Pulmonary microvascular response to hemorrhagic shock, resuscitation, and recovery ROBERT H. DEMLING, GARY NIEHAUS, AND JAMES A. WILL Department of Surgery and Veterinary Science, University of Wisconsin Center for Health Sciences, Madison, Wisconsin 53706
DEMLING,ROBERT H., GARYNIEHAUS,ANDJAMES A. WILL. Pulmonary microvascular response to hemorrhagic shock, resuscitation, and recovery. J. Appl. Physiol.: Respirat. Environ. Physiol. 46(3): 498-503, 1979.-We studied the effect of hemorrhagic shock, resuscitation, and recovery on the pulmonary microcirculation. We used lung lymph flow (QL) and lymph-toplasma protein ratio as sensitive indices of transvascular fluid filtration rate and protein permeability. We measured pulmonary vascular pressures, cardiac output, blood gases, lymph flow, and lymph and plasma proteins before and during a Z-h period of shock, a 3-h period of resuscitation, and a 72-h period of recovery, in nine unanesthetized sheep with chronic lung lymph fistula. We found a 30% decrease in QL during early shock as animals were bled into bags containing an acetate citrate dextrose solution until aortic pressure was 50 Torr. QL gradually increased to or exceeded base line in five of nine animals during late shock as pulmonary vascular resistance increased by 250%. During the 3-h resuscitation period, mean QL increased by llO%, with the lymph-to-plasma protein ratio being significantly decreased, indicating no protein permeability change. In five of nine studies, lymph became visibly bloody. The increased QL and lymph RBCs was felt to be secondary to an elevation in microvascular pressure. During the recovery period, pressuresand QL returned to base line. lung lymph; unanesthetized
sheep; lymph
and plasma proteins
have examined the pulmonary microcirculation during and after hemorrhagic shock. Findings have ranged from no pathological change (12, 13) to extensive destruction of the vascular endothelium with interstitial and alveolar edema and hemorrhage (16, 31). Some suggest that an increase in pulmonary vascular permeability to protein occurs (7,30). Others believe that an increase in pulmonary venous resistance raising microvascular pressure is the primary factor explaining the pathological findings (5, 19). For the most part, these studies have utilized anesthetized preparations over short time periods and have used postmortem histology as the major indicator of pathological change. It has become apparent that significant changes in fluid filtration and protein permeability can occur with no apparent histological change (14, 15). Anesthesia itself may be producing some of the changes (23). The purpose of our study was to continuously monitor microvascular integrity in the unanesthetized preparation during hemorrhagic shock, resuscitation, and recovery to more previously determine the pathophysiology MANY INVESTIGATORS
498
and time course of injury to the microcirculation. We used the chronic lung lymph fistula preparation described by Staub et al. (25) using lung lymph flow and lymph protein content as sensitive and reliable indicators of the microcirculation fluid filtration rate and protein permeability characteristics (24). METHODS
Chronic lung lymph fist&a preparation. Twelve adult sheep (50-70 kg) were prepared for collection of lung lymph according to the method of Staub et al. (25). Polyvinyl catheters were also placed in the aorta and superior vena cava through a neck incision and a SwanGanz thermodilution catheter (model 93A-131-7F Edwards, Santa Ana, CA) was placed in the pulmonary artery through the jugular vein. A urinary catheter was placed and connected to a closed drainage system. A heparin-penicillin solution (1,000 U/ml heparin, 10,000U penicillin/ml) was placed in all vascular catheters daily to maintain catheter patency. All procedures were done with minimal manipulation of the lung. Animals were allowed to recuperate for 5 days prior to any studies to allow for a steady-state lymph and protein flow. All studies were performed in the unanesthetized state. The sheep were unrestrained in a metabolic cage with free access to food and water. Measurements. Aortic, central venous, pulmonary artery, and left atria1 pressure were recorded (Gilson model lCT-58 polygraph) using calibrated pressure transducers (Statham P23db). Transducers were leveled at the point of the animals’ shoulder that we considered to be the level of the left atrium. Catheters were flushed each hour with l-2 ml of Ringers lactate containing 1,000 U heparin sodium/fluid. Arterial blood gas and pH (Radiometer Copenhagen) and cardiac output by the thermodilution method (Edwards model 9520) were measured. Lung lymph was collected in heparinized graduated tubes measuring flow every 30 min. Venous blood specimens were obtained in heparinized tubes every 2-4 h. Total protein (Biuret) and albumin concentrations (Doumas) (7) were determined on lymph and plasma samples and lymph-toplasma prote!in and albumin ratios calculated. Hematocrit, heart rate, respiratory rate, and urine output were monitored. Blood volume was estimated at 65.0 ml/kg body wt (10). Base-line measurements were obtained for at least 8 h prior to hemorrhagic shock. Hemorrhagic shock study. The study was performed
0161-7567/79/oooO-0000$01.25
Copyright
0 1979 the American
Physiological
Society
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LUNG
FLUID
AND
PROTEIN
TRANSPORT
AFTER
499
SHOCK
