CPAP reduces inspiratory work more than dyspnea during hyperinflation with intrinsic PEEP.

Hyperinflation with intrinsic positive end-expiratory pressure (PEEPi) loads the respiratory muscles and causes dyspnea in obstructive lung disease. Continuous positive airway pressure (CPAP) has shown some efficacy in reducing inspiratory work and dyspnea. However, in obstructive lung disease, inspiratory work and dyspnea may be increased by additional factors that may not be affected by CPAP. Therefore, to study the effects of hyperinflation with intrinsic PEEP and CPAP in isolation, we used a mechanical analog of airway closure to increase end-expiratory lung volume in normal subjects. In five subjects in whom inspiratory work was measured, increasing end-expiratory lung volume by 1 and 2 L increased inspiratory work per breath from 0.42 +/- 0.04 J to 1.17 +/- 0.15 J (p < 0.05 compared with baseline) and 1.58 +/- 0.22 J (p < 0.05 compared with baseline and to the lesser level of hyperinflation). Although CPAP reduced work per breath and per minute to levels not significantly different from baseline, it had little effect on dyspnea. In ten subjects hyperinflated to 2.4 +/- 0.12 L above FRC, breathing could be sustained 19.5 +/- 4.5 min before quitting the load. This was increased to 26.7 +/- 5.2 min by 10 cm H2O CPAP (p = 0.052). Inspiratory dyspnea was modestly reduced by CPAP during these endurance trials. We conclude that CPAP can substantially ameliorate the respiratory work load induced by hyperinflation with intrinsic PEEP. However, the effects of CPAP on dyspnea and endurance are more limited. This suggests that the limits to breathing at high lung volumes are related to factors in addition to respiratory muscle work, and that CPAP may be of more value in reducing the work than in relieving the distress of obstructive lung disease.

Low efficiency of oxygen utilization during exercise in hyperthyroidism.

STUDY OBJECTIVE: The mechanism of exercise intolerance in hyperthyroidism has not been fully elucidated. This study was undertaken to determine if hyperthyroidism reduced the efficiency of sub-maximal exercise. STUDY DESIGN: We measured cardiorespiratory variables up to the anaerobic threshold (AT) during ramp-loading cycle ergometry in 12 patients (New York Heart Association functional class II or III). Studies were performed in the hyperthyroid state and repeated in the euthyroid state after 10 months of medical treatment. In 10-W steps from rest to the AT, we measured oxygen uptake (VO2) as a measure of total body work rate, and pressure rate product (PRP) as a measure of cardiac work rate. Loading watts at AT divided by the increment of Vo2 from rest to the AT (delta Watt/delta VO2) was calculated as an index of work efficiency (where delta means the increment of each value from rest to the AT). RESULTS: VO2 and PRP at the AT were not significantly different between hyperthyroid and euthyroid states (VO2, 16.6 +/- 3.0 vs 17.5 +/- 2.3 mL/min/kg; PRP, 229 +/- 41 vs 218 +/- 28 x 10(2) mm Hg/min). However, loading watts at the AT were significantly lower in the hyperthyroid than the euthyroid state (28 +/- 22 vs 60 +/- 14 W: p < 0.01). VO2 and PRP while hyperthyroid were significantly higher than when euthyroid at every 10-W step during ramp-loading exercise. Furthermore, delta Watt/delta VO2 was significantly lower in hyperthyroid than euthyroid states (p < 0.001). There was a significant inverse correlation-ship between triiodothyronine and delta Watt/delta Vo2 (r = -0.654, p < 0.001). CONCLUSION: Hyperthyroidism causes low work efficiency, which may limit exercise tolerance.

Hyperinflation with intrinsic PEEP and respiratory muscle blood flow.

