Biomedical subjects
Publications and source records attributed to D R Dantzker.
The hypoxemia of ARDS may result from numerous and varied stresses to the system responsible for gas exchange in the lung. These may be both pulmonary and non-pulmonary in origin. A thorough understanding of all the factors involved is necessary to correctly interpret and treat these complex and critically ill patients.
We have found markedly nonuniform partitioning of flow in idealized models of physiological cascades of branches. Liquids having viscosities of 0.8-7.0 cP were used to investigate this effect systematically in a regime characterizing a limited range of pulmonary flows, comprising inlet flow rates of 500-3,000 ml/min and branch diameters of 1.0 cm ID. Factors that affect the nonuniformity of inspiratory flow include inlet velocity profile and flow rate, cascade aspect (L/D) ratio, exit pressure distribution, and, to a lesser extent, kinematic viscosity (mu/rho). More qualitative observations using sinusoidally oscillating airflow revealed inspiratory and expiratory flow patterns to be quite dissimilar, emphasizing the inadequacy of a resistance model of flow partitioning based on Kirchhoff's law. These results might suggest, in part, why regional ventilation in man is flow or frequency dependent and how bronchial smooth muscle could fine tune regional ventilation.
We have studied the influence of pulmonary vascular tone on ventilation-perfusion relationships in subjects with chronic obliterative pulmonary vascular disease. We administered oxygen, isoproterenol, or nitroprusside on 15 occasions in 7 subjects and observed a fall in pulmonary vascular resistance of greater than 15% in 8 of these 15 trials. When pulmonary vascular resistance was reduced, there was an increase in the perfusion of lung units with low ventilation-perfusion ratios (VA/Q) and/or shunt as determined by the multiple inert gas technique. The pattern of increased VA/Q inequality was independent of the specific agent used. In only one instance in which pulmonary vascular resistance was not reduced did drug administration lead to a worsening of VA/Q relationships. The detrimental effect of the increased perfusion of low VA/Q units on arterial oxygenation was frequently attenuated by an increased mixed venous oxygen content due to an increase in total cardiac output. We conclude that pulmonary vascular tone contributes to the maintenance of VA/Q matching in subjects with obstruction of the pulmonary vascular bed.
Vasodilators including isoproterenol, nitroprusside, nitroglycerin, and oxygen were administered to 5 patients with chronic pulmonary hypertension secondary to pulmonary embolism. The patients' mean pulmonary artery pressure was 54 +/- 8 mmHg, and their average total pulmonary resistance (TRP) was 17 +/- 11 mmHg/L/min. Each patient experienced a decrease in TRP in response to at least 1 of the vasodilators, and the mean maximal decrease was to 57 +/- 10% of the baseline value. Although these decrements in TRP were accompanied by an increase in cardiac output in all but 1 patient, changes in PAP were variable. Treatment with nitroglycerin was continued in 3 of the 5 patients and all 3 have reported improvement in their exercise tolerance. We conclude that the elevated TPR seen in patients with chronic embolic pulmonary hypertension is due to increased vascular tone in addition to fixed vascular obstruction.
Methacholine challenge testing was performed in 20 patients with pulmonary sarcoidosis and 13 normal control subjects. Increased methacholine responsiveness was demonstrated in 10 of 20 patients with sarcoidosis. Sarcoidosis patients with increased reactivity differed from those with normal reactivity in that they had more airway obstruction, smaller vital capacities, and lower single breath diffusing capacities for carbon monoxide. Responders tended to be more symptomatic with wheezing and cough and to have a longer duration of disease, although these differences did not reach statistical significance.
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Sarcoidosis involving the larynx presents with hoarseness, cough, dysphagia, and dyspnea secondary to upper airway obstruction. it may occur in patients with previously diagnosed sarcoidosis, or it may be the first or the only manifestation of the disease. Laryngoscopy reveals mucosal alterations including erythema and edema, punctate nodules, and mass lesions. The epiglottis is the most frequently affected area, but any portion of the larynx may be involved. The diagnosis is established by demonstrating granulomatous inflammation on laryngeal biopsy and excluding other causes of granulomatous laryngitis. Systemic corticosteroid therapy is the treatment of choice in most cases, but local steroid injection or surgical excision of affected areas may be useful in selected patients. Symptomatic laryngeal sarcoidosis can be managed successfully, but if it is left untreated, life-threatening upper airway obstruction may occur.