on unanesthetized animals. Food and water were removed. After base-line measurements, sheep were bled from the arterial line into standard blood bank bags containing acetate-citrate-dextrose (ACD) solution (220 ml/800 ml blood), over a 30-min period decreasing mean arterial pressure to 50 Torr. The shock period began when a mean arterial pressure of 50 Torr was reached. Blood was then removed as necessary over the next 2 h (shock period) to maintain mean blood pressure between 50 and 60 Torr. After 2 h of shock, 15 ml/kg iv Ringers lactate was given over 15-30 min. The shed blood, maintained at room temperature, was then reinfused through a standard blood filter over the next 90-120 min until base-line left atria1 pressure was reached. Sodium bicarbonate was given intravenously as necessary to correct severe acidosis. The resuscitation period was considered to be a 3-h time period beginning with the Ringers lactate infusion. The recovery period was defined as the next 72 h with the 24 h after resuscitation being considered the early recovery period. Food and water were replaced in the cages 24 h postshock. Dextrose and one-fourth normal saline was infused at a rate of l-2 liters a day during the recovery period to maintain hydration if the animal was not drinking satisfactorily. Lung water. Gravimetric lung water determinations were made on animals expiring before the end of the study period as well as surviving animals when killed at the termination of the recovery period. In addition, 15 other nonlymph preparation sheep were studied to obtain further lung water data. Five sheep were killed after the control period and five sheep were killed after both the shock period prior to resuscitation and after the resuscitation period. A lethal dose of pentothal sodium was given after which the sheep were immediately placed supine, the chest was rapidly opened through a midline sternotomy, the hila were clamped, and the lungs were removed. We determined extravascular lung water content according to a modified method of Pearce, Yamashita, and Beasell (21) whereby residual blood was calculated and subtracted from total lung water. Lung water was represented as grams of extravascular water per gram of dry bloodless lung. Statistical analysis. Statistical analysis was done by the two-tailed t test on individual paired differences. We considered P < 0.05 as significant. Data was tabulated as the mean t one SD. RESULTS
Data for all the individual studies is shown in Table 1. Data are represented as the mean of the group t SD. Nine of the twelve lymph fistulas remained patent for the entire study period. The remaining three fistulas stopped functioning prior to or during the base lineperiod. Base- Lineperiod. All animals appeared healthy during the base-line period with no evidence of respiratory problems. Hematocrit was 30 t 1.5, a normal value for sheep. Animals appeared to be comfortable standing in the metabolic cage with a normal respiratory rate of 32 t 6,
heart rate of 90 t 10 and temperature of 39°C (14). Lymph was clear and yellowish in color. Lymph-toplasma total protein and albumin ratios were 0.60 t 0.04 and 0.73 t 0.15, respectively. These values are identical to those described in previous studies (9). Mean pulmonary vascular resistance for the group was 252 (dyne so cm-“). Urine output was 70 t 10 ml/h. Lung water in five nonlymph fistula sheep was 4.2 t 0.2 g water/g dry bloodless lung (25). Shock period. The response of the animals to shock could be divided into an early and a late phase. The early shock phase consisted of the first 60-90 min of the 2-h shock period. Animals characteristically were quite agitated, lying down and standing up multiple times. Respiratory rate increased to 70 t lO/min with the animals panting vigorously. Heart rate increased to 190 t 20/ min. There was a significant decrease in vascular pressures and cardiac output as seen in the table. Pulmonary vascular resistance increased to (510 dyne socm-“). Lymph flow decreased in all nine fistula preparations by a mean of 20 t 9.0%; a significant decrease from base line. There was also a significant decrease in plasma total protein and albumin concentrations of 15% and 11% below base line. Lymph total protein and albumin decreased by 11% and 13%, respectively. Lymph-to-plasma total protein and albumin ratios were 0.63 t 0.06 and 0.75 t 0.10, not significantly different from base line. Urine output was 10 t 5 ml/h. The late shock phase consisted of the last 30-60 min of shock. Animals characteristically became much more lethargic. Respiratory rate decreased to 50 t 8/min. Heart rate remained at 180-200/min. Pulmonary artery, pressure and pulmonary vascular resistance increased significantly from early shock values, with PVR of 670 (dyn+cm-“). Left atria1 pressure and cardiac output remained at early shock levels. Lung lymph flow in six of nine animals began to increase toward base line with three of nine increasing above base line. Plasma total protein and albumin contents remained stable. Lymph-to-plasma total protein and albumin ratios decreased to 0.53 t 0.14 and 0.63 t 1. Summary data for 12 sheep before and after hemorrhagic shock TABLE
I’pa, Torr
Condition
Pla, Torr
PAO,
Torr
Cardiac Out1>ut, l/ min
L l;zh 8 ) rnl/‘ALh
6.0 0.6 ,
6.9 4.2
6.1 1.o
3.8 0.8
5.2” 0.7
100 ml
Base line Mean f SD
24 4.5
6 2.8
95 ’ 8
Early shock Mean f SD
13* 5.4
o* 1.4
50* 3
2.2* 0.4
5.8” 4.1
Late shock Mean f SD
19* 6.9
Of 2.0
60’ 4
2.5* 0.5
Resuscit Mean f SD
32’ 5.6
7 2.5
100 9
23 4.1
5 2.8
95 6
Early
ret
Mean f SD
__I_-Proteins ,TPPlasma, Alb, g/
1
Blood
Gases Pa, I%(.(, , pH
J-i 8.7
32 2.1
7.5 0.1
3.4 0.5
88 9.7
23 5.1
7.4 0.1
6.8 3.4
3.0” 0.9
87 6.5
22* 6.1
7.3* 0.1
6.2 1.0
14.6” 9.9
2.4* 0.6
fig* 8.0
32 2.5
7.5 0.1
6.0 0.4
8.2 7.8
83 6.9
33 1.8
7.5 0.1
C
Abbreviations: Ppa, pulmon&y artery pressure; Pla, left atria1 artery pressure; I’AO, pressure; TP Alb, total protein albumin: Pat,., arterial oxygen pressure; I’a(,(, , arterial dioxide pressure, Torr. * Significantly different from base line Y < 0.05.