Increased end-expiratory lung volume and intrinsic positive end-expiratory pressure (PEEP) are common in obstructive lung disease, especially during exacerbations or exercise. This loads the respiratory muscles and may also stress the circulatory system, causing a reduction or redistribution of cardiac output. We measured the blood flow to respiratory muscles and systemic organs using colored microspheres in 10 spontaneously breathing anesthetized tracheotomized dogs. Flows during baseline breathing (BL) were compared with those during hyperinflation (HI) induced by a mechanical analogue of airway closure and with those during an inspiratory resistive load (IR) that produced an equivalent increase in inspiratory work and time-integrated transdiaphragmatic pressure. Cardiac output was unchanged during IR (3.19 +/- 0.27 l/min at BL, 3.09 +/- 0.34 l/min during IR) but was reduced during HI (2.14 +/- 0.29 l/min; P < 0.01). Among the organs studied, flow was unaltered by IR but decreased to the liver and pancreas and increased to the brain during HI. For the respiratory muscles, flow to the diaphragm increased during IR. However, despite a 1.9-fold increase in inspiratory work per minute and a 2.5-fold increase in integrated transdiaphragmatic pressure during HI, blood flow to the diaphragm was unchanged and flow to the scalenes and sternomastoid fell. The only respiratory muscle to which flow increased during HI was the transversus abdominis, an expiratory muscle. We conclude that the circulatory effects of hyperinflation in this model impair inspiratory muscle perfusion and speculate that this may contribute to respiratory muscle dysfunction in hyperinflated states.

Effects of systolic and diastolic positive pleural pressure pulses with altered cardiac contractility.

Positive pleural pressure (Ppl) decreases left ventricular afterload and preload. The resulting change in cardiac output (CO) in response to these altered loading conditions varies with the baseline level of cardiac contractility. In an isolated canine heart-lung preparation, we studied the effects of positive Ppl applied phasically during systole or diastole on CO and on the cardiac function curve (the relationship between CO and left atrial transmural pressure). When baseline cardiac contractility was enhanced by epinephrine infusion, systolic and diastolic positive Ppl decreased CO equally (1,931 +/- 131 to 1,419 +/- 124 and 1,970 +/- 139 to 1,468 +/- 139 ml/min, P less than 0.01) and decreased the pressure gradient driving venous return. However, neither shifted the position of the cardiac function curve, suggesting that the predominant effect of positive Ppl was decreased preload. When baseline cardiac contractility was depressed by severe respiratory acidosis, diastolic positive Ppl pulses caused no significant change in CO (418 +/- 66 to 386 +/- 52 ml/min), the cardiac function curve, or the pressure gradient for venous return. However, systolic positive Ppl pulses increased CO from 415 +/- 70 to 483 +/- 65 ml/min (P less than 0.01) and significantly shifted the cardiac function curve to the left. Thus the effect of Ppl pulsations on CO works through different mechanisms, depending on the state of cardiac contractility.

Mechanism of reduced LV afterload by systolic and diastolic positive pleural pressure.

To investigate the mechanism by which increased pleural pressure (Ppl) assists left ventricular (LV) ejection, we compared the effects of phasic systolic or diastolic increases in Ppl (40-60 mmHg) with use of an isolated canine heart-lung preparation with constant venous return. Positive Ppl during systole (S) caused left atrial transmural pressure (Platm = Pla - Ppl) to decrease by 1.25 +/- 0.46 (SE) mmHg (P less than 0.025). Central blood volume (CBV), the volume of blood in the heart, lungs, and thoracic great vessels, decreased by 29 +/- 4.0 (SE) ml (P less than 0.001). When Ppl was raised for an equal duration during diastole (D), the decrease in Platm was not significant, but there was a significant decrease in CBV (10.5 +/- 4.1 ml, P less than 0.05). With constant venous return, these changes suggested that phasic elevations in Ppl in either S or D assisted LV ejection by decreasing LV afterload. To test the hypothesis that positive Ppl during D reduced afterload by emptying the thoracic aorta, we compared the effects of diastolic positive Ppl with a rigid aorta vs. a compliant aorta. Although there was no statistical difference in the effects of diastolic positive Ppl on Platm, the decrease in CBV was significantly greater when the aorta was compliant than when it was rigid (23 +/- 2.2 vs. 17 +/- 2.7 ml, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Urethan anesthesia protects rats against lethal endotoxemia and reduces TNF-alpha release.

