pressures. )n a later study (Abraham et el., 1969) an increase in the total and central blood volumes was demonstrated in patients with acute respiratory faiture and cardiac failure. Nowever, during the recovery period a reduction in the pulmonary hypertension occurred while the total and central blood volumes were still raised. Increased blood viscosity Hypoxaemia causes an increase in the red cell volume and ~his in sum increases the viscosity of the blood, Segel and Bishop (tg66) produced large reductions in the haematocrit by repeated venesection of patients wilh advanced secondary polycythaemia. They found that this resu}ted in only very sinai) changes in the pulmonary artery pressure. They eom cluded that ~he increased viscosity o1 the blood had no important effect on the pulmonary hypertension. Increased pulmonary venous pressure There is considerable controversy regarding the possibility that abnormar ful~clion of the left ventricle in patients wilb chronic bronchitis could result Jn an increase in ~he purmonary venous pressure and contribute to the development o1 pulmonary arterial hypertension. Post modem studies have shown that left venlricular hypertrophy commonly occurs in patients dying from chronic bronchigs and emphysema (Fluek et al., 1966). cgnical studies also described left venlricufar failude in patiests with cor pulmonale in the absence of any evidence of systemic hypertension or ischaemic head disease (Rue et al., 1968). Severar reports have documented the presence of increased pulmonary wedge
gressures in patients with chronic bronchi6s and emphysema (Herles et el., 1968; Lockhart et al.. 1969). It was argued that airways obstruction could cause an increase ip alveolar pressure and compress the alveolar vessels thereby raising the pulmonary wedge pressure. The pulmonary extravascuJar fluid volume is increased in patients with chronic bronchitis and a history of congesdve cardiac failure (McCredie, 1970; Tudno et el, 1970). It was suggested that this increase could raise the pulmonary vascular resistance. In addition to the demonstration of e raised pulmonary wedge pressure, direct measurement of left atria[ and left ventricular end-diastogc pressures showed that these pressures were also increased in some patients (Rao at al., 1968; Lockhart et al., 1969; 8aum et al., 197f J. The ~affer study also showed abnormal left ventricular function curves and increased wall thickness and end-diastolic volume on angicgrephy. The majority of investigators have demonstrated, however, that left ventdculer function is norrnaf in patients with chronic bronchitis (Williarns et el,, 1968; Davies and every, 1970; Ma!thay et al., 1976]. The weight of evidence would appear to favour the view that failure of the left ventricle is not the cause of the pulmonary hypertension in patients with chronic bronchitis. W h e n left vectricular failure occurs a separate cause such as ischaemic heart disease is likely to be responsible. Hypercapnia and acidaernia Because of alveolar hypoventilation hypercapnia is commonly present in patients with chronic bronchitis. The hypercapnia causes vasodilatation in the systemic circulation bul its direct effects on the purmenary 6irculatJon ere o1 minor sJgnificance. A slight rise in pub monary arterial pressure was found by Fishrnan et al. (1960) in tO patients with emphysema while they breathed 3 or 5 per cent carbon dioxide. The average
THE PULIvlONARYCIRCULATIONIN CHRONICBRONCHITIS increase was only 7 mm Hg and this could be accounted for by the accompanying rise in cardiac output. Although hypercapnia has little direct effect on 1he pulmonary circulation it could also exert an influence by causing an increase in hydrogen ion concentration. Experiments in animars have shown that such an increase causes pulmonary vasoconstriction (Bergofsky et el, 1963) The evidence that such an effect occurs in man is less convincing. Housley et al. (1970) showed that both acute and chronic increases in hydrogen ion concentration did not cause pulmonary vasoconstriction. I1 would appear ungkely therefore, that the small increases in hydrogen ion concentration that occur in patients with chronic bronchitis could have any major effect on the pulmonary arterial pressure Hypoxia Large areas of the pulmonary vascular tree may be obliterated by chronic bronchitis and emphysema. The work of Hicken et at. (1966) however, suggests