aortic carbon
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500
DEMLING,
0.15, respectively. Examples of an individual animal’s response to shock are found in Fig. 1. The relationship between lymph-to-plasma protein ratios, lymph flow, and vascular resistance are shown in Fig. 2. Body temperature decreased to a mean of 38.4"C. One animal died during the late shock period when blood pH decreased rapidly from 7.4 to 7.0 and ventricular fibrillation occurred. Total blood volume was calculated as 65 ml/kg (10). Mean blood loss for the group was 50 t 9.6% of total blood volume. Arterial oxygen tension increased in 6 of 12 studies. Arterial PCO~ progressively decreased in all studies as did arterial pH indicating an increasing base deficit. Extravascular lung water expressed as grams of water per gram of dry bloodless lung for six sheep was 4.0 -+ 0.3, not significantly different from controls. Resuscitation. Animals remained lethargic through the 3-h resuscitation period. One animal became progressively acidotic despite bicarbonate infusion and volume replacement and died during the resuscitation period. A&tic pressure and left atria7 pressure returned io base line levels in the remaining animals. Pulmonary artery pressure was significantly increased over base line. Cardiac output and pulmonary vascular resistance were 6.2 t 0.98 l/min and 320 (dyn s cm-“). Pulmonary vascular resistance at the end of resuscitation was significantly increased from base line, but decreased from the shock period. Lung lymph flow during the period was significantly increased in all animals over base-line and shock periods with a mean increase of 110% over base line. In five of nine lymph studies, lymph became visibly bloody during this period, but lymph hematocrit never exceeded 2%. Plasma total protein and albumin contents increased toward base line, while lymph total protein and albumin were significantly decreased from both base-line and shock values. Lymph-to-plasma protein and albumin ratios were also significantly decreased to 0.44 t 0.1 and 0.47 t 0.1, respectively (Fig. 3). Arterial PoB decreased in l
L
200
Percent Change Over Baseline Value
T!
NIEHAUS,
WILL
l -PVR
I
T
AND
100 o
I
I1
I
I
1I
1
2
3
4
5
6
1 , G-
7
Time (hours) 2. Mean values for lymph-to-plasma total protein and albumin ratios and for percent change over base line of pulmonary vascular resistance (PVR) and lung lymph flow (QL) for the 9 lymph fistula animals are compared with the time course of the study. Lymph-toplasma ratio varied inversely with changes in lung lymph flow and vascular resistance. The 32% decrease in lymph-to-plasma ratio at peak QL is compatible with an elevation in microvascular pressure. PVR and QL values returned to base line together. FIG.
l
Total Protein
.6 /
Ratio
.4 -
I I I I I
.2-
\
;
II I
Baseline
Percent
,
25
Increase
I
I
50
75
in Lymph
I
100
Flow
1
125
During
I
150
1
175
J
200
Resuscitation
3. Responses of the lymph-to-plasma protein ratio to changes in lymph flow for individual studies (so&I Lines) are compared with the regression line (broken line) calculated from the data of Erdmann comparing changes in lymph-to-plasma ratio and QI, due to elevations in microvascular pressure (0.7062 = 1.84 x lo-;’ x + b; r = 0.96). Decrease in lymph-to-plasma ratio in data is very similar to that anticipated with an increase in microvascular pressure. FIG.
S-2 I I6 Baseline
Mean Pulmonary Vascular Pressure (mmtig) Lung Lymph Flow (ml/30min)
Shock
Resuscitation
I
i
‘O
8c
II
I
i
64d 2-
I I1
I
I I
Time
I I
I
I I
I
2
3
4
‘Sk-
(hours)
FIG. 1. Pulmonary microvascular response of one animal to shock, resuscitation and 24 h of recovery. Lymph flow and vascular pressures decreased during early shock. Lymph flow then increased over baseline levels as pulmonary artery pressure returned toward base line. Lymph-to-plasma protein ratio decreased during this period indicating that the sieving effect for protein was intact. Lymph flow remained increased during the resuscitation period with pulmonary artery pressure increasing significantly. All parameters returned to base line by 24-h postshock.
10 of 12 studies from both base-line and shock values with a mean value for the group of 69 t 8 Torr. Arterial Pcog and pH returned toward the base-line value. A mean of 70 t 10% of the shed blood was reinfused along with 15 ml/kg of Ringers lactate to return left atrial pressure and cardiac output to base-line levels. Lung water for six animals was 4.3 t 0.4, not significantly different from controls or shock period animals. Recouery. Three animals died during the recovery period, 6 h, and 3 and 4 days after shock, no death being due to respiratory failure. One animal that died and one that survived had episodes of what appeared to be generalized seizures unrelated to manipulation or flushing of catheters. The remaining seven animals improved and were essentially at base line values for all parameters monitored by 5 days postshock. The animals that died or were killed during the recovery period did not have elevated lung waters with the
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LUNG
FLUID
AND
PROTEIN
TRANSPORT
AFTER
mean value being 4.2 * 0.3, not significantly from the other groups of animals.