Urethan is a commonly used animal anesthetic for nonrecovery laboratory surgery. However, urethan has diverse biological effects that may complicate the interpretation of experimental findings. This study examined the effect of urethan on the response to an intravenous bolus of lipopolysaccharide (LPS; 30 mg/kg) in rats. In instrumented rats, urethan (1.2 gm/kg i.p.) completely prevented the fall in arterial pressure immediately after LPS administration but did not prevent late cardiovascular collapse. In uninstrumented rats, urethan also attenuated indexes of organ injury measured 4 h after LPS administration, including mural bowel hemorrhage, hemoconcentration, hypoglycemia, metabolic acidosis, and lung myeloperoxidase activity, a measure of neutrophil sequestration. The peak increase in tumor necrosis factor-alpha (TNF-alpha) 90 min after LPS administration was reduced 88% by urethan (2,060 +/- 316 vs. 16,934 +/- 847 pg/ml; P < 0.001). In uninstrumented animals, urethan at 1.2 gm/kg reduced the 90% mortality rate of a lethal dose of LPS to 0-10% when given up to 24 h before LPS administration but did not reduce mortality when given 2 h after LPS. Urethan neither directly bound LPS by Limulus assay nor inhibited LPS-stimulated TNF-alpha mRNA expression in cultured mouse peritoneal macrophages, but TNF-alpha mRNA expression was suppressed by serum from a urethan-treated rat. Moreover, rauwolscine, which shares alpha 2-adrenoceptor-blocking activity with urethan, also prevented death from a subsequent 90% lethal dose LPS bolus. We conclude that urethan or its metabolites protect against LPS, in part, by reducing TNF-alpha release and speculate that this may be mediated by alpha 2-adrenoceptors. These actions of urethan make it an undesirable anesthetic agent for in vivo studies of sepsis or LPS.

Effects of hyperinflation and CPAP on work of breathing and respiratory failure in dogs.

Increased end-expiratory lung volume (EELV) and airway resistance are both characteristic features of obstructive lung disease. Increased EELV alone loads the respiratory muscles and may cause respiratory failure, changes that could be reversed by continuous positive airway pressure (CPAP). To study the effects of elevated EELV on respiration without increased airway resistance, we used a mechanical analogue of airway closure to increase EELV in six spontaneously breathing anesthetized dogs. Hyperinflation of 0.84 +/- 0.11 liter for 30 min decreased minute ventilation from 4.8 +/- 0.37 to 3.5 +/- 0.21 l/min and increased arterial PCO2 from 40.3 +/- 1.5 to 73.2 +/- 8.1 Torr (both P < 0.01). Inspiratory work per breath increased 3-fold, work per liter increased 3.7-fold, and work per minute increased 2.8-fold (all P < 0.01). CPAP at 15 cmH2O restored minute ventilation to 4.3 +/- 0.3 l/min and reduced arterial PCO2 to 54 +/- 6.6 Torr (NS vs. baseline). All measurements of inspiratory work were also restored to baseline, but cardiac output was reduced (baseline 3.09 +/- 0.36, hyperinflation 2.71 +/- 0.36, hyperinflation + CPAP 1.94 +/- 0.29 l/min; P < 0.05, baseline vs. hyperinflation + CPAP). We conclude that increases in EELV mimic important features of airway obstruction, increase inspiratory work, and can cause respiratory failure independent of increased airway resistance. This respiratory failure is reversed by CPAP at the potential expense of hemodynamic compromise.

Mechanical ventilation in acute lung injury and acute respiratory distress syndrome.

Mechanical ventilation provides life-sustaining support for most patients with acute lung injury and acute respiratory distress syndrome; however, traditional approaches to mechanical ventilation may cause ventilator-associated lung injury, which could exacerbate or perpetuate respiratory failure caused initially by conditions such as pneumonia, sepsis, and trauma. This article reviews the theory, laboratory data, and results of recent clinical trials that suggest that modified ventilator strategies can reduce ventilator-associated lung injury and improve clinical outcomes.

