Comparison of 99mTc-DTPA and urea for measuring cefepime concentrations in epithelial lining fluid.

The efficacy of antimicrobial agents against pulmonary infections depends on their local concentrations in the lung. The aims of the present study were to: 1) compare technetium-99m diethylenetriaminepenta-acetic acid (99mTc-DTPA) and urea as markers of epithelial lining fluid (ELF) dilution for measuring ELF concentrations of pharmaceuticals; 2) quantify ELF cefepime concentrations in normal and injured lung; and 3) measure the increase in permeability to cefepime following oleic acid-induced acute lung injury. A modified bronchoalveolar lavage technique, based on equilibration of infused 99mTc-DTPA, was used to measure ELF volume. Cefepime was administered intravenously at steady plasma levels. Six serial bronchoalveolar lavages were performed 5 h after the beginning of infusion. ELF to plasma cefepime concentration ratios were 95 +/- 17 and 100 +/- 14.5% in normal and injured lung respectively. When urea was used as marker, cefepime concentration ratios were underestimated at 16.4 +/- 2.7 and 73.9 +/- 8.4% respectively. Cefepime blood/ airspace clearance increased from 3.8 +/- 0.7 micro x min(-1) in controls to 39.8 +/- 4.9 microL x min(-1) in acute lung injury. It was concluded that: 1) cefepime concentrations in epithelial lining fluid were in equilibrium with those in plasma in both normal and injured lung after 5 h at steady plasma concentrations; 2) epithelial lining fluid cefepime concentration by the urea method was much less underestimated in injured versus normal lung; and 3) acute lung injury induces a 10-fold elevation of cefepime blood/airspace clearance.

In vivo measurement of lung capillary-alveolar macromolecule permeability by saturation bronchoalveolar lavage.

OBJECTIVE: Measurement of capillary-alveolar permeability to fluorescein isothiocyanate-dextran (FITC-D) (molecular mass, 71,300 daltons) by a sequential bronchoalveolar lavage (BAL) technique. DESIGN: Animal research. SETTING: The Department of Physiology at a scientific and medical university. SUBJECTS: Nine anesthetized and mechanically ventilated dogs. INTERVENTIONS: Two separate experiments were performed in each subject-an initial control experiment followed by an oleic acid-induced lung injury. The indicator was administered at constant blood concentration before serial BAL including eight fluid instillation-recovery cycles. MEASUREMENTS: Plasma to BAL solute clearance at saturation (capillary-alveolar clearance at saturation, mL/min) was calculated and normalized to lavage fluid volume (measured by 1251 serum albumin dilution) to obtain a transport rate (TR) constant. MAIN RESULTS: TR for FITC-D70 was 4.0+/-0.8 and 46.1+/-18.1 x 10(-5) x min(-1) in control and injured lung, respectively (p < .02). Capillary-alveolar clearance of FITC-D70 was not affected by the lavage procedure itself. TR reflected essentially epithelial permeability in normal lung and combined epithelial and endothelial permeability in injured lung. A significant correlation was found between cardiac output and TR in injured lung. CONCLUSIONS: Saturation BAL allowed us to estimate capillary-alveolar macromolecule permeability in vivo in dogs. Further study may allow bedside evaluation of lung injury by BAL in patients.

Time-dependent pressure distortion in a catheter-transducer system: correction by fast flush.

BACKGROUND: Distortion of the pressure wave by a liquid-filled catheter-transducer system leads most often to an overestimation in systolic arterial blood pressure in pulmonary and systemic circulations. The pressure distortion depends on the catheter-transducer frequency response. Many monitoring systems use either mechanical or electronic filters to reduce this distortion. Such filters assume, however, that the catheter-transducer frequency response does not change over time. The current study aimed to study the changes with time of the catheter-transducer frequency response and design a flush procedure to reverse these changes back to baseline. METHODS: An in vitro setup was devised to assess the catheter-transducer frequency response in conditions approximating some of those met in a clinical environment (slow flushing, 37 degrees C, 48-h test). Several flush protocols were assessed. RESULTS: Within 48 h, catheter-transducer natural frequency decreased from 17.89 +/- 0.36 (mean +/- SD) to 7.35 +/- 0.25 Hz, and the catheter-transducer damping coefficient increased from 0.234 +/- 0.004 to 0.356 +/- 0.010. Slow and rapid flushing by the flush device built into the pressure transducer did not correct these changes, which were reversed only by manual fast flush of the transducer and of the catheter. These changes and parallel changes in catheter-transducer compliance may be explained by bubbles inside the catheter-transducer. CONCLUSIONS: Catheter-transducer-induced blood pressure distortion changes with time. This change may be reversed by a manual fast flush or "rocket flush" procedure, allowing a con. stant correction by a filter.

