Yale Enson

Current concepts in the pathogenesis of the obesity-hypoventilation syndrome: Mechanical and circulatory factors

Abstract The pathogenesis of carbon dioxide retention associated with obesity, the obesity hypoventilation syndrome (OHS), remains obscure. In an attempt to Identify factors which might Initiate or contribute to this syndrome, we reviewed respiratory and circulatory function in two groups of obese subjects: those who were not hypercapnic (simple obesity) and those who were (OHS). Obese subjects in both groups display reduction of lung and chest wall compliance, normal airway resistance, closure of peripheral lung units and increased energy cost of breathing. These abnormalities are more severe in those who hypoventilate, especially the reduction In compliance. Respiratory muscle efficiency is reduced in both groups. Inspiratory muscle strength of patients with OHS is 60 to 70 per cent of normal. In OHS arterial carbon dioxide tension (PaCO 2 ), vital capacity and maximum voluntary ventilation improve significantly with weight toss, whereas in simple obesity there Is little change in these factors with weight loss. In both groups the major circulatory findings are increased total and pulmonary blood volume, with preservation of a normal ratio between the two; and good perfusion but marked underventilation of dependent regions of the lung. These changes are more pronounced In OHS. Left ventricular end diastolic pressure is elevated in some patients, but the rise is not confined to those with OHS. In OHS alveolar hypoxia and acidemia produce pulmonary arterial vasoconstriction and pulmonary arterial hypertension. As a consequence pulmonary artery pressure exceeds left ventricular pressure at the end of diastole. We suggest that excessive reduction of chest wall compliance and inspiratory muscle weakness interact with the circulatory abnormalities already present in simple obesity to generate carbon dioxide retention. The contribution of altered central nervous system function to this process remains controversial.

The Influence of Hydrogen Ion Concentration and Hypoxia on the Pulmonary Circulation

Pulmonary hypertension has been found to be reversible in certain patients with, cor pulmonale due to chronic bronchitis, bronchiolitis, and/or emphysema. In these individuals, as disturbances in gas exchange are corrected, pulmonary artery pressures fall (1). The high degree of correlation between the level of pulmonary artery pressures and the degree of hypoxemia (2, 3) as well as the pressor response to acutely induced hypoxia (4, 5) has implicated a reduced oxygen tension within the lungs as a major factor in the appearance of pulmonary hypertension (6). Since these patients almost invariably demonstrate hypercapnia, carbon dioxide tension has also been invoked as a cause of pulmonary hypertension (3). Anatomic reduction of the pulmonary vascular bed cannot be assigned a dominant role in the genesis of this hypertension because of its reversibility. Nonetheless, we may assume that the effects of reactivity of the vascular compartment to various stimuli will be more readily discernible in the presence of a restricted bed. Liljestrand has recently come to the conclusion that an increased hydrogen ion concentration in the blood is the chemical stimulus for pulmonary

Some Effects of Nitroglycerin upon the Splanchnic, Pulmonary, and Systemic Circulations

Splanchnic, pulmonary, and systemic hemodynamics were studied in 18 patients afterthe sublingual administration of nitroglycerin. The drug, contrary to expectations, produced an over-all vasoconstrictive effect on the splanchnic circulation rather than vasodilatation. There was no evidence of venous pooling in this bed, and indeed the data may indicate a splanchnic supportive role in augmenting venous return to the heart with disengorgement of its own volume. In contrast, there was vasodilatation and pooling of blood in the pulmonary vascular bed. The systemic circulation probably sustains several effects by nitroglycerin, including arterial vasodilatation. A direct change in large artery distensibility probably explains the modest fall in systolic blood pressure seen. Further decline in arterial pressure may depend on venous pooling of a small or large degree. Probably the fall in systemic and specific organ flows is also linked to decreased venous return and the vascular readjustments provoked thereby. Pulsus alternans was produced by nitroglycerin, a previously unreported effect of the drug, but the mechanism by which it arose could not be defined.