The relationship between delivery and uptake of O2 was evaluated in 20 patients with the adult respiratory distress syndrome (ARDS). Eleven patients were studied acutely, after progressive increments in positive end-expiratory pressure. The remaining 9 patients underwent serial determinations of gas exchange and O2 uptake during several days, because O2 delivery varied secondary to changes in clinical status or therapeutic interventions. In all but one patients, decreasing delivery of O2 led to similar decreases in uptake of O2. In general, changes in mixed-venous PO2 were variable and had no consistent relation to cardiac output or O2 delivery. In a contrasting group of 12 patients without ARDS, delivery and uptake of O2 were not related, and mixed-venous PO2 correlated well with cardiac output. We conclude that in patients with ARDS, there is a direct relationshipl between delivery of O2 and uptake of O2. Changes in mixed-venous PO2 may not reflect changes in O2 delivery, cardiac output, or the adequacy of tissue oxygenation. Failure to recognize this may lead to inappropriate evaluation of the clinical status of the patient or the efficacy of therapy.
The relationship between changes in cardiac output and intrapulmonary shunt associated with mechanical ventilation was evaluated in 20 patients with the adult respiratory distress syndrome (ARDS). The distribution of ventilation-perfusion (VA/Q) ratios and the level of intrapulmonary shunt was determined by the multiple inert gas technique. Pulmonary blood flow was distributed predominantly to either effective gas-exchanging units or shunt units. Positive end-expiratory pressure (PEEP) or high tidal volume ventilation led to decreases in shunt and cardiac output without altering the overall pattern of VA/Q distributions. Changes in shunt and cardiac output were quantitatively and qualitatively silimar and a strong correlation was found between changes in shunt and cardiac output with both PEEP and high tidal volumes (r = 0.76). Cardiac output depression associated with tese modes of ventilation appears to be a mechanism of shunt reduction in ARDS. Interpretation of improvements in gas exchange in ARDS must take into account concomitant hemodynamic changes.
A case of idiopathic pulmonary hypertension is associated with portal venous thrombosis. The patient's chest roentgenogram revealed numerous nodular densities which at necropsy were found to have been caused by an exuberant fibroblastic reaction around small pulmonary arterioles. This is an example of the unusual association of idiopathic pulmonary hypertension and portal venous thrombosis, and to our knowledge, the first report of roentgenographically visible pulmonary nodules secondary to the pathologic alterations of idiopathic pulmonary hypertension.
A chest bruit and evidence of pulmonary hypertension developed in a woman with sarcoidosis. A perfusion lung scan revealed decreased perfusion to the right upper lobe and to the entire left lung, while a ventilation scan was normal. Pulmonary angiography demonstrated multiple bilateral concentric pulmonary artery stenoses most consistent with extrinsic compression by mediastinal granulomatous inflammation and fibrosis. The patient was treated with systemic corticosteroids for one year without improvement. Major pulmonary artery stenosis should be considered in patients with sarcoidosis who developed pulmonary hypertension and are found to have lung scans showing segmental perfusion defects in normally ventilated areas or who develop an unexplained chest bruit.
The effect of changing cardiac output on intrapulmonary shunt was studied in the setting of hemorrhagic pulmonary edema induced by intravenous oleic acid in 17 alpha-chloralose-anesthetized dogs. The dogs were mechanically ventilated and cardiac output was alternately depressed and augmented using either pharmacologic means or mechanical alteration of venous return. Following oleic acid, the measured ventilation-perfusion distributions, as measured by the multiple inert gas elimination technique, demonstrated a two-compartment blood flow distribution consisting of shunt and normal units. Changes in cardiac output were not associated with change in the shape of the distributions but there was a significant linear correlation between the level of cardiac output and the shunt fraction. The shunt fraction also varied directly with the mixed venous partial oxygen pressure and inversely with the pulmonary vascular resistance. These data suggest that shunt and nonshunt vessels behave differently in response to alterations of blood flow and emphasize that any interpretation of changes in shunt in the setting of diffuse lung injury must be interpreted in light of changes in cardiac output.
The distribution of ventilation-perfusion ratios, as determined by the multiple inert gas elimination technique, was measured in 16 patients with the adult respiratory distress syndrome. In each case, the distribution of ventilation-perfusion ratios was bimodal. The upper mode consisted of units with normal ventilation-perfusion ratios that received a mean of 52% of the cardiac output. The lower mode, which received the remainder of the cardiac output, consisted of either pure shunt or shunt plus a small number of units with very low ventilation-perfusion ratios (less than 0.01). The measured arterial PO2 and that predicted from the distribution of ventilation-perfusion ratios were very closely correlated (r = 0.93), indicating that the hypoxemia was completely explained by the measured ventilation-perfusion inequality. In 12 patients, the effect of positive end-expiratory pressure on the distribution of ventilation-perfusion ratios was also determined. The addition of positive end-expiratory pressure uniformly resulted in a decrease in blood flow to the lower mode and an increase in the ventilation of unperfused alveoli. Increasing positive end-expiratory pressure also led to a uniform decrease in cardiac output. We conclude that the hypoxemia of the adult respiratory distress syndrome is caused by the presence of shunt or units of very low ratio of ventilation to perfusion and that positive end-expiratory pressure increases the arterial PO2 by decreasing the perfusion of unventilated lung. The mechanism of this decrease is yet to be defined.
