Roberta M. Goldring

Survival in Patients with Primary Pulmonary Hypertension: Results from a National Prospective Registry

OBJECTIVE To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. DESIGN Registry with prospective follow-up. SETTING Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. PATIENTS Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. MEASUREMENTS At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. MAIN RESULTS The estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. CONCLUSIONS Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.

Primary pulmonary hypertension. A national prospective study.

A national registry was begun in 1981 to collect data from 32 centers on patients diagnosed by uniform criteria as having primary pulmonary hypertension. Entered into the registry were 187 patients with a mean age (+/- SD) of 36 +/- 15 years (range, 1 to 81), and a female-to-male ratio of 1.7:1 overall. The mean interval from onset of symptoms to diagnosis was 2 years. The most frequent presenting symptoms included dyspnea (60%), fatigue (19%), and syncope (or near syncope) (13%). Raynaud phenomenon was present in 10% (95% of whom were female) and a positive antinuclear antibody test, in 29% (69% female). Pulmonary function studies showed mild restriction (forced vital capacity [FVC], 82% of predicted) with a reduced diffusing capacity for carbon monoxide (DLCO), and hypoxemia with hypocapnia. The mean (+/- SD) right atrial pressure was 9.7 +/- 6 mm Hg; mean pulmonary artery pressure, 60 +/- 18 mm Hg; cardiac index, 2.3 +/- 0.9 L/min X m2; and pulmonary vascular resistance index, 26 +/- 14 mm Hg/L/min X m2 for the group. Although no deaths or sustained morbid events occurred during the diagnostic evaluation of the patients, the typically long interval from initial symptoms to diagnosis emphasizes the need to develop strategies to make the diagnosis earlier.

Hermansky-Pudlak syndrome. Pulmonary manifestations of a ceroid storage disorder.

The Hermansky-Pudlak syndrome is a form of oculocutaneous albinism, characterized by a qualitative platelet defect and deposition of ceroid-like material throughout the reticuloendothelial system. During a 16 month period five patients with Hermansky-Pudlak syndrome presented with symptoms, chest films and pulmonary function studies consistent with restrictive pulmonary disease. In two patients, lung biopsies revealed diffuse interstitial fibrosis. However, light and electron microscopy demonstrated ceroid-like material within alveolar macrophages. In addition, two patients presented with inflammatory bowel disease with deposition of ceroid-like material in the colon. This disorder appears to be more common than is currently recognized and should be considered in the differential diagnosis of diffuse interstitial pulmonary disease and inflammatory bowel disease. A relationship between the deposition of ceroid-like material and pulmonary fibrosis is discussed in light of recent research concerning inflammatory processes. In view of the serious pulmonary, gastrointestinal and hematologic consequences of this syndrome, there is a need for genetic counseling of these patients.

Role of circulatory congestion in the cardiorespiratory failure of obesity

The role of circulatory congestion in the cardiorespiratory dysfunction of massive obesity was investigated in 18 patients. They were hypervolemic and had increased cardiac outputs proportionate to their weight. The average resting left ventricular filling pressure was within the upper limits of normal, but it increased to abnormally high levels with increased venous return of passive leg raising, and further during exercise. The elevations in pressure were associated with high resting central blood volumes which increased significantly with exertion. These findings are consistent with reduced distensibility of the central circulation in these congested patients. Weight reduction was accompanied by a decrease in central blood volumes and restoration of a normal left ventricular response in three of four patients and a return toward normal in one. The improvement in ventricular function with relief of edema and dyspnea. In 14 patients with normal or only minimal alveolar hypoventilation, there were no significant transpulmonary diastolic pressure gradients despite a marked increase in left ventricular end-diastolic pressures. One patient, after regaining weight, subsequently had an abnormal gas exchange and an increased pulmonary vascular resistance. He and two others with severe alveolar hypoventilation demonstrated cor pulmonale on a background of left ventricular dysfunction and congestion of the circulation. Two other patients, the least obese of the group, had hypoventilation and cor pulmonale with normal left ventricular pressures. Hypervolemia and a hyperdynamic state are common features of the obese patients. High cardiac output is maintained despite marked circulatory congestion which may result in generalized anasarca and increased ventricular filling pressures. This clinical syndrome may be present in obese patients without intrinsic heart disease and may be reversible with weight reduction. The central circulatory congestion may contribute to the development of the alveolar hypoventilation syndrome in certain obese patients.

Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation

BackgroundThe lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils.ResultsBAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, α, or β diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022).ConclusionA pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.

Combined ventilator and bicarbonate strategy in the management of status asthmaticus

Management of intubated hypercapnic asthmatic patients requires a delicate balance between the control of pH with adequate ventilation and the risk of barotrauma associated with the high pressures that may be required. The present report documents a strategy of mechanical ventilation combined with infusion of large amounts of bicarbonate in three patients with severe status asthmaticus requiring intubation. This strategy reduced peak inflation pressure by decreasing ventilation and maintained a physiologic pH while allowing pCO2 to remain elevated.

Obstructive Airways Disease With Air Trapping Among Firefighters Exposed to World Trade Center Dust

BACKGROUND The World Trade Center (WTC) collapse produced a massive exposure to respirable particulates in New York City Fire Department (FDNY) rescue workers. This group had spirometry examinations pre-September 11, 2001, and post-September 11, 2001, demonstrating declines in lung function with parallel declines in FEV(1) and FVC. To date, the underlying pathophysiologic cause for this has been open to question. METHODS Of 13,234 participants in the FDNY-WTC Monitoring Program, 1,720 (13%) were referred for pulmonary subspecialty evaluation at a single institution. Evaluation included 919 full pulmonary function tests, 1,219 methacholine challenge tests, and 982 high-resolution chest CT scans. RESULTS At pulmonary evaluation (median 34 months post-September 11, 2001), median values were FEV(1) 93% predicted (interquartile range [IQR], 83%-101%), FVC 98% predicted (IQR, 89%-106%), and FEV(1)/FVC 0.78 (IQR, 0.72-0.82). The residual volume (RV) was 123% predicted (IQR, 106%-147%) with nearly all participants having normal total lung capacity, functional residual capacity, and diffusing capacity of carbon monoxide. Also, 1,051/1,720 (59%) had obstructive airways disease based on at least one of the following: FEV(1)/FVC, bronchodilator responsiveness, hyperreactivity, or elevated RV. After adjusting for age, gender, race, height and weight, and tobacco use, the decline in FEV(1) post-September 11, 2001, was significantly correlated with increased RV percent predicted (P < .0001), increased bronchodilator responsiveness (P < .0001), and increased hyperreactivity (P = .0056). CT scans demonstrated bronchial wall thickening that was significantly associated with the decline in FEV(1) post-September 11, 2001 (P = .024), increases in hyperreactivity (P < .0001), and increases in RV (P < .0001). Few had evidence for interstitial disease. CONCLUSIONS Airways obstruction was the predominant physiologic finding underlying the reduction in lung function post-September 11, 2001, in FDNY WTC rescue workers presenting for pulmonary evaluation.