The Effect of Digoxin in the Splanchnic Circulation in Ventricular Failure

Splanchnic hemodynamics were examined in 22 patients with heart disease, 16 of whom had evidence of ventricular insufficiency at the time of study. The response of the splanchnic vasculature to the exhibition of intravenous digoxin was also studied in nine of these subjects.Ventricular insufficiency was associated with splanchnic vasoconstriction proportional to a generalized increase in peripheral vascularresistance. Splanchnic blood volume was disproportionately increased with respect to total blood volume in patients having visceral congestion with right ventricular failure and combined ventricular failure. A significant relationship between central venous pressure and splanchnic blood volume was demonstrated in these cases. The greater elevation of the former than of the latter suggested the presence of splanchnic venoconstriction.The vascular readjustment to digoxin resulted in a relative intensification of the already existing vasoconstriction of the splanchnic bed as compared to the diffuse systemic vasodilatation which occurred at the same time as the consequence of the inotropic action of the drug: estimated splanchnic blood flow and splanchnic blood volume diminished at a time when systemic flow rose and peripheral vascular resistance decreased. The ultimate distribution of the volume of blood translocated out of the splanchnic bed during this process remains to be determined.

Further Observations on the Effect of Hydrogen Ion on the Pulmonary Circulation

The effects of an acutely induced and modest increase in blood hydrogen-ion concentration on pulmonary hemodynamics were studied in 15 patients with obstructive lung disease. Pulmonary arterial pressure rose when the blood hydrogen-ion concentration increased; this change was greater when the arterial oxyhemoglobin saturation was lower than 91%. The pressor response was independent of change in cardiac output, pulmonary blood volume, and left veno-atrial pressure and is ascribed to pulmonary arterial vaso-constriction. Increased concentration of hydrogen ion is a factor in the production of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Since infusion of acid produced a marked increase in ventilation, the effects of voluntary hyperventilation on pulmonary hemodynamics were studied in three patients with similar pulmonary diseases. In these subjects pulmonary arterial pressure fell as ventilation was increased by a degree comparable to that which occurred during the infusion of acid.

The influence of heart rate on pulmonary arterial-left ventricular pressure relationships at end-diastole.

Increased resistance to blood flow stemming from structural and functional abnormalities of the lungs may cause pressure in the pulmonary artery to exceed that in the left ventricle at the end of ventricular diastole. This study explores the possible contribution of heart rate to the diastolic pressure gradient observed in the presence of acutely induced hypoxia. Pulmonary hemodynamics were examined in mongrel dogs with chronic atrioventricular dissociation with and without hypoxia at two different heart rates and during sequential increments in heart rate while the animals breathed room air. Studies during sequential pacing indicate that heart rate was of greater importance than blood flow in determining the magnitude of the gradient. Heart rate has to be considered when the causes of pulmonary hypertension and the effects of drugs or other agents on the pulmonary circulation are being investigated.

Mixing in the right ventricle and pulmonary artery in man: evaluation of ventricular volume measurements from indicator washout curves

To assess the mixing characteristics of the right ventricle and pulmonary artery, radioiodinated (131)I serum albumin and indocyanine green dye were injected simultaneously in 16 subjects. One indicator was injected into the atrium and the other into the ventricle, or both were injected at different sites in the ventricle. Washout curves were obtained by rapid catheter sampling alternately just above or just below the pulmonic valve. The washout of radioisotope was also recorded with a precordial scintillation detection probe. Indicator washout from the ventricular inflow tract was rapid, while washout from the region of the ventricular apex was quite slow. Protosystolic dips in indicator concentration, noted in curves drawn below the pulmonic valve, suggest that the ventricle emptied sequentially. Flow values computed from curves sampled below the valve, when compared with reference values, suggest that a significant volume of atrial blood passed through the ventricle without mixing, or mixing to only a small extent, with the residual volume of the chamber. Peak concentration of indicator was higher below the pulmonic valve than above. This finding, plus the close agreement between flow values computed from curves sampled above the valve and the reference values, indicates that further mixing occurred above the valve. Ventricular volumes computed from washout downslopes are systematically falsely high. This overestimate appeared to be larger in normal subjects than in patients with low stroke volumes. Progressive mixing of blood leaving the atrium occurs during its passage through the ventricle, pulmonic valve, and pulmonary artery and permits accurate estimation of flow.

