Positive End-expiratory Pressure Ventilation Increases Extravascular Lung Water Due to a Decrease in Lung Lymph Flow

We assessed pulmonary endothelial and epithelial permeability and lung lymph flow in nine adult sheep under base-line conditions and after resuscitation from profound hemorrhagic shock. Animals were mechanically ventilated and maintained on 1% halothane anesthesia while aortic pressure was held at 40 Torr for 3 h. Systemic heparin was not used. After reinfusion of shed blood, sheep recovered from anesthesia and we measured lung lymph flow (QL), lymph-to-plasma concentration ratio for proteins, and time taken to reach half-equilibrium concentration of intravenous tracer albumin in lymph (t1/2). Twenty-four hours after bolus injection of radio-albumin we lavaged subsegments of the right upper lobe and determined fractional equilibration of the tracer in the alveolar luminal-lining layer. In each sheep we had measured these parameters 7 days earlier under base-line conditions. Animals were killed, and the lungs were used for gravimetric determination of extravascular lung water (gravimetric extravascular lung water-to-dry weight ratio) 24 h after resuscitation from shock. Pulmonary endothelial injury after resuscitation was evidenced by marked increase in QL, without fall in lymph-to-plasma ratio. Time taken to reach half-equilibrium concentration fell from 169 +/- 47 (SD) min in base-line studies to 53 +/- 33 min after shock. There was no evidence of lung epithelial injury. Gravimetric extravascular lung water-to-dry weight ratio was significantly increased in these animals killed 24 h after resuscitation (4.94 +/- 0.29) compared with values in our laboratory controls (4.13 +/- 0.09, mean +/- SD). These data demonstrate a loss of lung endothelial integrity in sheep after resuscitation from profound hemorrhagic shock.

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Chronic interleukin-2 treatment in awake sheep causes minimal or no injury to the lung microvascular barrier

Journal of Applied Physiology ◽

10.1152/jappl.1996.81.4.1730 ◽

1996 ◽

Vol 81 (4) ◽

pp. 1730-1738 ◽

Cited By ~ 1

Author(s):

E. Heidi Jerome ◽

Keiji Enzan ◽

Dominique Douguet ◽

Dachuan Lei ◽

Gary Jesmok ◽

...

Keyword(s):

Plasma Protein ◽

Extravascular Lung Water ◽

Protein Concentration ◽

Interleukin 2 ◽

Lymph Flow ◽

Lung Water ◽

Plasma Protein Concentration ◽

Pulmonary Hemodynamics ◽

Lung Lymph ◽

Lung Lymph Flow

Jerome, E. Heidi, Keiji Enzan, Dominique Douguet, Dachuan Lei, Gary Jesmok, Carol W. Johnson, Maritza Neuburger, and Norman C. Staub. Chronic interleukin-2 treatment in awake sheep causes minimal or no injury to the lung microvascular barrier. J. Appl. Physiol. 81(4): 1730–1738, 1996.—Interleukin-2 (IL-2) is reputed to cause a “vascular leak syndrome.” We studied pulmonary hemodynamics and lymph dynamics in six sheep treated for 7 days with IL-2 (1.8 million IU/kg twice daily or 1.8 million IU/kg each day as a continuous infusion). Lung lymph flow increased from 4.8 ± 2 ml/15 min pre-IL-2 to 14.4 ± 6.8 ml/15 min on the seventh day of IL-2. The lymph-to-plasma protein concentration ratio was unchanged (0.70 ± 0.06 vs. 0.63 ± 0.13). The plasma-to-lymph equilibration half-time of radiolabeled albumin was 2.0 ± 0.6 h pre-IL-2 and 1.0 ± 0.7 h on day 7 of IL-2. Pulmonary arterial pressure was 24 ± 7 cmH2O pre-IL-2, increased to 32 ± 4 cmH2O on the fourth day of IL-2, and returned to 29 ± 5 cmH2O on the seventh day of IL-2. Extravascular lung water was normal (4.07 ± 0.25 g/g dry lung). To clearly determine whether the increase in lung lymph flow was due to hemodynamic changes or to increased leakiness of the microvascular barrier, we volume loaded six sheep with lactated Ringer solution before and after 3 days of IL-2 treatment (1.8 million IU/kg twice daily). Lung lymph flows increased fivefold during 4 h of crystalloid infusion compared with baseline and were higher after 3 days of IL-2. However, lymph-to-plasma protein concentration ratios decreased to the same low levels pre- and post-IL-2 (0.39 ± 0.06 vs. 0.41 ± 0.10), indicating an intact microvascular barrier. Extravascular lung water was elevated (5.56 ± 0.39 g/g dry lung) but was not different from lung water in three volume-loaded control sheep (4.87 ± 0.53 g/g dry lung). We conclude that IL-2 causes minimal or no injury to the pulmonary microvascular barrier and that volume expansion during IL-2 treatment can cause hydrostatic pulmonary edema.