In vivo quantitation of epithelial lining fluid in dog lung.

We used an original saturation bronchoalveolar lavage (SBAL) technique (Eur. Respir. J. 1995;8[Suppl. 19]398S) to quantitate lung epithelial lining fluid volume (VELF) in dogs in two separate experiments: control and after oleic-acid-induced injury. We confirmed the hypothesis that 99mTc-DTPA, infused at constant plasma activity, reaches equilibrium with epithelial lining fluid after 90 min. We performed eight sequential lavages 215 min after beginning the infusion of 99mTc-DTPA. 99mTc-DTPA activity (Qn) in the lavage fluid increased linearly with time, suggesting transport from the plasma into the alveoli during lavage. We extrapolated Qn to time zero (Q0), when 99mTc-DTPA was not affected by lavage. VELF was calculated from: VELF = Q0/Cp, (Cp: 99mTc-DTPA mean plasma activity). 125I-albumin was used as a nondiffusible alveolar indicator to measure the fluid volume present in the lavaged segment (Vt,n). Vt,n plateaud for n >= 4. VELF/Vt,n(n = 5,8) was 1.7 +/- 0.4 and 25.0 +/- 4.4% (p < 0.05) in control and injury experiments, respectively. SBAL allowed reliable measurements of VELF and detection of alveolar edema fluid in the injured lung.

Blood flow vs. venous pressure effects on filtration coefficient in oleic acid-injured lung.

On the basis of changes in capillary filtration coefficient (Kfc) in 24 rabbit lungs, we determined whether elevations in pulmonary venous pressure (Ppv) or blood flow (BF) produced differences in filtration surface area in oleic acid-injured (OA) or control (Con) lungs. Lungs were cyclically ventilated and perfused under zone 3 conditions by using blood and 5% albumin with no pharmacological modulation of vascular tone. Pulmonary arterial, venous, and capillary pressures were measured by using arterial, venous, and double occlusion. Before and during each Kfc-measurement maneuver, microvascular/total vascular compliance was measured by using venous occlusion. Kfc was measured before and 30 min after injury, by using a Ppv elevation of 7 cmH2O or a BF elevation from 1 to 2 l . min-1 . 100 g-1 to obtain a similar double occlusion pressure. Pulmonary arterial pressure increased more with BF than with Ppv in both Con and OA lungs [29 +/- 2 vs. 19 +/- 0.7 (means +/- SE) cmH2O; P < 0. 001]. In OA lungs compared with Con lungs, values of Kfc (200 +/- 40 vs. 83 +/- 14%, respectively; P < 0.01) and microvascular/total vascular compliance ratio (86 +/- 4 vs. 68 +/- 5%, respectively; P < 0.01) increased more with BF than with Ppv. In conclusion, for a given OA-induced increase in hydraulic conductivity, BF elevation increased filtration surface area more than did Ppv elevation. The steep pulmonary pressure profile induced by increased BF could result in the recruitment of injured capillaries and could also shift downstream the compression point of blind (zone 1) and open injured vessels (zone 2).

Air contamination with nitric oxide: effect on exhaled nitric oxide response.