Respiratory Complications of Cardiac Transplantation

The authors evaluated all respiratory complications of cardiac transplantation in a 10-year study of 94 consecutive recipients. Mean follow-up time was 20 +/- 17 months. The initial 20 patients were treated with azathioprine and prednisone, while the subsequent 74 patients received cyclosporine and prednisone. In the azathioprine group, respiratory infections accounted for 24 of 60 (40%) infections. Two-thirds of the respiratory infections occurred in the first 3 postoperative months and were generally localized processes (focal pneumonitis, nodule(s), abscess, or empyema). Gram-positive and gram-negative bacteria (8/30) and aspergillus (8/30) were the predominant pathogens. Respiratory failure occurred in 29% of infectious episodes. In the cyclosporine group, there were significantly fewer respiratory infections. There was also a reduction in the number of nonrespiratory infections; hence, the percentage of total infections due to respiratory causes, 26 of 50 (52%), was not significantly different. In contrast, however, nearly two-thirds of the respiratory infections in cyclosporine-treated patients occurred after the first 3 postoperative months, and were usually diffuse processes. Despite diffuse disease, respiratory failure was observed with similar frequency (19%). Pneumocystis carinii (9/31) and cytomegalovirus (CMV) (7/31) were the predominant pathogens. CMV pneumonitis tended to occur earlier than that due to P. carinii (2.9 +/- 1.9 mo vs. 9.8 +/- 11.2 mo, respectively), but there was considerable overlap. In comparison with infectious processes, there were 50% fewer noninfectious respiratory complications in both groups. These were primarily pleural (46%) or thromboembolic (18%) disorders. Four of five pulmonary emboli occurred in patients with intercurrent cardiorespiratory illness, and were detected only at autopsy. The authors conclude that respiratory infections account for one-half of all infections observed in cardiac transplant recipients, despite the reduced infection rate associated with the use of cyclosporine. Furthermore, respiratory infections in cyclosporine-treated patients exhibit different clinical and etiologic features than those seen in azathioprine-treated patients. Finally, occult thromboemboli may be difficult to recognize in cardiac transplant recipients because of the high incidence of coexisting cardiorespiratory disease.

The effect of acutely induced hypervolemia on resistance to pulmonary blood flow and pulmonary arterial compliance in patients with chronic obstructive lung disease

Abstract The presence of alveolar hypoxia and respiratory acidemia in patients with chronic obstructive lung disease alters the normal relation between pulmonary arterial and left heart pressures at the end of diastole; usually these pressures are the same. With vasoconstriction of the small pulmonary arteries the pulmonary arterial diastolic pressure rises, whereas the mean wedge pressure remains unchanged. Thus, a pressure gradient across the pulmonary circulation appears at the end of diastole representing an increased resistance to pulmonary blood flow. The magnitude of this gradient is closely related to the systemic arterial blood oxyhemoglobin saturation, which is used as an index of alveolar oxygen tension, and to the blood hydrogen ion concentration. In the present study acutely induced hypervolemia caused striking alterations in mean wedge pressure and blood flow. However, the diastolic gradient did not change. The pulmonary diastolic pressure gradient reflects the degree of resistance to pulmonary blood flow regardless of the level of the left heart pressure or the cardiac output. On the other hand, left heart pressure does contribute to the level of the pulmonary arterial diastolic pressure. The pulse pressures recorded in the elastic pulmonary arteries reflect their compliance characteristics and the effect of stroke volume imposed upon them. We have assessed compliance indirectly by examining the relationships between pulmonary arterial systolic pressure, diastolic pressure and stroke volume. The compliance characteristics of the elastic arteries in patients with chronic obstructive lung disease do not differ from normal before or during acutely induced hypervolemia.

Hemodynamic Studies on Cholera Effects of Hypovolemia and Acidosis

The hemodynamic effects of hypovolemia and acidosis were studied in 23 patients with cholera. Studies were made before and during fluid replacement and administration of alkali.The major hemodynamic abnormalities encountered before rehydration can be ascribed to a reduction in circulating blood volume. Hypovolemia was associated with a reduction in cardiac output, blood pressures, and central blood volume. Restoration of blood volume returned these variables toward normal.The chief effect of acidosis appeared to be a redistribution of blood from the peripheral to the central circulation; consequently, central blood volume, lesser circulation pressures, and cardiac output were relatively well maintained despite hypovolemia. Fluid administration without correction of acidosis favored a disproportionate increase in central blood volume, while reduction in hydrogen ion concentration attending fluid replacement resulted in a more even distribution of the circulating blood volume and reduced the possibility of engorgement of the pulmonary bed.It is postulated that this redistribution of blood stems from peripheral venoconstriction and a reduction in the capacity of venous reservoirs induced by acidosis.