Friction in femoral prosthesis and photoelastic model cone taper joints.

Static axial push-on and lift-off, and push-on and twist-off experiments were designed and performed to measure the effective, room-temperature coefficient of friction mu for different design femoral prosthesis cone taper joints comprising a universal head on a stem spigot. Alumina and metal heads were tested on metal spigots using either distilled water, Ringer's solution, blood or no lubricant. Complementary push-on and lift-off friction tests of Araldite model joints for subsequent frozen-stress, photoelastic stress analysis were performed at 130 degrees C. It was found that lubricant caused little decrease in the values of the coefficient of friction in prosthesis tapers. The values measured were typically mu = 0.2 for an alumina head on a Co-Cr-Mo or Ti-6Al-4V spigot, mu = 0.15 for a Co-Cr-Mo head on a Co-Cr-Mo or Ti-6Al-4V spigot and mu = 0.13 for a stainless steel head on a stainless steel spigot. For Araldite photoelastic models of an alumina head on a Vitallium spigot, as-cast taper surfaces lubricated with silicone grease gave consistent friction of typically mu = 0.14. The axial displacement of model heads on their spigots were compared with predicted values and previously measured values for prosthesis heads.

A study of stresses in alumina universal heads of femoral prostheses.

Three-dimensional, frozen-stress photoelasticity was used to study the best shape for a proposed alumina universal head loaded on to a Vitallium cone taper spigot with a 30 degrees inclined force, as in vivo. Typical cone taper friction values were reproduced in the photoelastic models. The location of the highest tensile stresses in the Mark I shape with a flat crown was found to be on the inner surface of the crown. Changing to a torispherical surface in the Mark II shape reduced this magnitude. However, the Mark III shape with a hemispherical inner crown surface gave even lower stress there, equal to the maximum value of the hoop stress at the taper, which was measured to be fairly uniform both around and along the taper except at the ends where contact pressure concentrations were found to occur and it became reduced. Lamé axisymmetric cylinder stress predictions were found to be useful approximations to measured values and were generally overestimates of the tensile hoop stress at the head taper surface.

Estimating pulmonary artery pressures by echocardiography in patients with emphysema.

In patients with emphysema being evaluated for lung volume reduction surgery, Doppler echocardiography has been used to screen for pulmonary hypertension as an indicator of increased peri-operative risk. To determine the accuracy of this test, the present authors compared the results of right heart catheterisations and Doppler echocardiograms in 163 patients participating in the cardiovascular substudy of the National Emphysema Treatment Trial. Substudy patients had both catheterisation and Doppler echocardiography performed before and after randomisation. In 74 paired catheterisations and echocardiograms carried out on 63 patients, the mean values of invasively measured pulmonary artery systolic pressures and the estimated right ventricular systolic pressures were similar. However, using the World Health Organization's definitions of pulmonary hypertension, echocardiography had a sensitivity of 60%, specificity of 74%, positive predictive value of 68% and a negative predictive value of 67% compared with the invasive measurement. Bland-Altman analysis revealed a bias of 0.37 kPa with 95% limits of agreement from -2.5-3.2 kPa. In patients with severe emphysema, echocardiographic estimates of pulmonary artery pressures correlate very weakly with right heart catheterisations, and the test characteristics (e.g. sensitivity, specificity, etc.) of echocardiographic assessments are poor.

Heart-lung interactions: applications in the critically ill.

Since the circulatory and pulmonary systems are both driven by pressure and share space in the thorax, it is inevitable that they interact. These mechanical interactions, whilst relatively few in number, are protean in their manifestations. The circulatory system of the critically ill is often particularly susceptible to interference from respiration. Compensatory reserve is limited, ventilatory effort increased, and many critical care respiratory interventions place strain on the circulation, not seen in health. This review will examine the basic physiological mechanisms through which the pulmonary and circulatory systems interact. These mechanisms will then be applied to a variety of weaning, positive end-expiratory pressure (PEEP), and cardiopulmonary resuscitation techniques. It is hoped that this will provide the tools to understand clinical observations which would otherwise appear inexplicable.