501
SHOCK
different
We considered the fluid transport equation describing fluid flux across the lung to be &f = Kf[ (Pmv - Ppmv) - &Trnv - rpmv)]
DISCUSSION
The development of pulmonary insufficiency after hemorrhagic shock appears to be due to a disruption of microvascular integrity manifested by interstitial edema and hemorrhage with progression to alveolar flooding (1). Major issues are whether microvascular damage actually occurs from the episode of shock, and if it does, whether the damage occurs during shock or during resuscitation. Findings ranging from no damage to severe injury to microvascular endothelium with edema and hemorrhage have been described in the lung during or after shock (6, 12, 19, 31). Several factors have produced these discrepancies. First, many studies have utilized the standard Wigger model whereby animals are bled into a reservoir maintained at a constant level to obtain a constant low blood pressure, then rapidly reinfused (5). This model requires systemic heparinization to avoid clotting in the reservoir. Heparin may significantly alter the findings due to shock and has been proposed by some as an agent that can prevent the lung damage (11). Rapid reinfusion of unfiltered blood may itself produce injury (4). Secondly, most studies have been performed under a variety of general anesthetics. Anesthetics have major cardiopulmonary effects that may alter findings (23). Third, most studies have been performed over a short time course either including only shock or shock and early resuscitation. Any delayed effects of shock as occur in the clinical situation (1) will be missed and a distinction will not be made as to whether these early pathological findings are transient or progressive in nature. And fourth, for the most part, conclusions have been based on postmortem histology (12, 16, 19). This may not accurately reflect physiological change (18). Significant changes in fluid filtration and protein permeability can also occur with no apparent histological change (14, 15). This is probably due in part to the efficiency of the pulmonary lymphatics in handling high fluid and protein flows while maintaining a normal fluid content in the lung (26). In our experiment we utilized a preparation whereby we could avoid anesthesia and study the effects of shock over a long time course incorporating shock, resuscitation, and recovery. We continuously monitored microvascular integrity by measuring lung lymph flow, lymph protein transport, and lymph-to-plasma protein ratios; sensitive and reliable indicators of transvascular fluid filtration rate and microvascular protein permeability (2, 24, 29). The sheep lung is also similar to the human lung morphologically and in its response to shock (10, 17). Our shock model was designed to avoid the use of heparin except for the minute amounts necessary to maintain catheter patency. The resuscitation protocol was designed to reproduce the standard clinical resuscitation protocol for patients in hemorrhagic shock (28). This entailed infusing Ringers lactate solution 15-20 ml/ kg prior to the gradual return of the shed blood as necessary to maintain base-line left atria1 pressure. A similar protocol has been used by other investigators (13).
(24)
where &f is the net transvascular fluid filtration rate; K* is the filtration coefficient, Pmv and Ppmv are the microvascular hydrostatic and perimicrovascular interstitial pressures; 0 is the reflection coefficient and rrnv and npmv are the microvascular and perimicrovascular colloid osmotic pressures. In our preparation we considered lymph flow QL to be an accurate index of & (9) and rpmv to be equal to lymph osmotic pressure (29). Erdmann et al. (9) and Staub et al. (24) demonstrated that lung lymph flow increases linearly with increases in microvascular pressure caused by elevating left atria1 pressure. As QL and &f increase, lymph protein content decreases as does the lymph to plasma protein ratio, indicating the sieving effect of the microvascular membrane for large molecules. Brigham et al. (3) demonstrated that when the permeability characteristics to protein of the microvascular membrane are damaged as after Pseudomonas bacteremia, the sieving effect is diminished. The lymph-to-plasma protein ratio under these circumstances remains relatively constant or may actually increase as lymph flow increases. The shock state in our study was characterized by a progressive increase in pulmonary vascular resistance (Fig. 2) as has been previously described (16). The initial response of the pulmonary microcirculation was a decrease in transvascular fluid filtration rate as evidenced by the decrease in lung lymph flow and the slight increase in lymph-to-plasma protein ratio as protein transport remained constant with a decreased fluid transport (6). As the shock period progressed, lymph flow returned toward base line with a decreasing lymph-to-plasma protein ratio while pulmonary vascular resistance continued to increase (Fig. 2). The increasing QL with a decreasing lymph-to-plasma ratio can be explained by an increase in microvascular pressure in the areas of the lung being perfused. This would be possible in the presence of a decreased left atria1 pressure if a large portion of the increase in total pulmonary vascular resistance occurred on the venous side. The presence of pulmonary venoconstriction has been implicated by others (16,19) as a cause of the injury to the lung seen after severe shock and resuscitation. Lung water measurements after hemorrhagic shock were unchanged from the base-line value. This finding has been reported by others (6, 20). The maintenance of pulmonary blood volume during shock by an increased pulmonary venous resistance would explain this finding. The large increase in lung lymph flow during resuscitation appeared to be due to an accentuation of the process seen during late shock. The lymph-to-plasma protein ratio was significantly decreased with increasing lymph flow. We reanalyzed the data of Erdmann et al. (9) to quantitate the response in the lymph-to-plasma ratio to increases in lymph flow secondary to increased vascular pressure. The regression line is shown in Fig. 3. A 40% decrease in the lymph plasma protein ratio was noted with a twofol .d increase in lymph flow. This can be compared with a 9% decrease in lymph-to-plasma ratio with a greater than fivefold increase in QL after a Pseu-
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502 domonas-induced protein permeability change (3). We noted a 32% mean decrease in lymph-to-plasma ratio with the 110% increase in QL in our data. The relationship between QL and lymph-to-plasma ratio in our studies is compared with that due to elevated pressure (9) (Fig. 3), in the same m .odel. As indicated, our results are very similar to that of Erdmann and strongly suggest an increase in pressure as the met hanism for the increase in QL. The larie decrease in the lymph-to-plasma ratio we noted does not appear compatible with an increase in protein permeability. The increased vascular pressure is probably unevenly distributed throughout the lung so that some areas may be subject to very high pressure, producing capillary disruptions. This would explain the presence of bloody lymph in five of nine animals and also explain the focal lung hemorrhages described in the literature (1). An increase in the membrane fluid filtration coefficient or a change in interstitial pressure that was not measured are also possible explanations for our findings. The significant decrease in arterial oxygen tension during resuscitation can be best explained by an increase in ventilation to perfusion mismatch. The 110% increase in lymph flow with a normal lung water during resuscitation demonstrates the efficiency of the lung
DEMLING,
NIEHAUS,
AND
WILL
lymphatics in preventing edema (26). The increased fluid filtration rate and interstitial hemorrhage were very transient as all parameters returned toward base line during the recovery period. Part of the discrepancy as to the severity of lung damage caused by shock can be explained by the fact that many studies were terminated during or immediately after resuscitation, and what we found to be a temporary injury may have been interpreted by others as being progressive, eventually producing respiratory failure (16, 22, 31). The seizure activity present in three animals during recovery remains unexplained. No pulmonary damage was evidenced during the recovery period and postmortem lung water measurements were normal. We can conclude that hemorrhagic shock to the degree produced in our protocol produces a transient increase in transvascular fluid filtration rate manifested during the resuscitation period with no evidence of a generalized permeability change to protein. We thank Sue Retzlaff and Gordon Johnson for their technical assistance. This work was supported by National Institutes of Health Grant HL-21076 and the College of Agriculture and Life Sciences. Received
10 July
1978; accepted
in final
form
5 October
1978.
