John F. Murray

Circulatory changes in chronic liver disease

Abstract The circulatory findings in twenty-four patients with portal cirrhosis were compared with results in six patients with biliary cirrhosis, six patients with extrahepatic portal vein obstruction and fourteen normal subjects. Half the patients with portal cirrhosis had a cardiac index above the upper limit of normal. Clinically, these patients had evidence of increased peripheral blood flow and ejection systolic murmurs. Roentgenographic or electrocardiographic changes were uncommon. Patients with biliary cirrhosis and portal vein obstruction had normal cardiac indices. An increased total blood volume, mainly plasma volume, was found in patients with portal cirrhosis who had an increased cardiac index, a large portal-systemic collateral circulation, arterial oxygen desaturation and low serum albumin levels. The increased portal venous network did not account for the increased blood volume in portal cirrhosis as patients with extrahepatic portal vein obstruction had virtually normal blood volumes. The low serum albumin levels may in part represent the dilution of a normal amount of circulating albumin by an increased plasma volume. Four patients had low arterial oxygen saturation. Cardiac catheterization data in one patient and studies in two others suggest that the arterial desaturation may be due to the shunting of blood through pulmonary arteriovenous anastomoses. One of these cases is presented in detail. In most patients with portal cirrhosis the increased cardiac output was tolerated without evidence of decomposition. Congestive heart failure was present in one patient reported in detail. As liver function and the clinical status of patients with portal cirrhosis improved, the cardiac output returned toward normal. The mechanism of production of the hyperdynamic circulatory state in portal cirrhosis is unknown. There is profound vasodilatation and the mechanism of this is discussed.

The value of edema fluid protein measurement in patients with pulmonary edema

Alveolar fluid and plasma proteins were analyzed in 24 patients with florid pulmonary edema, in 21 of whom pulmonary capillary wedge pressure (Pcw) was also measured. In all patients with Pcw less than 20 mm Hg, the edema fluid to plasma protein ratio exceeded 0.6; the mean edema fluid to plasma protein ratio in the four patients with cardiogenic edema (increased Pcw) was 0.46. In the 21 patients in whom full data were available, the net intravascular filtration force (Pcw - plasma colloid osmotic pressure) was less than -4 mm Hg, the value at which (according to others) pulmonary edema should occur, in only 10. When the interstitial colloid osmotic pressure, approximated by the osmotic pressure of edema fluid protein, was added, the net filtration force became positive in 17 of 21 patients. Comparison of the protein concentrations of edema fluid and plasma aids in the diagnostic separation of increased permeability from high hydrostatic pressure edema and adds to our understanding of the relative osmotic and hydrostatic forces that contribute to pulmonary edema when the alveolar-capillary membrane is damaged.

Cursed Duet: HIV Infection and Tuberculosis

Tuberculosis remains a health problem of extraordinary magnitude, especially in developing countries. Unfortunately, many of the same countries have the additional burden of a remarkably high prevalence of HIV infection. Because of the inherent capacity of tubercle bacilli to take advantage of deficiencies in cell-mediated immunity, tuberculosis has become an extremely important infectious complication of HIV disease in those developing countries in which the two infections coexist; the same is true, although to a lesser extent, in developed countries among those groups of patients with HIV infection in which there is also a high prevalence of remotely acquired tuberculosis. Prof. Chrétien helped call attention to the link between tuberculosis and HIV infection in France. Now, it is obvious that his cogent observations extend to much of the rest of the world.

Tuberculosis and HIV Infection: A Global Perspective

The incidence of HIV-associated tuberculosis has been increasing worldwide since the beginning of the AIDS epidemic, and is expected to increase even further during the foreseeable future, especially in developing countries. There is no doubt now that, in the presence of HIV infection, new-onset tuberculous infection progresses rapidly to clinically significant disease and the likelihood that latent tuberculous infection progresses rapidly to clinically significant disease and the likelihood that latent tuberculous infection will reactivate is enormously increased. The accelerating and amplifying influence of HIV infection is contributing to the increasing incidence of disease caused by multidrug-resistant strains of Mycobacterium tuberculosis. Neither clinical features nor radiographic abnormalities reliably distinguish the majority of patients with HIV-associated tuberculosis from those without HIV infection. Some persons with HIV infection, however, present with atypical manifestations of tuberculosis and these patients may be difficult to diagnose. Six months of daily or thrice weekly chemotherapy with the usual regimen of 4 then 2 antituberculosis drugs cures most patients, but many die during or after treatment of other AIDS-related complications.