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Effect of interstitial edema on lung lymph flow in goats in the absence of filtration

Journal of Applied Physiology ◽

10.1152/jappl.1992.72.3.1142 ◽

1992 ◽

Vol 72 (3) ◽

pp. 1142-1148 ◽

Cited By ~ 10

Author(s):

K. Kambara ◽

K. E. Longworth ◽

V. B. Serikov ◽

N. C. Staub

Keyword(s):

Lymph Flow ◽

Alveolar Wall ◽

Half Time ◽

Interstitial Edema ◽

Lung Water ◽

Pulmonary Arterial ◽

The Mean ◽

Lung Lymph ◽

Normal Lungs ◽

Lung Lymph Flow

We tested the effect of interstitial edema on lung lymph flow when no filtration occurred. In 16 anesthetized open-thorax ventilated supine goats, we set pulmonary arterial and left atrial pressures to nearly zero and measured lymph flow for 3 h from six lungs without edema and ten with edema. Lymph flow decreased exponentially in all experiments as soon as filtration ceased. In the normal lungs the mean half time of the lymph flow decrease was 12.7 +/- 4.8 (SD) min, which was significantly shorter (P less than 0.05) than the 29.1 +/- 14.8 min half time in the edematous lungs. When ventilation was stopped, lymph flow in the edematous lungs decreased as rapidly as in the normal lungs. The total quantity of lymph after filtration ceased was 2.7 +/- 0.8 ml in normal lungs and 9.5 +/- 6.3 ml in edematous lungs, even though extravascular lung water was doubled in the latter (8.4 +/- 2.4 vs. 3.3 +/- 0.4 g/g dry lung, P less than 0.01). Thus the maximum possible clearance of the interstitial edema liquid by the lymphatics was 6.3 +/- 4.8%. When we restarted pulmonary blood flow after 1–2 h in four additional goats, lymph flow recovered within 30 min to the baseline level. These findings support the hypothesis that lung lymph flow originates mainly from alveolar wall perimicrovascular interstitial liquid and that the contribution of the lung lymphatic system to the clearance of interstitial edema (bronchovascular cuffs, interlobular septa) is small.

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Increasing duration of smoke exposure induces more severe lung injury in sheep

Journal of Applied Physiology ◽

10.1152/jappl.1988.64.3.1107 ◽

1988 ◽

Vol 64 (3) ◽

pp. 1107-1113 ◽

Cited By ~ 89

Author(s):

R. Kimura ◽

L. D. Traber ◽

D. N. Herndon ◽

H. A. Linares ◽

H. J. Lubbesmeyer ◽

...

Keyword(s):

Lung Injury ◽

Inhalation Injury ◽

Lymph Flow ◽

Smoke Inhalation ◽

Lung Water ◽

Arterial Blood ◽

Chronic Study ◽

Lung Lymph ◽

Severe Lung ◽

Lung Lymph Flow

Eighteen sheep previously prepared for chronic study were divided into three groups of six animals each. These were given graded inhalation injury utilizing smoke obtained from burning cotton-toweling material. Smoke was insufflated into animals with a modified bee smoker at temperatures less than 40 degrees C. Group H, which received 64 breaths of smoke, showed the most pronounced changes in pulmonary function. The changes consisted mainly of a profound increase in lung lymph flow following a reduced P/F ratio (PO2 in arterial blood/inspired O2 fraction) and an elevation in both thermal and gravimetrically measured extravascular lung water. Similar changes were seen in group M (48 breaths of smoke) and group L (32 breaths of smoke). However, the injury was graded based on the changes in gravimetrically measured lung water and lung lymph flow. These were highest in group H and lowest in group L. These studies confirm our ability to accurately quantitate the injury induced by smoke inhalation. In addition, it demonstrates that lung injury associated with the inhalation of smoke can be graded depending on the duration of exposure.

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Role of sulfidopeptide leukotrienes in synthetic smoke inhalation injury in sheep

Journal of Applied Physiology ◽

10.1152/jappl.1990.68.5.1962 ◽

1990 ◽

Vol 68 (5) ◽

pp. 1962-1969 ◽

Cited By ~ 29

Author(s):

D. A. Quinn ◽

D. Robinson ◽

W. Jung ◽

C. A. Hales

Keyword(s):