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PROTEIN
TRANSPORT
AFTER
SHOCK
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503 Obstet. 134: 675-687, 1972. 31. WILSON, J. W., N. B. RATLIFF, AND D. B. HAVEL. The lung in hemorrhagic shock. I. In uiuo observations of the pulmonary microcirculation in cats. Am. J. PathoZ. 58: 337-351, 1970. 32. WYCHE, M. O., AND B. E. MARSHALL. Lung function, pulmonary extravascular water volume and hemodynamics in early hemorrhagic shock in anesthetized dogs. Ann. Surg. 174: 296-303, 1971.
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DEMLING,ROBERT H., GARYNIEHAUS,ANDJAMES A. WILL. Pulmonary microvascular response to hemorrhagic shock, resuscitation, and recovery. J. Appl. Physiol.: Respirat. Environ. Physiol. 46(3): 498-503, 1979.-We studied the effect of hemorrhagic shock, resuscitation, and recovery on the pulmonary microcirculation. We used lung lymph flow (QL) and lymph-toplasma protein ratio as sensitive indices of transvascular fluid filtration rate and protein permeability. We measured pulmonary vascular pressures, cardiac output, blood gases, lymph flow, and lymph and plasma proteins before and during a Z-h period of shock, a 3-h period of resuscitation, and a 72-h period of recovery, in nine unanesthetized sheep with chronic lung lymph fistula. We found a 30% decrease in QL during early shock as animals were bled into bags containing an acetate citrate dextrose solution until aortic pressure was 50 Torr. QL gradually increased to or exceeded base line in five of nine animals during late shock as pulmonary vascular resistance increased by 250%. During the 3-h resuscitation period, mean QL increased by llO%, with the lymph-to-plasma protein ratio being significantly decreased, indicating no protein permeability change. In five of nine studies, lymph became visibly bloody. The increased QL and lymph RBCs was felt to be secondary to an elevation in microvascular pressure. During the recovery period, pressuresand QL returned to base line. lung lymph; unanesthetized
sheep; lymph
and plasma proteins
have examined the pulmonary microcirculation during and after hemorrhagic shock. Findings have ranged from no pathological change (12, 13) to extensive destruction of the vascular endothelium with interstitial and alveolar edema and hemorrhage (16, 31). Some suggest that an increase in pulmonary vascular permeability to protein occurs (7,30). Others believe that an increase in pulmonary venous resistance raising microvascular pressure is the primary factor explaining the pathological findings (5, 19). For the most part, these studies have utilized anesthetized preparations over short time periods and have used postmortem histology as the major indicator of pathological change. It has become apparent that significant changes in fluid filtration and protein permeability can occur with no apparent histological change (14, 15). Anesthesia itself may be producing some of the changes (23). The purpose of our study was to continuously monitor microvascular integrity in the unanesthetized preparation during hemorrhagic shock, resuscitation, and recovery to more previously determine the pathophysiology MANY INVESTIGATORS
498
and time course of injury to the microcirculation. We used the chronic lung lymph fistula preparation described by Staub et al. (25) using lung lymph flow and lymph protein content as sensitive and reliable indicators of the microcirculation fluid filtration rate and protein permeability characteristics (24). METHODS
Chronic lung lymph fist&a preparation. Twelve adult sheep (50-70 kg) were prepared for collection of lung lymph according to the method of Staub et al. (25). Polyvinyl catheters were also placed in the aorta and superior vena cava through a neck incision and a SwanGanz thermodilution catheter (model 93A-131-7F Edwards, Santa Ana, CA) was placed in the pulmonary artery through the jugular vein. A urinary catheter was placed and connected to a closed drainage system. A heparin-penicillin solution (1,000 U/ml heparin, 10,000U penicillin/ml) was placed in all vascular catheters daily to maintain catheter patency. All procedures were done with minimal manipulation of the lung. Animals were allowed to recuperate for 5 days prior to any studies to allow for a steady-state lymph and protein flow. All studies were performed in the unanesthetized state. The sheep were unrestrained in a metabolic cage with free access to food and water. Measurements. Aortic, central venous, pulmonary artery, and left atria1 pressure were recorded (Gilson model lCT-58 polygraph) using calibrated pressure transducers (Statham P23db). Transducers were leveled at the point of the animals’ shoulder that we considered to be the level of the left atrium. Catheters were flushed each hour with l-2 ml of Ringers lactate containing 1,000 U heparin sodium/fluid. Arterial blood gas and pH (Radiometer Copenhagen) and cardiac output by the thermodilution method (Edwards model 9520) were measured. Lung lymph was collected in heparinized graduated tubes measuring flow every 30 min. Venous blood specimens were obtained in heparinized tubes every 2-4 h. Total protein (Biuret) and albumin concentrations (Doumas) (7) were determined on lymph and plasma samples and lymph-toplasma prote!in and albumin ratios calculated. Hematocrit, heart rate, respiratory rate, and urine output were monitored. Blood volume was estimated at 65.0 ml/kg body wt (10). Base-line measurements were obtained for at least 8 h prior to hemorrhagic shock. Hemorrhagic shock study. The study was performed