that the reduction must be extreme before it produces pulmonary hypertension. The cause of the increased pulmonary vascular resistance must be sough1 elsewhere therefore and the overwhelming evidence points to the predominant role of hypoxia. Hypoxia appears to have two important effects (a) pulmonary vasoconstriction and (b) the production of permanent structural changes in the arterJaJ walls. (a) Active pulmonary vasoconstriction Acute anoxia causes pulmonary hypertension in animals (Von Euler and Liljestrand, 1946) and in normal man (Motley et ab, 1947). Two possible mechanisms may be responsible for the pulmonary vasoconstriction a~veolar hypoxia causing the release of chemical mediators such as histamine or alternatively a direct effect on the smooth muscle of the pulmonary arteries. An inverse correlation between the arterial oxygen saturation and the pul-
235
mcnary arterial pressure has been demonstrated Jn patients with chronic bronchitis and emphysema (Harvey et al., 1951). This relationship was subsequently confirmed by other workers (Mounsey et at., 1952; Evans et al., 1963). That this relationship is causal is suggested by serial observations in individuals which show a progressive increase in pulmonary vascular resistance accompanied by a reduction in arterial oxygen saturation (Segel and Bishop, 1966). In patients with chronic bronchitis an exacerbation of the pulmonary hypertension occurs during the course of congestive cardiac failure. During the period of recovery serial measurements by Abraham et al. (1969) showed a considerable fall in the pulmonary arterial pressures. Oxygen therapy in the early stages also caused a substantial reduction in the pulmonary hypertension. However, this response to acute oxygen administration diminished throughout the recovery period until the effect was minima~ when the signs of congestive cardiac failure had disappeared, The tailure of acute oxygen administration to produce a reduction in pulmonary vascular resislance in the steady state iraplies that pulmonary vasoconstriction cannot have an important role at this stage and that structural changes in the pulmonary arteries are responsible for the increased pulmonary vascular resistance. (b) Structural arterial changes Structural changes occurring in the pulmonary vessels in hypoxic states were described by Hasleton et al. (1966). They demonstrated muscularization of the pulmonary arterioles and the development of longitudinal bundles of smooth muscle in the intima of the small arteries and arterioles. It was postulated that if the hyperplastic changes in the pulmonary vessels were caused by hypoxia that it should be possible to reverse them by correcting the hypo• Reversal of the struc-
236
IRISH JOURNALOF MEDICALSCIENCE
tural changes should result in a reduction of the pulmonary vascular resistance. Studies were designed to systematica~{y test th{s hypothesis. A.
Oxygen administration for 24 hours daily (Abraham et eL, 1968)
This study was pe#ormed on six patients with chronic bronchitis and emphysema who were hypoxic and in whom pulmonary hypertension had been confirmed. They were given oxygen continuously for 24 hours daily in a concentration of approximately 30 per cent for 4-8 weeks. The pulmonary artery pressures and the pulmonary blood flow were measured at intervals and it was shown that a progressive decrease in the pulmonary arterial pressure and the pu~monsry vascular resistance occurred. To ensure that this response was not due to an acute effect of the oxygen administration, the cardiac cafheterisalions were done two hours after discontinuation of the oxygen therapy. The effect was therefore a prolonged one and the results were interpreted as good evidence for regression of the structural vessel changes, The measurements were repeated several weeks after the period of oxygen therapy had ended and Jt was dfscovered that the pulmonary hypertension had recurred in all the patients. Direct histological proof that the hyperplastic vessel changes had regressed was not obtained Some experimental support was derived from an experimental study in rats (Abraham ef el., t97t). Rats maintained [n an hypoxic environment for six weeks developed muscular hyperplasia in the pulmonary arteries and also right ventricuJar hypertrophy. When the animals were a/lowed to breathe air again for six weeks the structural changes regressed.
B.