PEEP and pulmonary edema

A fter a few early trials, the modern usage of positive end-expiratory pressure (PEEP) in adults began with Ashbaugh and co-workers [l] in 1967. During the subsequent 14 years, this method of ventilation has quickly been accepted and widely applied. PEEP appears to be particularly useful in the treatment of patients with pulmonary edema resulting from increased alveolar-capillary membrane permeability (the so-called adult respiratory distress syndrome) or from increased hydrostatic pressure (primarily cardiogenic edema). Compared with ventilation with atmospheric expiratory pressure, PEEP increases end-expiratory lung volume by opening airways, recruiting alveoli and, possibly, redistributing liquid within the lung. Collectively, these effects nearly always increase the Po2 of arterial blood by diminishing intrapulmonary shunting of blood and improving the matching of ventilation and perfusion. Although PEEP usually increases arterial oxygenation, its effects on overall 02 transport are varied and depend on the net balance between the beneficial increase in arterial 02 content and the deleterious decrease in cardiac output that often occurs [2]. The effects of PEEP on blood gases, pulmonary function, and hemodynamics are thoroughly documented and reasonably well understood. A much more controversial issue, despite considerable investigation in recent years, concerns whether or not PEEP actually affects the amount of pulmonary edema fluid in patients with adult respiratory distress syndrome or heart failure. The purpose of this editorial is to examine the question, is the application of PEEP fundamentally therapeutic, in the sense of reducing pulmonary edema, or is it simply supportive, capable of assisting patients through episodes of severe hypoxemia until the underlying process subsides and their lungs recover? For purposes of this discussion, we define pulmonary edema as an abnormal increase in the amount of extravascular water in the lungs. In both health and disease, this quantity is determined by the balance between the rate of filtration and the rate of removal of liquid in the lungs. Thus, to examine the effects on pulmonary edema of PEEP, we must consider how PEEP influences both the formation and the clearance of lung liquid. As originally formulated by Starling, the major determinants of filtration include (1) the net hydrostatic pressure, the difference between the hydrostatic pressures of the intravascular and surrounding interstitial compartments; (2) the net protein osmotic pressure, the difference between the oncotic pressures of the intravascular and interstitial compartments; and (3) the permeability of those small vessels in the lung called the microcirculation, through which filtration occurs. The term permeability describes not only the leakiness of the microcirculation but also the total vascular surface area available for filtration. In contrast to the multiple factors that govern filtration, there is a single major pathway for clearance of liquid from the lung, lymphatic removal. A brief discussion of each of these factors is necessary to clarify PEEP’s diverse effects on pulmonary edema. Hydrostatic Pressure. Application of PEEP usually increases intravascular hydrostatic pressure throughout the pulmonary circulation. But to understand how this might influence filtration, it is necessary to know how the same amount of PEEP affects the hydrostatic pressures in the interstitial spaces that surround the microcirculation. This analysis is complicated by the existence of two types of vessels in the lung that are distinguished by the prevailing pressures in their respective interstitial spaces and by how they respond to lung inflation. Although the exact anatomic boundaries of these vessels are not known, filtration can occur from each type and thus the effects of PEEP on both must be considered. On the one hand, alveolar vessels narrow as the lung is inflated and they are surrounded by an interstitial pressure that is believed to be slightly less than the pressure in the neighboring alveoli; on the other

The components of the alveolar-arterial oxygen tension difference in normal subjects and in patients with pneumonia and obstructive lung disease

Abstract The contributions of the pulmonary shunt and total right to left shunt to the alveolar-arterial oxygen tension difference were studied in twenty normal subjects, ten patients with severe pneumonia and eleven patients with chronic obstructive pulmonary disease. The total right to left shunt was measured by the oxygen breathing method, and the pulmonary shunt component of the total shunt was measured by a combined indicator dilution technic with radioactive xenon and indocyanine green dye injected intravenously and sampled from a peripheral artery. The dye curve and the amount of xenon in the collection syringe were used to calculate the pulmonary shunt since only shunted blood would retain dissolved xenon. The difference between the total shunt (oxygen breathing method) and the pulmonary shunt (xenon method) was used to estimate the post-pulmonary shunt. In normal subjects all of the alveolar-arterial oxygen tension difference was due to shunting, most (69 per cent) of which was postpulmonary shunt. In pneumonia there were large pulmonary shunts that caused most of the hypoxemia, although the postpulmonary component became larger in very severe pneumonia. In patients with COPD there is an insignificant increase in the pulmonary shunt and no increase in the postpulmonary shunt. The pulmonary shunt was measured with this combined indicator technic both on air and oxygen; 100 per cent oxygen breathing did not have an important effect on the pulmonary shunt.