Accuracy of hemodynamic measurements during partial liquid ventilation with perflubron.

Patients undergoing partial liquid ventilation (PLV) are often monitored with pulmonary artery catheters and receive positive end-expiratory pressure (PEEP). PEEP can dissociate wedge pressure (Pcw) from transmural left atrial pressure (Platm) by elevating pleural pressure and can dissociate Pcw from Pla by elevating alveolar pressure, PLV, like PEEP, also elevates pleural and alveolar pressures. However, the artifacts PLV may cause in measured vascular pressures are unknown. In 6 anesthetized, paralyzed healthy adult sheep, we compared effects of gas ventilation (GV) and PLV with 10 and 30 ml/kg perflubron on pericardial pressure (Pperi), Pcw, Pla, thermodilution cardiac output, and pulmonary artery flow measured with a doppler probe. PEEP was applied from 0-15 mm Hg during GV and PLV. PLV changed pericardial pressure or cardiac output minimally (at PEEP(0), GV: Pperi = -1.7 +/- 0.6 mm Hg, CO = 3. 2 +/- 0.1 L/m; 10 ml/kg perflubron: Pperi = -1.3 +/- 0.6 mm Hg, CO = 3.4 +/- 0.2 L/m; 30 ml/kg perflubron: Pperi = -1.6 +/- 0.7 mm Hg, CO = 3.4 +/- 0.2 L/m; all mean +/- SEM). On PEEP, Pcw agreed with Pla and Platm as well or better during PLV as during gas ventilation. Cardiac output by thermodilution and probe agreed equally well under all conditions. We conclude that hemodynamic values are as accurate during PLV as during gas ventilation.

Lung volume reduction surgery and airflow limitation.

Interest has recently been renewed in lung volume reduction surgery (LVRS) for end-stage emphysema. However, numerous questions about its role in the treatment of emphysema remain, including the clinical characteristics of optimal candidates and its mechanism of improvement in pulmonary function. In this report, we develop a mathematical analysis and graphic depiction of the mechanism of improvement in expiratory airflow and vital capacity. This analysis is based on consideration of the interaction between lung function and respiratory muscle function. We also reexamine previously published pulmonary mechanics in patients with alpha1-antitrypsin deficiency, chronic obstructive pulmonary disease, and asthma. We find a major determinant of airflow limitation common to these diseases is the ratio of residual volume to total lung capacity (RV/TLC). Moreover, RV/TLC is found to be the single most important determinant of the improvement in pulmonary function after LVRS. Regardless of the specific underlying lung disease, the impairment of airflow is due primarily to mismatch between the sizes of the lung and the chest wall, and the effects of LVRS are almost exclusively due to improvement of that match. This analysis can be used to develop testable hypotheses to guide patient selection for this procedure.

Polystyrene microspheres decrease bronchial artery resistance in anesthetized sheep.

The use of microspheres to measure tissue blood flow requires that the microspheres themselves do not alter regional arterial tone. To determine whether microspheres affected bronchial artery resistance, we cannulated and perfused the bronchial artery in anesthetized sheep. In seven sheep, the change in bronchial artery pressure at constant flow was recorded during infusion of 5 doses (1 x 10(5), 2 x 10(5), 5 x 10(5), 1 x 10(6), and 1.5 x 10(6)) of 15-microns microspheres. Microspheres produced a dose-dependent, self-limited decrease in bronchial artery pressure (1.5 x 10(6) microspheres decreased bronchial artery pressure by 36% for 31 min). This was a decrease in bronchial artery resistance, as evidenced by a shift in the slope, but not the intercept, of a pressure-flow curve (n = 4 sheep). Left atrial injection of 1 x 10(7) microspheres decreased bronchial artery resistance by 17% in six sheep with intact bronchial arteries in which flow was measured by ultrasound probe. The adenosine-receptor antagonist 8-phenyltheophylline attenuated the fall in resistance by 79% (n = 4 sheep). Cyclooxygenase inhibition by indomethacin attenuated the response by 37% (n = 4 sheep). These results suggest that microspheres caused the release of adenosine and a vasodilator prostaglandin. Repetitive measurements of bronchial blood flow by microspheres could overestimate true bronchial blood flow if the interval between measurements is < 30 min.