Daily requirement of oxygen to reverse pulmonary hypertension (Stark et al,, 1972)
Having demonstrated the reversal of pulmonary hypertension with continuous oxygen therapy the next step was to
ascertain the minimum daily requirement of oxygen to achieve this effect. Eleven patients with advanced chronic bronchitis in whom at least one episode of congestive cardiac fadure had been documented were seIected for study. They were all hypoxaem~c and the mean P~ 0= for the groups was 49 mm Pig. while breathing 30 per cent oxygen the mean P, 0~ increased to 70 mm Hg. The circulatory studies were done with the patient breathing air at least two hours after cessation of oxygen therapy in order to ensure that the responses could not be attributed to an acute effect of the oxygen therapy.
1. Oxygen therapy for 18 hours daffy. Four patients were given 3O per cent oxygen for 18 hours daily over a period of six weeks. Cardiac catheterisation at at the end of that period showed that there had been a significant reduction in the mean pulmonary artery pressure for the group from 5f to 31 mm Fig (p
Pulmonary hypertension There is general agreement that pulmonary hypertension is the major factor in the causation of congestive cardiac failure in patients with chronic bronchitis and emphysema. It is noteworthy that not all patients with chronic bronchitis have raised pulmonary artery pressures. Burrows et al. I1972) described different patterns of cardiovascular dysfunction associated w~th chronic obstructive lung disease. The patients with mild ventilatory impairment had normal pulmonary artery pressures at rest but they developed pulmcnary hypertension during exercise, In patients with predominant emphysema the cardiac output was low and the pulmonary artery pressures were only sgghtly above the normal range. The patients with predominant bronchitis and marked bypcxaemia, however, had well maintained cardiac outputs and more
severe pulmonary hypertension. The authors suggested that the pulmonary hypertension was caused by the fact that the cardiac output was well maintained in the presence of an increased pulmonary vascular resistance. This study also showed an inverse correlation between the survival rate and the pulmonary vascular resistance. A similar relationship has been demonstrated in a group of 128 patients studied in Birmingham (Bishop, 1975). The development of pulmonary hypertension is therefore important in terms of morbidity and mortality,
Causes of pulmonary hypertension A number of factors have been implicated in the causation of the pulmonary hypertension including changes in cardiac output and pulmonary blood volume; the abnormal blood viscosity; increased pulmonary venous pressure; acidaemia and hypoxaemia, The evidence relating to these features will be briefly reviewed. Cardiac output When the technique of cardiac catheterisation was first used in patients with chronic bronchitis and emphysema an increased cardiac output was reported by several authors (Howarth et al., 1947; Harvey et al., 1951) and the concept of high output cardiac failure was postulated. Subsequent studies failed to substantiate the earlier findings and in a review of the subject Wade and Bishop (1962) concluded that only a small minority of patients had abnormally large cardiac outputs. The argument that an increased pulmonary blood flow was responsible for the pulmonary hyperten-
234
IRISH JOURNALOF MEDICALSCIENCE
sion must be rejected. However, unlike other patients with heart failure, the cardiac output is not reduced except in a small minority. Pulmonary blood volume Abraham et al. (1967) showed that an acute increase in the pulmonary blood volume raised the pulmonary arterial and venous pressures. )n a later study (Abraham et el., 1969) an increase in the total and central blood volumes was demonstrated in patients with acute respiratory faiture and cardiac failure. Nowever, during the recovery period a reduction in the pulmonary hypertension occurred while the total and central blood volumes were still raised. Increased blood viscosity Hypoxaemia causes an increase in the red cell volume and ~his in sum increases the viscosity of the blood, Segel and Bishop (tg66) produced large reductions in the haematocrit by repeated venesection of patients wilh advanced secondary polycythaemia. They found that this resu}ted in only very sinai) changes in the pulmonary artery pressure. They eom cluded that ~he increased viscosity o1 the blood had no important effect on the pulmonary hypertension. Increased