0161-7567/79/oooO-0000$01.25
Copyright
0 1979 the American
Physiological
Society
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LUNG
FLUID
AND
PROTEIN
TRANSPORT
AFTER
499
SHOCK
on unanesthetized animals. Food and water were removed. After base-line measurements, sheep were bled from the arterial line into standard blood bank bags containing acetate-citrate-dextrose (ACD) solution (220 ml/800 ml blood), over a 30-min period decreasing mean arterial pressure to 50 Torr. The shock period began when a mean arterial pressure of 50 Torr was reached. Blood was then removed as necessary over the next 2 h (shock period) to maintain mean blood pressure between 50 and 60 Torr. After 2 h of shock, 15 ml/kg iv Ringers lactate was given over 15-30 min. The shed blood, maintained at room temperature, was then reinfused through a standard blood filter over the next 90-120 min until base-line left atria1 pressure was reached. Sodium bicarbonate was given intravenously as necessary to correct severe acidosis. The resuscitation period was considered to be a 3-h time period beginning with the Ringers lactate infusion. The recovery period was defined as the next 72 h with the 24 h after resuscitation being considered the early recovery period. Food and water were replaced in the cages 24 h postshock. Dextrose and one-fourth normal saline was infused at a rate of l-2 liters a day during the recovery period to maintain hydration if the animal was not drinking satisfactorily. Lung water. Gravimetric lung water determinations were made on animals expiring before the end of the study period as well as surviving animals when killed at the termination of the recovery period. In addition, 15 other nonlymph preparation sheep were studied to obtain further lung water data. Five sheep were killed after the control period and five sheep were killed after both the shock period prior to resuscitation and after the resuscitation period. A lethal dose of pentothal sodium was given after which the sheep were immediately placed supine, the chest was rapidly opened through a midline sternotomy, the hila were clamped, and the lungs were removed. We determined extravascular lung water content according to a modified method of Pearce, Yamashita, and Beasell (21) whereby residual blood was calculated and subtracted from total lung water. Lung water was represented as grams of extravascular water per gram of dry bloodless lung. Statistical analysis. Statistical analysis was done by the two-tailed t test on individual paired differences. We considered P < 0.05 as significant. Data was tabulated as the mean t one SD. RESULTS
Data for all the individual studies is shown in Table 1. Data are represented as the mean of the group t SD. Nine of the twelve lymph fistulas remained patent for the entire study period. The remaining three fistulas stopped functioning prior to or during the base lineperiod. Base- Lineperiod. All animals appeared healthy during the base-line period with no evidence of respiratory problems. Hematocrit was 30 t 1.5, a normal value for sheep. Animals appeared to be comfortable standing in the metabolic cage with a normal respiratory rate of 32 t 6,
heart rate of 90 t 10 and temperature of 39°C (14). Lymph was clear and yellowish in color. Lymph-toplasma total protein and albumin ratios were 0.60 t 0.04 and 0.73 t 0.15, respectively. These values are identical to those described in previous studies (9). Mean pulmonary vascular resistance for the group was 252 (dyne so cm-“). Urine output was 70 t 10 ml/h. Lung water in five nonlymph fistula sheep was 4.2 t 0.2 g water/g dry bloodless lung (25). Shock period. The response of the animals to shock could be divided into an early and a late phase. The early shock phase consisted of the first 60-90 min of the 2-h shock period. Animals characteristically were quite agitated, lying down and standing up multiple times. Respiratory rate increased to 70 t lO/min with the animals panting vigorously. Heart rate increased to 190 t 20/ min. There was a significant decrease in vascular pressures and cardiac output as seen in the table. Pulmonary vascular resistance increased to (510 dyne socm-“). Lymph flow decreased in all nine fistula preparations by a mean of 20 t 9.0%; a significant decrease from base line. There was also a significant decrease in plasma total protein and albumin concentrations of 15% and 11% below base line. Lymph total protein and albumin decreased by 11% and 13%, respectively. Lymph-to-plasma total protein and albumin ratios were 0.63 t 0.06 