Systemic Vascular Resistance ◽

Vascular Resistance ◽

Weight Ratio ◽

Inhalation Injury ◽

Lymph Flow ◽

Smoke Inhalation ◽

Lung Water ◽

Smoke Inhalation Injury ◽

Lung Lymph ◽

Lung Lymph Flow

Acute lung injury with smoke inhalation results in significant morbidity and mortality. Previously we have shown that synthetic smoke composed of carbon and acrolein, a common component of smoke, causes delayed-onset noncardiogenic pulmonary edema. To study the possible role of the vasoactive and edemagenic sulfidopeptide leukotrienes (SPLT) in smoke inhalation injury, we measured pulmonary hemodynamics, lung lymph flow, and SPLT and leukotriene (LT) B4 in lung lymph before and after 10 min of synthetic acrolein smoke exposure. After smoke exposure there was a significant rise in pulmonary vascular resistance caused by a rise in pulmonary arterial pressure, a fall in cardiac output, and no change in pulmonary capillary wedge pressure. This was accompanied by an increase in total systemic vascular resistance (P less than 0.05), lung lymph flow (P less than 0.05), and extravascular lung water-to-lung dry weight ratio (P less than 0.05). Both SPLT and LTB4 clearance rose significantly (P less than 0.05), but there was a 10-fold increase in SPLT over LTB4 clearance. In sheep pretreated with FPL55712, a SPLT antagonist, the early rise in pulmonary vascular resistance was attenuated, and the rise in systemic vascular resistance was blocked. This was associated with an attenuated and delayed fall in cardiac output. FPL55712 had no effect on lung lymph flow or extravascular lung water-to-dry weight ratio. SPLT, and especially LTD4, may have a role in increased pulmonary and systemic vascular resistance after smoke inhalation injury but does not appear to affect vascular permeability.

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Lung fluid balance in lambs before and after birth

Journal of Applied Physiology ◽

10.1152/jappl.1982.53.4.992 ◽

1982 ◽

Vol 53 (4) ◽

pp. 992-1004 ◽

Cited By ~ 87

Author(s):

R. D. Bland ◽

T. N. Hansen ◽

C. M. Haberkern ◽

M. A. Bressack ◽

T. A. Hazinski ◽

...

Keyword(s):

Fluid Balance ◽

Endothelial Permeability ◽

Lymph Flow ◽

Lung Water ◽

Fluid Exchange ◽

Lung Fluid ◽

Lung Fluid Balance ◽

Before And After ◽

Lung Lymph ◽

Lung Lymph Flow

To study lung fluid balance before and after birth, we measured lung lymph flow and concentrations of protein in lymph and plasma of 22 unanesthetized fetal lambs and compared results with previous studies done on 26 newborn lambs, 1–2 wk old. Lymph flow, relative to lung mass, was less in fetuses than in newborns; lymph protein clearance was not significantly different. Less lymph flow before birth probably reflects less available surface area for fluid exchange in microcirculation of fetal lungs, compared with newborn lungs, with no difference in endothelial permeability to protein. Extravascular lung water, measured gravimetrically for 24 fetuses (10 without labor, nine in labor, five 6 h after vaginal birth), decreased by 45% (15 +/- 2 g/kg body wt) before birth and by an additional 38% (6 +/- 1 g/kg) after birth. In five lambs killed after birth, we measured lung lymph flow before and during labor and for 6 h after breathing began. Lymph flow was unaffected by labor but increased transiently after birth, accounting for 11% of the liquid removed from lungs postnatally. Liquid clearance studies performed in eight anesthetized 3-wk-old lambs confirmed the observation that lung lymphatics drain only a small fraction of liquid in potential air spaces. Most of that liquid probably leaves the lungs directly through pulmonary circulation.

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Increased pulmonary vascular permeability following acid aspiration

Journal of Applied Physiology ◽

10.1152/jappl.1981.51.2.335 ◽

1981 ◽

Vol 51 (2) ◽

pp. 335-345 ◽

Cited By ~ 37

Author(s):

F. A. Grimbert ◽

J. C. Parker ◽

A. E. Taylor

Keyword(s):

Intratracheal Instillation ◽

Human Albumin ◽

Lymph Flow ◽

Lung Water ◽

Fluid Filtration ◽

Pulmonary Vascular Permeability ◽

Acid Aspiration ◽

Anesthetized Dogs ◽

Lung Lymph ◽

Lung Lymph Flow

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.

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Total lung lymph flow and fluid compartmentation in edematous dog lungs

Journal of Applied Physiology ◽

10.1152/jappl.1981.51.5.1268 ◽

1981 ◽

Vol 51 (5) ◽

pp. 1268-1277 ◽

Cited By ~ 24

Author(s):

J. C. Parker ◽

M. Crain ◽

F. Grimbert ◽

G. Rutili ◽

A. E. Taylor

Keyword(s):

Time Course ◽

Specific Activity ◽

Lymph Flow ◽

Solute Flux ◽

Tissue Fluid ◽

Lung Water ◽

Lung Weight ◽

Area Product ◽

Lung Lymph ◽

Lung Lymph Flow

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.

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