This study examines the response of exhaled nitric oxide (NO) concentration (ECNO) and quantity of exhaled NO over time (EVNO) in 10 healthy subjects breathing into five polyethylene bags, one in which synthetic air was free of NO and four in which NO was diluted to concentrations of 20 +/- 0.6, 49 +/- 0.8, 98 +/- 2, and 148 +/- 2 ppb, respectively. Each subject was connected to each bag for 10 min at random. Minute ventilation and ECNO were measured continuously, and EVNO was calculated continuously. ECNO and EVNO values were significantly higher for an inhaled NO concentration of 20 ppb than for NO-free air. Above 20 ppb, ECNO and EVNO increased linearly with inhaled NO concentration. It is reasonable to assume that a share of the quantity of inspired NO over time (InspVNO) because of air contamination by pollution is rejected by the ventilatory pathway. Insofar as InspVNO does not affect endogenous production or the metabolic fate of NO in the airway, this share may be estimated as being approximately one third of InspVNO, the remainder being taken by the endogenous pathway. Thus, air contamination by the NO resulting from pollution greatly increases the NO response in exhaled air.

Chlorine gas induced acute lung injury in isolated rabbit lung.

This study was designed to investigate the pathogenesis of chlorine gas (Cl2) induced acute lung injury and oedema. Isolated blood-perfused rabbit lungs were ventilated either with air (n=7) or air plus 500 parts per million (ppm) of Cl2 (n=7) for 10 min. Capillary pressure, measured by analysing the pressure/time transients of pulmonary arterial, venous and double (both arterial and venous) occlusions, was unchanged in both groups. In Cl2-exposed lungs, the fluid filtration rate increased from -0.228+/-0.25 to 1.823+/-1.23 mL min(-1) x 100 g(-1) (p<0.001) and the filtration coefficient increased from 0.091+/-0.01 to 0.259+/-0.07 mL x min(-1) x cmH2O(-1) x 100 g(-1) (p<0.001). No changes were observed in the control lungs. The extravascular lung water/blood-free dry weight ratio was 8.6+/-1.6 in the Cl2 group and 4.0+/-0.5 in the control group (p<0.001), confirming that the increase in lung weight was related to accumulation of extravascular fluid. Although the alveolar flooding by oedema is explained, in part, by the Cl2-induced epithelial injury, our results suggest that Cl2 exposure induces acute lung injury and oedema due to an increased microvascular permeability.

Nitric oxide response in exhaled air during an incremental exhaustive exercise.

This study examines the response of the exhaled nitric oxide (NO) concentration (CNO) and the exhaled NO output (VNO) during incremental exercise and during recovery in six sedentary women, seven sedentary men, and eight trained men. The protocol consisted of increasing the exercise intensity by 30 W every 3 min until exhaustion, followed by 5 min of recovery. Minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production, heart rate, CNO, and VNO were measured continuously. The CNO in exhaled air decreased significantly provided that the exercise intensity exceeded 65% of the peak VO2. It reached similar values, at exhaustion, in all three groups. The VNO increased proportionally with exercise intensity up to exhaustion and decreased rapidly during recovery. At exhaustion, the mean values were significantly higher for trained men than for sedentary men and sedentary women. During exercise, VNO correlates well with VO2, carbon dioxide production, VE, and heart rate. For the same submaximal intensity, and thus a given VO2 and probably a similar cardiac output, VNO appeared to be similar in all three groups, even if the VE was different. These results suggest that, during exercise, VNO is mainly related to the magnitude of aerobic metabolism and that this relationship is not affected by gender differences or by noticeable differences in the level of physical training.

Capillary pressure estimates from arterial and venous occlusion in intact dog lung.

We performed pulmonary venous occlusions in order to check the validity of the pulmonary capillary pressure measurements obtained using pulmonary arterial occlusion in the intact animal. The venous and arterial postocclusion pressure profiles were recorded using balloon catheters introduced, respectively, into a left lower lobe vein and into a right pulmonary artery in the anaesthetized open-chest dog. The pressure profiles were fitted by a biexponential function with an early exponential and a late exponential presenting, respectively, a short and a long time constant. We used the zero-time extrapolation of the late slow exponential to obtain an arterial (Pc,ao) and a venous (Pc,vo) estimate of the pulmonary capillary pressure. Each Pc,ao and Pc,vo made it possible to calculate a fractional arterial or venous pressure gradient when referenced to the arteriovenous pressure gradient measured during the occlusion process. In nine dogs, when referenced to the whole lung, the arterial, middle and venous fractional pressure gradients were 37 +/- 11, 10 +/- 6, and 53 +/- 12%, respectively. As the middle fractional pressure gradient is low, we conclude that pulmonary capillary pressure estimates from arterial occlusion are close to the venous occlusion estimates of capillary pressure in the intact dog lung.