and 0.75 t 0.10, not significantly different from base line. Urine output was 10 t 5 ml/h. The late shock phase consisted of the last 30-60 min of shock. Animals characteristically became much more lethargic. Respiratory rate decreased to 50 t 8/min. Heart rate remained at 180-200/min. Pulmonary artery, pressure and pulmonary vascular resistance increased significantly from early shock values, with PVR of 670 (dyn+cm-“). Left atria1 pressure and cardiac output remained at early shock levels. Lung lymph flow in six of nine animals began to increase toward base line with three of nine increasing above base line. Plasma total protein and albumin contents remained stable. Lymph-to-plasma total protein and albumin ratios decreased to 0.53 t 0.14 and 0.63 t 1. Summary data for 12 sheep before and after hemorrhagic shock TABLE
I’pa, Torr
Condition
Pla, Torr
PAO,
Torr
Cardiac Out1>ut, l/ min
L l;zh 8 ) rnl/‘ALh
6.0 0.6 ,
6.9 4.2
6.1 1.o
3.8 0.8
5.2” 0.7
100 ml
Base line Mean f SD
24 4.5
6 2.8
95 ’ 8
Early shock Mean f SD
13* 5.4
o* 1.4
50* 3
2.2* 0.4
5.8” 4.1
Late shock Mean f SD
19* 6.9
Of 2.0
60’ 4
2.5* 0.5
Resuscit Mean f SD
32’ 5.6
7 2.5
100 9
23 4.1
5 2.8
95 6
Early
ret
Mean f SD
__I_-Proteins ,TPPlasma, Alb, g/
1
Blood
Gases Pa, I%(.(, , pH
J-i 8.7
32 2.1
7.5 0.1
3.4 0.5
88 9.7
23 5.1
7.4 0.1
6.8 3.4
3.0” 0.9
87 6.5
22* 6.1
7.3* 0.1
6.2 1.0
14.6” 9.9
2.4* 0.6
fig* 8.0
32 2.5
7.5 0.1
6.0 0.4
8.2 7.8
83 6.9
33 1.8
7.5 0.1
C
Abbreviations: Ppa, pulmon&y artery pressure; Pla, left atria1 artery pressure; I’AO, pressure; TP Alb, total protein albumin: Pat,., arterial oxygen pressure; I’a(,(, , arterial dioxide pressure, Torr. * Significantly different from base line Y < 0.05.
aortic carbon
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500
DEMLING,
0.15, respectively. Examples of an individual animal’s response to shock are found in Fig. 1. The relationship between lymph-to-plasma protein ratios, lymph flow, and vascular resistance are shown in Fig. 2. Body temperature decreased to a mean of 38.4"C. One animal died during the late shock period when blood pH decreased rapidly from 7.4 to 7.0 and ventricular fibrillation occurred. Total blood volume was calculated as 65 ml/kg (10). Mean blood loss for the group was 50 t 9.6% of total blood volume. Arterial oxygen tension increased in 6 of 12 studies. Arterial PCO~ progressively decreased in all studies as did arterial pH indicating an increasing base deficit. Extravascular lung water expressed as grams of water per gram of dry bloodless lung for six sheep was 4.0 -+ 0.3, not significantly different from controls. Resuscitation. Animals remained lethargic through the 3-h resuscitation period. One animal became progressively acidotic despite bicarbonate infusion and volume replacement and died during the resuscitation period. A&tic pressure and left atria7 pressure returned io base line levels in the remaining animals. Pulmonary artery pressure was significantly increased over base line. Cardiac output and pulmonary vascular resistance were 6.2 t 0.98 l/min and 320 (dyn s cm-“). Pulmonary vascular resistance at the end of resuscitation was significantly increased from base line, but decreased from the shock period. Lung lymph flow during the period was significantly increased in all animals over base-line and shock periods with a mean increase of 110% over base line. In five of nine lymph studies, lymph became visibly bloody during this period, but lymph hematocrit never exceeded 2%. Plasma total protein and albumin contents increased toward base line, while lymph total protein and albumin were significantly decreased from both base-line and shock values. Lymph-to-plasma protein and albumin ratios were also significantly decreased to 0.44 t 0.1 and 0.47 t 0.1, respectively (Fig. 3). Arterial PoB decreased in l
L
200
Percent Change Over Baseline Value
T!
NIEHAUS,
WILL
l -PVR
I
T
AND
100 o
I
I1
I
I
1I
1
2
3
4
5
6
1 , G-
7
Time (hours) 2. Mean values for lymph-to-plasma total protein and albumin ratios and for percent change over base line of pulmonary vascular resistance (PVR) and lung lymph flow (QL) for the 9 lymph fistula animals are compared with the time course of the study. Lymph-toplasma ratio varied inversely with changes in lung lymph flow and vascular resistance. The 32% decrease in lymph-to-plasma ratio at peak QL is compatible with an elevation in microvascular pressure. PVR and QL values returned to base line together. FIG.
l
Total Protein
.6 /
Ratio
.4 -
I I I I I
.2-
\
;
II I
Baseline
Percent
,
25
Increase
I
I
50
75
in Lymph
I
100
Flow
1
125
During
I
150
1
175
J
200
Resuscitation
3. Responses of the lymph-to-plasma protein ratio to changes in lymph flow for individual studies (so&I Lines) are compared with the regression line (broken line) calculated from the data of Erdmann comparing changes in lymph-to-plasma ratio and QI, due to elevations in microvascular pressure (0.7062 = 1.84 x lo-;’ x + b; r = 0.96). Decrease in lymph-to-plasma ratio in data is very similar to that anticipated with an increase in microvascular pressure. FIG.