Respiratory adjustment to chronic metabolic alkalosis in man

This study examined the ventilatory adjustment to chronic metabolic alkalosis induced under controlled conditions in normal human volunteers. Metabolic alkalosis induced by buffers (sodium bicarbonate, trishydroxymethylamine methane) or ethacrynic acid was associated with alveolar hypoventilation, as evidenced by a rise in arterial Pco(2), a fall in arterial Po(2), a reduced resting tidal volume, and a diminished ventilatory response to CO(2) inhalation. Alveolar hypoventilation did not occur when metabolic alkalosis was induced in the same subjects by thiazide diuretics or aldosterone despite comparable elevations of the arterial blood pH and bicarbonate concentration.The different ventilatory responses of the two groups could not be ascribed to differences among individuals comprising each group, pharmacological effects of the alkalinizing agents, differences in the composition of the lumber spinal fluid, changes in extracellular fluid volume, or sodium and chloride balance.The differences in ventilatory adjustments were associated with differences in the patterns of hydrogen and potassium ion balance during the induction of alkalosis. Alveolar hypoventilation occurred when hydrogen ions were buffered (sodium bicarbonate, trishydroxymethylamine methane) or when renal hydrogen ion excretion was increased (ethacrynic acid). Alveolar hypoventilation did not occur when induction of similar degrees of extracellular alkalosis was accompanied by marked potassium loss and no demonstrable increase in external hydrogen loss (thiazides and aldosterone).These observations suggest that respiratory depression does not necessarily accompany extracellular alkalosis but depends on the effect of the mode of induction of the alkalosis on the tissues involved in the control of ventilation.

Case–Control Study of Lung Function in World Trade Center Health Registry Area Residents and Workers

RATIONALE Residents and area workers who inhaled dust and fumes from the World Trade Center disaster reported lower respiratory symptoms in two World Trade Center Health Registry surveys (2003-2004 and 2006-2007), but lung function data were lacking. OBJECTIVES To examine the relationship between persistent respiratory symptoms and pulmonary function in a nested case-control study of exposed adult residents and area workers 7-8 years after September 11, 2001. METHODS Registrants reporting post September 11th onset of a lower respiratory symptom in the first survey and the same symptom in the second survey were solicited as potential cases. Registrants without lower respiratory symptoms in either Registry survey were solicited as potential control subjects. Final case-control status was determined by lower respiratory symptoms at a third interview (the study), when spirometry and impulse oscillometry were also performed. MEASUREMENTS AND MAIN RESULTS We identified 180 cases and 473 control subjects. Cases were more likely than control subjects to have abnormal spirometry (19% vs. 11%; P < 0.05), and impulse oscillometry measurements of elevated airway resistance (R5; 68% vs. 27%; P < 0.0001) and frequency dependence of resistance (R₅₋₂₀; 36% vs. 7%; P < 0.0001). When spirometry was normal, cases were more likely than control subjects to have elevated R₅ and R₅₋₂₀ (62% vs. 25% and 27% vs. 6%, respectively; both P < 0.0001). Associations between symptoms and oscillometry held when factors significant in bivariate comparisons (body mass index, spirometry, and exposures) were analyzed using logistic regression. CONCLUSIONS This study links persistent respiratory symptoms and oscillometric abnormalities in World Trade Center-exposed residents and area workers. Elevated R₅ and R₅₋₂₀ in cases despite normal spirometry suggested distal airway dysfunction as a mechanism for symptoms.

Respiratory-renal adjustments in chronic hypercapnia in man: Extracellular bicarbonate concentration and the regulation of ventilation

Abstract In patients with stable mechanical ventilatory limitation and chronic hypercapnia, chloride depletion by administration of diuretics leads to elevations in extracellular bicarbonate levels which are inordinate for the carbon dioxide tension (PaCO 2 ). Chloride replacement returns this bicarbonate-PaCo 2 relationship o a predicted level. Ammonium chloride induces an inordinate reduction in extracellular bicarbonate concentrations for the levels of PaCO 2 in arterial blood. The ventilatory responsiveness to inhalation of 5 per cent carbon dioxide following these interventions is related exponentially to the extracellular bicarbonate concentration and not to the level of extracellular hydrogen ion activity measured prior to carbon dioxide inhalation. However, the increase in ventilation per unit increment in extracellular hydrogen ion activity induced by carbon dioxide inhalation (ΔVEΔH+) is constant. This suggests that the extracellular bicarbonate concentration acts to modulate the ventilatory response to stimulation with carbon dioxide whereas the changes in hydrogen ion activity during carbon dioxide inhalation act as the determinants of the ventilatory response to inhaled carbon dioxide.