Segmental pulmonary vascular resistances during oleic acid lung injury in rabbits.

We studied in isolated rabbit lungs the effects of oleic acid (OA) injury on the segmental distribution of vascular resistance. Vascular occlusion pressures were measured in control and OA-injured preparations over 90 min. Capillary filtration coefficient KF,C increased from 0.61 (+/- 0.10) to 0.91 (+/- 0.14) g.min-1.mmHg-1.(100 g)-1 in OA-injured lungs whereas it remained constant in control lungs. Total pulmonary vascular resistance changed little in both control and OA-injured lungs. OA injury resulted in a 15% increase of the double occlusion capillary pressure. In addition, the contribution of the microvascular to the total vascular resistance rose from 8% to 22%. The increase in microvascular resistance was significant 15 min after OA on the arteriolar side and became significant 30 min later on the venular side. Oleic acid injury does not change the total pulmonary vascular resistance but alters the distribution of segmental resistances in the isolated rabbit lung, thereby contributing to the accumulation of lung water in this model of low pressure permeability edema.

Theoretical analysis of occlusion techniques for measuring pulmonary capillary pressure.

We have developed a model including three serial compliant compartments (arterial, capillary, and venous) separated by two resistances (arterial and venous) for interpreting in vivo single pulmonary arterial or venous occlusion pressure profiles and double occlusion. We formalized and solved the corresponding system of equations. We showed that in this model 1) pulmonary capillary pressure (Pc) profile after arterial or venous occlusion has an S shape, 2) the estimation of Pc by zero time extrapolation of the slow component of the arterial occlusion profile (Pcao) always overestimates Pc, 3) symmetrically such an estimation on the venous occlusion profile (Pcvo) always underestimates Pc, 4) double occlusion pressure (Pcdo) differs from Pc. We evaluated the impact of varying parameter values in the model with parameter sets drawn either from the literature or from arbitrary arterial and venous pressures, being respectively 20 and 5 mmHg. Resulting Pcao-Pc differences ranged from 0.4 to 5.4 mmHg and resulting Pcvo-Pc differences ranged from -0.3 to -5.0 mmHg. Pcdo-Pc was positive or negative, its absolute value in general being negligible (< 1.1 mmHg).

Pulmonary capillary pressure: a review.

OBJECTIVES: To demonstrate the importance of a) measuring effective pulmonary capillary pressure and b) evaluating the longitudinal distribution of pulmonary vascular resistance relative to pre- and postcapillary resistances. To review the development of methods used to determine pulmonary capillary pressure in experimental animal and clinical studies. DATA SOURCES: Human, animal, and modeling studies published since 1966 identified through MEDLINE and a review of bibliographies of relevant articles. STUDY SELECTION AND DATA EXTRACTION: All studies identified were reviewed with an emphasis on recent studies and those studies identifying various methodologies used to determine capillary pressure. Experimental studies were selected for their historical value and applicability to the clinical setting. DATA SYNTHESIS: Different models of the pulmonary circulation have been proposed. The electrical circuit model, which incorporated capacitance elements and two or four resistive elements, has been the basis for the determination of pulmonary capillary pressure in isolated lungs and in situ lungs in animals and patients. Methods used to determine pulmonary capillary pressure from a pulmonary arterial pressure tracing after balloon occlusion are: a) division of waveform into two components and logarithmic extrapolation of the slow component to occlusion time; b) visual determination of the pressure inflection point of the pulmonary arterial pressure tracing; and c) computer processing of the total arterial pressure transient. Both ease of calculations and difficulties can arise when each method is used. CONCLUSIONS: Pulmonary capillary hydrostatic pressure is an important determinant of pulmonary edema especially in the setting of pulmonary hypertension and adult respiratory distress syndrome. Hypoxia, sepsis, cardiac valvular disease, and inflammatory mediators produce variable changes in the longitudinal distribution of pulmonary vascular resistance so that an increased capillary pressure cannot be predicted by the pulmonary arterial or occlusion pressure. For proper therapy aimed at decreasing pulmonary vascular resistance, it is important to determine whether or not the particular therapy increases capillary pressure. Pulmonary capillary pressure is the most important determinant of lung fluid balance and is the major physiologic parameter that should be measured when various forms of plasma volume expansion and pulmonary vasodilators are used in the critically ill patient.