Tuberculosis and HIV Infection: Global Perspectives

Abstract This paper reviews the epidemiological and clinical aspects of the interaction between Mycobacterium tuberculosis and HIV infection. The incidence of HIV‐associated tuberculosis is increasing worldwide and is expected to increase further, especially in Africa and parts of Asia. HIV infection appears to increase the likelihood that tuberculous infection will occur after tubercle bacilli are inhaled into the lungs. Moreover, there is persuasive evidence that in the presence of HIV infection, new‐onset tuberculous infection will progress rapidly to clinically significant disease and the probability that latent tuberculous infection will reactivate is enormously increased. The accelerating and amplifying influence of HIV infection is also contributing to the increasing incidence of disease caused by multidrug‐resistant strains of M. tuberculosis. Neither clinical nor radiographic features reliably distinguish the majority of patients with HIV‐associated tuberculosis from those who are non‐HIV‐infected. Some HIV‐infected patients, however, have atypical manifestations and are difficult to diagnose. Chemotherapy for 6 months with conventional antituberculosis drugs cures most patients, but many died during or after treatment of other AIDS‐related complications. HIV is contributing heavily to the worldwide increase in tuberculosis. There is also mounting evidence that tuberculosis accelerates the course of co‐existing HIV disease.

Hemodynamic effects of two beta-adrenergic blocking drugs in anesthetized intact dogs☆

Abstract The hemodynamic effects of two beta-blocking drugs were evaluated in intact dogs anesthetized with chloralose-urethane. Nethalide (5 mg. per kilogram intravenously in 15 minutes) significantly increased cardiac output, heart rate, and stroke volume, and decreased end-systolic volume/end-diastolic volume ratio and systemic vascular resistance. The decrease in calculated end-systolic force per unit of end-systolic circumference suggests a negative inotropic effect. The preponderant effect of the drug was arterial dilatation, which cannot be explained by beta-adrenergic blockade. Better ventricular emptying was probably secondary to decreased afterload, since end-diastolic volume did not change. The chief site of activity of propranolol (0.5 mg. per kilogram intravenously in 5 minutes) was on the myocardium; left ventricular end-diastolic pressure increased without a change in end-diastolic volume, which indicates that diastolic distensibility was reduced. In addition, mean circumferential shortening velocity decreased, which suggests a negative inotropic effect; end-diastolic volume and stroke work were unchanged, and end-systolic force per unit of end-systolic circumference increased. The latter is perhaps due to an increased contribution of elasticity to end-systolic tension. We do not know whether these results are due to inhibition of beta-adrenergic activity or to direct effects on the myocardium.

Epidemiology of human immunodeficiency virus-associated pulmonary disease.

HIV/AIDS was initially characterized as a progressively worsening disorder of cellular immunosuppression. In 1996, HIV/AIDS was separated into 2 diagnostic, management, prognostic categories: high-income and low-income groups. High-income people with HIV have had access to antiretroviral therapeutic agents, which have transformed HIV from a lethal to an indolent disease, with life expectancy comparable with other chronic conditions. About 50% of low-income people with HIV who are candidates for antiretroviral therapy actually receive it. Since 1996, the principal HIV-associated pulmonary disease in high-income countries has changed from Pneumocystis pneumonia to community-acquired pneumonia; tuberculosis has predominated in low-income countries as long as HIV has prevailed.

Treatment of Tuberculosis. A Historical Perspective

Of all achievements in medicine, the successful treatment of tuberculosis has had one of the greatest impacts on society. Tuberculosis was a leading cause of disease and a mortal enemy of humanity for millennia. The first step in finding a cure was the discovery of the cause of tuberculosis by Robert Koch in 1882. The sanatorium movement that began shortly afterward in Europe, and soon spread to the United States, brought attention to the plight of afflicted persons, and catalyzed public health action. The antituberculosis benefit of streptomycin was announced in 1945, although application was limited by the rapid development of resistance. para-Aminosalicylic acid, also discovered in 1945, when combined with streptomycin was found to greatly reduce the occurrence of drug resistance. In 1952, isoniazid opened the modern era of treatment; it was inexpensive, well tolerated, and safe. In the early 1960s, ethambutol was shown to be effective and better tolerated than para-aminosalicylic acid, which it replaced. In the 1970s, rifampin found its place as a keystone in the therapy of tuberculosis. The use of rifampin enabled the course of treatment to be reduced to nine months. Incorporation of pyrazinamide into the first-line regimen led to a further reduction of treatment duration to six months. Treatment of multiple drug-resistant tuberculosis remains a difficult problem requiring lengthy treatment with toxic drugs. However, shortened regimens show promise, and two new drugs, bedaquiline and delamanid, have demonstrated effectiveness in preliminary studies and are being used for extensively drug-resistant tuberculosis.