pulmonary venous pressure There is considerable controversy regarding the possibility that abnormar ful~clion of the left ventricle in patients wilb chronic bronchitis could result Jn an increase in ~he purmonary venous pressure and contribute to the development o1 pulmonary arterial hypertension. Post modem studies have shown that left venlricular hypertrophy commonly occurs in patients dying from chronic bronchigs and emphysema (Fluek et al., 1966). cgnical studies also described left venlricufar failude in patiests with cor pulmonale in the absence of any evidence of systemic hypertension or ischaemic head disease (Rue et al., 1968). Severar reports have documented the presence of increased pulmonary wedge
gressures in patients with chronic bronchi6s and emphysema (Herles et el., 1968; Lockhart et al.. 1969). It was argued that airways obstruction could cause an increase ip alveolar pressure and compress the alveolar vessels thereby raising the pulmonary wedge pressure. The pulmonary extravascuJar fluid volume is increased in patients with chronic bronchitis and a history of congesdve cardiac failure (McCredie, 1970; Tudno et el, 1970). It was suggested that this increase could raise the pulmonary vascular resistance. In addition to the demonstration of e raised pulmonary wedge pressure, direct measurement of left atria[ and left ventricular end-diastogc pressures showed that these pressures were also increased in some patients (Rao at al., 1968; Lockhart et al., 1969; 8aum et al., 197f J. The ~affer study also showed abnormal left ventricular function curves and increased wall thickness and end-diastolic volume on angicgrephy. The majority of investigators have demonstrated, however, that left ventdculer function is norrnaf in patients with chronic bronchitis (Williarns et el,, 1968; Davies and every, 1970; Ma!thay et al., 1976]. The weight of evidence would appear to favour the view that failure of the left ventricle is not the cause of the pulmonary hypertension in patients with chronic bronchitis. W h e n left vectricular failure occurs a separate cause such as ischaemic heart disease is likely to be responsible. Hypercapnia and acidaernia Because of alveolar hypoventilation hypercapnia is commonly present in patients with chronic bronchitis. The hypercapnia causes vasodilatation in the systemic circulation bul its direct effects on the purmenary 6irculatJon ere o1 minor sJgnificance. A slight rise in pub monary arterial pressure was found by Fishrnan et al. (1960) in tO patients with emphysema while they breathed 3 or 5 per cent carbon dioxide. The average
THE PULIvlONARYCIRCULATIONIN CHRONICBRONCHITIS increase was only 7 mm Hg and this could be accounted for by the accompanying rise in cardiac output. Although hypercapnia has little direct effect on 1he pulmonary circulation it could also exert an influence by causing an increase in hydrogen ion concentration. Experiments in animars have shown that such an increase causes pulmonary vasoconstriction (Bergofsky et el, 1963) The evidence that such an effect occurs in man is less convincing. Housley et al. (1970) showed that both acute and chronic increases in hydrogen ion concentration did not cause pulmonary vasoconstriction. I1 would appear ungkely therefore, that the small increases in hydrogen ion concentration that occur in patients with chronic bronchitis could have any major effect on the pulmonary arterial pressure Hypoxia Large areas of the pulmonary vascular tree may be obliterated by chronic bronchitis and emphysema. The work of Hicken et at. (1966) however, suggests that the reduction must be extreme before it produces pulmonary hypertension. The cause of the increased pulmonary vascular resistance must be sough1 elsewhere therefore and the overwhelming evidence points to the predominant role of hypoxia. Hypoxia appears to have two important effects (a) pulmonary vasoconstriction and (b) the production of permanent structural changes in the arterJaJ walls. (a) Active pulmonary vasoconstriction Acute anoxia causes pulmonary hypertension in animals (Von Euler and Liljestrand, 1946) and in normal man (Motley et ab, 1947). Two possible mechanisms may be responsible for the pulmonary vasoconstriction a~veolar hypoxia causing the release of chemical mediators such as histamine or alternatively a direct effect on the smooth muscle of the pulmonary arteries. An inverse correlation between the arterial oxygen saturation and the pul-
235