Lymph flow during increases in pulmonary blood flow and microvascular pressure in dogs.

We studied the effects of an increase in pulmonary blood flow (PBF) on steady-state lung lymph flow (QL) and protein transport in anesthetized dogs (n = 7) to estimate the effect of vascular recruitment in zone 3 on transvascular filtration. At the end of each experiment, we increased left atrial pressure to 25-30 mmHg using a balloon catheter and obtained a washdown of the lymph protein concentration. PBF was increased with an extracorporeal circuit, which pumped blood from the left to the right atrium, and increases in pulmonary capillary pressure (Pc) were minimized by lowering left atrial pressure. PBF was measured by thermodilution, and Pc was measured by transient analysis of arterial occlusion pressure with a Swan-Ganz catheter. PBF increases averaged 78% with increases ranging from 36 to 118%. Pc increases ranged from 0.5 to 6.3 mmHg, and QL increases averaged 31% with changes ranging from -2 to +138%. We observed a 16% increase in QL for each 1-mmHg increase in Pc during increased PBF, which was comparable to the relationship previously observed after an increased left atrial pressure. Lymph-to-plasma total protein concentration ratios (CL/CP) decreased from 0.71 +/- 0.04 to 0.625 +/- 0.06 during increased PBF. The relationship between CL/CP, QL, and Pc for both increased blood flow and increased left atrial pressure were within the expected range for increased pressure alone. These data suggest that there was minimal vascular recruitment for transvascular filtration in zone 3 when pulmonary blood flow was increased. Microvascular filtration pressure was the main determinant of fluid and protein transvascular filtration under these conditions.

Increase in pulmonary capillary permeability in dogs exposed to 100% O2.

Changes in pulmonary capillary filtration induced by hyperoxia were investigated in 15 dogs. After 12 h of normobaric hyperoxic exposure, animals were anesthetized and artificially ventilated with 100% O2. A pulmonary lymphatic vessel was cannulated, and lymph flow and protein content were measured together with pulmonary and systemic hemodynamics. An increase in pulmonary capillary filtration was found when compared with reference data (normoxic dogs in similar conditions) gathered from available literature: lymph flow increased from 21.8 +/- 13.4 to 125.2 +/- 131.6 microliter/min, and the lymph-to-plasma protein concentration ratio increased from 0.67 +/- 0.08 to 0.78 +/- 0.08. To characterize the mechanisms involved, left atrial pressure was increased in two stages (approximately 10 and approximately 25 mmHg). The results clearly indicated an increase in pulmonary capillary permeability as evidenced by a decrease of the minimal estimate of the protein reflection coefficient from 0.62 +/- 0.05 to 0.42 +/- 0.05.

Effect of acute hypoxia on lung fluid balance in the prerecruited dog lung.

Lung lymph flow and protein transport were measured in eight anaesthetized dogs while acute hypoxic exposure (FIO2 = 0.10) was performed on prerecruited lung (achieved by an increased left atrial pressure). It was found that the lung lymph flow increase observed during hypoxia (from 71.8 +/- 47.5 to 100.8 +/- 78.4 microliters X min-1; p less than 0.05) was associated to an unchanged lymph/plasma protein concentration ratio (from 0.60 +/- 0.9 to 0.60 +/- 0.11). During recovery from hypoxia, lymph flow remained at a higher level than before hypoxia (respectively 87.8 +/- 49.5 and 71.8 +/- 47.5 microliters X min-1). These results suggest that the mild hypoxia-induced oedema is rather a high permeability oedema than an haemodynamic oedema. A graphic representation of protein clearance changes versus lymph flow changes was used in order to discriminate between high permeability and haemodynamic oedemas at their early stage.