We have examined the mechanisms of abnormal gas exchange in seven patients with chronic obliteration of the pulmonary vascular bed secondary to recurrent pulmonary emboli or idiopathic pulmonary hypertension. All of the patients had a widened alveolar-arterial oxygen gradient and four were significantly hypoxemic with arterial partial presssures of oxygen less than 80 torr. Using the technique of multiple inert gas elimination, we found that ventilation-perfusion (VA/Q) relationships were only minimally abnormal with a mean of 10% (range, 2--19%) of cardiac output perfusing abnormal units. These units consisted of shunt and units with VA/Q ratios less than 0.1. In addition, the dead space was found to be normal in each patient. There was no evidence for diffusion impairment, and the widened alveolar-arterial oxygen gradient was completely explained by VA/ inequality. Significant hypoxemia occurred only when VA/Q inequality was combined with a low mixed venous oxygen content.
Gas exchange following experimental pulmonary thromboembolization was studied with an inert gas elimination technique in 17 dogs. Pulmonary arterial, systemic arterial, and expired gas concentrations of six gases infused intravenously were measured before embolization and 5, 10, 15, 30, 60, and 120 minutes after embolization. Distributions of ventilation-perfusion (VA/Q) ratios were derived from the measured concentrations. In all dogs, embolization caused an increase in blood flow and ventilation to VA/Q ratios less than 1. There were no lung units with VA/Q ratios between 10 and 100 before embolization, but, in two-thirds of the dogs, such regions developed after embolization. Ventilation to unperfused lung showed a transient increase of 2-6%. Radioisotope studies of lobes removed post-mortem indicated that thromboemboli rarely caused complete abolition of lobar blood flow. Pulmonary embolization did not cause arteriovenous shunts to appear. The hypoxemia caused by embolization could be accounted for by the changes in VA/Q distributions. Over the 2-hour period after embolization, lung function improved as the distributions partially returned toward the preembolization patterns.
Ventilation-perfusion (Va/Q) inequality was measured by a multiple inert gas elimination method in 6 asymptomatic patients with asthma and in a seventh patient during a severe asthmatic episode. Measurements were made before and at 5-min intervals after administration of aerosolized isoproterenol. All patients had some residual airway obstruction as measured during forced expirations. All except one patient had clearly bimodal distributions of Va/Q ratios during all phases of the study, as confirmed by an extensive exploration of distributions compatible with each set of inert gas data. One mode lay within the normal range of Va/Q, but the other, containing 19.8 per cent of the cardiac output on the average, was centered on a Va/Q ratio of only 0.07. There was essentially no shunt. Five min after the administration of isoproterenol, the blood flow to the low Va/Q mode approximately doubled, accounting for the observed decrease in arterial PO2. Breathing 100 per cent O2 had little effect on the distribution. The presence of a bimodal distribution of Va/Q ratios without shunt suggests that collateral ventilation may be an important mechanism determining the distribution of Va/Q ratios and preventing the development of shunts. This study also showed that in some asymptomatic asthmatic patients, as many as one half of the lung units may lie behind completely closed airways and have very low but finite Va/Q ratios as a result of collateral ventilation.
A multiple inert gas elimination method was used to study the mechanism of impaired gas exchange in 23 patients with advanced chronic obstructive pulmonary disease (COPD). Three patterns of ventilation-perfusion (Va/Q) inequality were found: (a) A pattern with considerable regions of high (greater than 3) VA/Q, none of low (less than 0.1) VA/Q, and essentially no shunt. Almost all patients with type A COPD showed this pattern, and it was also seen in some patients with type B. (b) A pattern with large amounts of low but almost none of high VA/Q, and essentially no shunt. This pattern was found in 4 of 12 type B patients and 1 of type A. (c) A pattern with both low and high VA/Q areas was found in the remaining 6 patients. Distributions with high VA/Q areas occurred mostly in patients with greatly increased compliance and may represent loss of blood-glow due to alveolar wall destruction. Similarly, well-defined modes of low VA/Q areas were seen mostly in patients with severe cough and sputum and may be due to reduced ventilation secondary to mechanical airways obstruction or distortion. There was little change in the VA/Q distributions on exercise or on breathing 100% O2. The observed patterns of VA/Q inequality and shunt accounted for all of the hypoxemia at rest and during exercise. There was therefore no evidence for hypoxemia caused by diffusion impairment. Patients with similar arterial blood gases often had dissimilar VA/Q patterns. As a consequence the pattern of VA/Q inequality could not necessarily be inferred from the arterial PO2 and PCO2.
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