mcnary arterial pressure has been demonstrated Jn patients with chronic bronchitis and emphysema (Harvey et al., 1951). This relationship was subsequently confirmed by other workers (Mounsey et at., 1952; Evans et al., 1963). That this relationship is causal is suggested by serial observations in individuals which show a progressive increase in pulmonary vascular resistance accompanied by a reduction in arterial oxygen saturation (Segel and Bishop, 1966). In patients with chronic bronchitis an exacerbation of the pulmonary hypertension occurs during the course of congestive cardiac failure. During the period of recovery serial measurements by Abraham et al. (1969) showed a considerable fall in the pulmonary arterial pressures. Oxygen therapy in the early stages also caused a substantial reduction in the pulmonary hypertension. However, this response to acute oxygen administration diminished throughout the recovery period until the effect was minima~ when the signs of congestive cardiac failure had disappeared, The tailure of acute oxygen administration to produce a reduction in pulmonary vascular resislance in the steady state iraplies that pulmonary vasoconstriction cannot have an important role at this stage and that structural changes in the pulmonary arteries are responsible for the increased pulmonary vascular resistance. (b) Structural arterial changes Structural changes occurring in the pulmonary vessels in hypoxic states were described by Hasleton et al. (1966). They demonstrated muscularization of the pulmonary arterioles and the development of longitudinal bundles of smooth muscle in the intima of the small arteries and arterioles. It was postulated that if the hyperplastic changes in the pulmonary vessels were caused by hypoxia that it should be possible to reverse them by correcting the hypo• Reversal of the struc-
236
IRISH JOURNALOF MEDICALSCIENCE
tural changes should result in a reduction of the pulmonary vascular resistance. Studies were designed to systematica~{y test th{s hypothesis. A.
Oxygen administration for 24 hours daily (Abraham et eL, 1968)
This study was pe#ormed on six patients with chronic bronchitis and emphysema who were hypoxic and in whom pulmonary hypertension had been confirmed. They were given oxygen continuously for 24 hours daily in a concentration of approximately 30 per cent for 4-8 weeks. The pulmonary artery pressures and the pulmonary blood flow were measured at intervals and it was shown that a progressive decrease in the pulmonary arterial pressure and the pu~monsry vascular resistance occurred. To ensure that this response was not due to an acute effect of the oxygen administration, the cardiac cafheterisalions were done two hours after discontinuation of the oxygen therapy. The effect was therefore a prolonged one and the results were interpreted as good evidence for regression of the structural vessel changes, The measurements were repeated several weeks after the period of oxygen therapy had ended and Jt was dfscovered that the pulmonary hypertension had recurred in all the patients. Direct histological proof that the hyperplastic vessel changes had regressed was not obtained Some experimental support was derived from an experimental study in rats (Abraham ef el., t97t). Rats maintained [n an hypoxic environment for six weeks developed muscular hyperplasia in the pulmonary arteries and also right ventricuJar hypertrophy. When the animals were a/lowed to breathe air again for six weeks the structural changes regressed.
B.
Daily requirement of oxygen to reverse pulmonary hypertension (Stark et al,, 1972)
Having demonstrated the reversal of pulmonary hypertension with continuous oxygen therapy the next step was to
ascertain the minimum daily requirement of oxygen to achieve this effect. Eleven patients with advanced chronic bronchitis in whom at least one episode of congestive cardiac fadure had been documented were seIected for study. They were all hypoxaem~c and the mean P~ 0= for the groups was 49 mm Pig. while breathing 30 per cent oxygen the mean P, 0~ increased to 70 mm Hg. The circulatory studies were done with the patient breathing air at least two hours after cessation of oxygen therapy in order to ensure that the responses could not be attributed to an acute effect of the oxygen therapy.
1. Oxygen therapy for 18 hours daffy. Four patients were given 3O per cent oxygen for 18 hours daily over a period of six weeks. Cardiac catheterisation at at the end of that period showed that there had been a significant reduction in the mean pulmonary artery pressure for the group from 5f to 31 mm Fig (p