Effect of acute hypoxia on lung transvascular filtration in anaesthetized dogs.

The pulmonary transvascular filtration changes were investigated in nine anaesthetized open-chest dogs during acute hypoxic exposure. The tracheobronchial pulmonary lymph flow, the lymph and plasma protein concentration, the pulmonary vascular pressures and the cardiac output were measured during three consecutive steady states of about 2 h each: 1) base-line, 2) hypoxia (FIO2 = 0.10), 3) recovery from hypoxia. It was found that pulmonary arterial pressure and lung lymph flow increased in all animals during hypoxia, respectively from (average +/- SD) 19.4 +/- 4.5 to 27.1 +/- 5.6 Torr, and from 27.2 +/- 10.2 to 59.8 +/- 23.8 microliters . min-1; lymph to plasma protein concentration ratio remained unchanged. During recovery, lung lymph flow remained elevated in some animals, while it returned to its initial value in the others. Control experiments with normoxic hyperventilation in five dogs showed no increase in lymph flow. The extravascular water/blood free dry lung ratio was moderately increased in animals that had been made hypoxic (4.64 +/- 0.67) compared to a control group (3.46 +/- 0.36). These results suggest that acute hypoxic exposure causes an increased pulmonary transvascular filtration in anaesthetized dogs.

Total lung lymph flow and fluid compartmentation in edematous dog lungs.

The effect of fluid volume loading on lung tissue fluid compartments and pulmonary lymph flow was studied in 7 dogs. A bolus of 125I-labeled albumin was administered 1 h after a 10--15% body weight Tyrode infusion. Then concentrations of labeled and endogenous albumin in pulmonary lymph and plasma were monitored for 4--6 h. The time course of plasma and lymph [125I]albumin specific activities was analyzed using kinetic and both the linear and nonlinear solute flux equations. Plasma specific activity exhibited a two-component decay with mean rate constants of 2.65 and 0.071 h-1. Albumin equilibrated between plasma and lymph at a rate of 0.327 h-1, or with a half time of 2.12 h. For albumin, the mean permeability-surface area product was 0.043 ml/min, and total distribution volume was 22.6 ml. This indicated that the cannulated lymphatics drained 25% of total lung weight, and that lung lymph flow was 0.063 ml . min-1 . 100 g-1 in normally hydrated lungs, and 0.225 ml . min-1 . 100 g-1 in edematous lungs. During edema the extravascular 99mTc-DTPA (diethylenetriamine pentaacetic acid) space increased by 79% and the total extravascular lung water by 40%. The extravascular albumin space was only one-third that predicted for the extent of edema. This indicates a significant volume of edema fluid sequestered in tissue compartments, such as perivascular cuffs and alveolar spaces, which did not equilibrate rapidly with capillary filtrate draining into the pulmonary lymphatics.

Increased pulmonary vascular permeability following acid aspiration.

The effect of hydrochloric acid aspiration on transvascular fluid and protein flux and lung water content was studied in 21 anesthetized dogs. We measured steady-state lung lymph flow, pulmonary arterial and left atrial pressures, and the concentration of total protein and albumin in both lymph and plasma after intratracheal instillation of 2 ml/kg 0.1 N HCl. Acid injury produced a twofold increase in lung lymph flow and lymph protein clearance when compared with control. This indicated an increase in pulmonary microvascular permeability. In dogs given 25 g concentrated human albumin and 1 mg/kg furosemide 10 min after the acid injury, the acid-induced increase in fluid filtration was prevented. However, the decrease in fluid filtration was not attributed to an increase in the transvascular protein osmotic pressure gradient but to a more direct effect of furosemide. Treatment with furosemide alone prevented the increase in lung lymph flow induced by acid injury, whereas albumin alone did not. In all acid-injured animals there was an increase in lung water when compared wtih control. Therefore acid aspiration produced localized areas of damage to filtration vessels that lead to increased leakage of protein and water. Furosemide treatment prevented much of this increased fluid and protein flux by an undefined mechanism.