In-line digital holographic interferometry.

An optical system based on in-line digital holography for the evaluation of deformations is described. In-line holograms are recorded on a CCD chip. The problem of overlapping twin images typical for the in-line arrangement is solved by digital reconstruction and filtering of the unwanted wave fronts. Two separate interferograms of an object under test in its undeformed and deformed states are recorded each on a CCD chip. The phases of the two wave fronts are obtained from the complex amplitudes of the digital reconstructed wave fronts, and the deformation is calculated from the phase differences. Experimental results are presented.

Positive pleural pressure decreases coronary perfusion.

Pressure surrounding the heart (PSH) rises with maneuvers that increase pleural pressure. This may decrease left ventricular (LV) oxygen demand by reducing LV afterload. However, positive PSH may also directly impede coronary flow. To study the effects of positive PSH on coronary perfusion, PSH was increased in 10-mmHg increments from 0 to 60 mmHg in an isolated canine heart-lung preparation with constant venous return, arterial pressure, and lung volume. Increased PSH caused a rapid significant (P less than 0.001) fall in left atrial transmural pressure (PLATM) of up to 1.28 +/- 0.31 mmHg. With constant venous return and lung volume, this was interpreted to reflect decreased LV afterload. However, at levels of PSH greater than 30 mmHg, initial decreases in PLATM were followed by sustained increases, suggesting that there was a deterioration in cardiac function despite the lower level of afterload. Increased PSH was also associated with decreases in circumflex coronary artery flow [flow (ml/min) = 52.4 - 0.4PSH, P less than 0.01]. Moreover, when the circumflex coronary artery was maximally dilated with adenosine, the effects of PSH were amplified [flow (ml/min) = 137.9 - 1.78PSH, P less than 0.001], indicating that positive PSH mechanically impeded coronary flow. When PSH was raised to 60 mmHg for 90 s, the aortic-coronary sinus lactate concentration difference fell from 0.71 +/- 0.09 to 0.10 +/- 0.21 mM (mean +/- SE, P less than 0.001, n = 8), suggesting myocardial ischemia. We conclude that positive PSH directly decreases myocardial perfusion. This may lead to ischemic cardiac dysfunction, especially in patients with low arterial pressure or coronary artery disease.

Alpha-2 adrenoceptor blockade protects rats against lipopolysaccharide.

Alpha-2 adrenoceptors are widely distributed in vascular and nonvascular tissue where they mediate diverse physiologic effects. We noted the laboratory anesthetic urethane, which possesses alpha-2 adrenergic blocking activity, protected rats against lethal endotoxemia (1). Therefore, we undertook the present study to examine whether specific alpha-2 adrenoceptor antagonism would protect against lethality and organ injury induced by lipopolysaccharide (LPS). Sprague-Dawley rats were pretreated with doses of the alpha-2 antagonist rauwolscine up to 1 mg/kg, followed by 20 mg/kg LPS. The highest rauwolscine dose decreased mortality from 100% to zero. In contrast, the alpha-2 agonists xylazine or UK 14,304 increased the lethality of a lower, 10-mg/kg dose of LPS from 20% to 80 to 100%. Rauwolscine administered after LPS had no protective effect against mortality. Rauwolscine pretreatment significantly reduced bowel hemorrhage and liver dysfunction induced by 20 mg/kg LPS, but it had no effect on hematologic changes, the rise in plasma creatinine, or lung myeloperoxidase content. Peak tumor necrosis factor-alpha levels were decreased from 1,305 +/- 333 to 493 +/- 155 pg/ml (p < 0.05) in animals pretreated with rauwolscine. Arterial pressure and heart rate was higher after LPS in animals pretreated with rauwolscine. We conclude that alpha-2 adrenergic blockade protects against LPS, either by decreasing tumor necrosis factor-alpha production or through direct effects on the target tissues of endotoxemia.