S-2 I I6 Baseline
Mean Pulmonary Vascular Pressure (mmtig) Lung Lymph Flow (ml/30min)
Shock
Resuscitation
I
i
‘O
8c
II
I
i
64d 2-
I I1
I
I I
Time
I I
I
I I
I
2
3
4
‘Sk-
(hours)
FIG. 1. Pulmonary microvascular response of one animal to shock, resuscitation and 24 h of recovery. Lymph flow and vascular pressures decreased during early shock. Lymph flow then increased over baseline levels as pulmonary artery pressure returned toward base line. Lymph-to-plasma protein ratio decreased during this period indicating that the sieving effect for protein was intact. Lymph flow remained increased during the resuscitation period with pulmonary artery pressure increasing significantly. All parameters returned to base line by 24-h postshock.
10 of 12 studies from both base-line and shock values with a mean value for the group of 69 t 8 Torr. Arterial Pcog and pH returned toward the base-line value. A mean of 70 t 10% of the shed blood was reinfused along with 15 ml/kg of Ringers lactate to return left atrial pressure and cardiac output to base-line levels. Lung water for six animals was 4.3 t 0.4, not significantly different from controls or shock period animals. Recouery. Three animals died during the recovery period, 6 h, and 3 and 4 days after shock, no death being due to respiratory failure. One animal that died and one that survived had episodes of what appeared to be generalized seizures unrelated to manipulation or flushing of catheters. The remaining seven animals improved and were essentially at base line values for all parameters monitored by 5 days postshock. The animals that died or were killed during the recovery period did not have elevated lung waters with the
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LUNG
FLUID
AND
PROTEIN
TRANSPORT
AFTER
mean value being 4.2 * 0.3, not significantly from the other groups of animals.
501
SHOCK
different
We considered the fluid transport equation describing fluid flux across the lung to be &f = Kf[ (Pmv - Ppmv) - &Trnv - rpmv)]
DISCUSSION
The development of pulmonary insufficiency after hemorrhagic shock appears to be due to a disruption of microvascular integrity manifested by interstitial edema and hemorrhage with progression to alveolar flooding (1). Major issues are whether microvascular damage actually occurs from the episode of shock, and if it does, whether the damage occurs during shock or during resuscitation. Findings ranging from no damage to severe injury to microvascular endothelium with edema and hemorrhage have been described in the lung during or after shock (6, 12, 19, 31). Several factors have produced these discrepancies. First, many studies have utilized the standard Wigger model whereby animals are bled into a reservoir maintained at a constant level to obtain a constant low blood pressure, then rapidly reinfused (5). This model requires systemic heparinization to avoid clotting in the reservoir. Heparin may significantly alter the findings due to shock and has been proposed by some as an agent that can prevent the lung damage (11). Rapid reinfusion of unfiltered blood may itself produce injury (4). Secondly, most studies have been performed under a variety of general anesthetics. Anesthetics have major cardiopulmonary effects that may alter findings (23). Third, most studies have been performed over a short time course either including only shock or shock and early resuscitation. Any delayed effects of shock as occur in the clinical situation (1) will be missed and a distinction will not be made as to whether these early pathological findings are transient or progressive in nature. And fourth, for the most part, conclusions have been based on postmortem histology (12, 16, 19). This may not accurately reflect physiological change (18). Significant changes in fluid filtration and protein permeability can also occur with no apparent histological change (14, 15). This is probably due in part to the efficiency of the pulmonary lymphatics in handling high fluid and protein flows while maintaining a normal fluid content in the lung (26). In our experiment we utilized a preparation whereby we could avoid anesthesia and study the effects of shock over a long time course incorporating shock, resuscitation, and recovery. We continuously monitored microvascular integrity by measuring lung lymph flow, lymph protein transport, and lymph-to-plasma protein ratios; sensitive and reliable indicators of transvascular fluid filtration rate and microvascular protein permeability (2, 24, 29). The sheep lung is also similar to the human lung morphologically and in its response to shock (10, 17). Our shock model was designed to avoid the use of heparin except for the minute amounts necessary to maintain catheter patency. The resuscitation protocol was designed to reproduce the standard clinical resuscitation protocol for patients in hemorrhagic shock (28). This entailed infusing Ringers lactate solution 15-20 ml/ kg prior to the gradual return of the shed blood as necessary to maintain base-line left atria1 pressure. A similar protocol has been used by other investigators (13).
(24)
where &f is the net transvascular fluid filtration rate; K* is the filtration coefficient, Pmv and Ppmv are the microvascular hydrostatic and perimicrovascular interstitial pressures; 0 is the reflection coefficient and rrnv and npmv are the microvascular and perimicrovascular colloid osmotic pressures. In our preparation we considered lymph flow QL to be an accurate index of & (9) and rpmv to be equal to lymph osmotic pressure (29). Erdmann et al. (9) and Staub et al. (24) demonstrated that lung lymph flow increases linearly with increases in microvascular pressure caused by elevating left atria1 pressure. As QL and &f increase, lymph protein content decreases as does the lymph to plasma protein ratio, indicating the sieving effect of the microvascular membrane for large molecules. Brigham et al. (3) demonstrated that when the permeability characteristics to protein of the microvascular membrane are damaged as after Pseudomonas bacteremia, the sieving effect is diminished. The lymph-to-plasma protein ratio under these circumstances remains relatively constant or may actually increase as lymph flow increases. The shock state in our study was characterized by a progressive increase in pulmonary vascular resistance (Fig. 2) as has been previously described (16). The initial response of the pulmonary microcirculation was a decrease in transvascular fluid filtration rate as evidenced by the decrease in lung lymph flow and the slight increase in lymph-to-plasma protein ratio as protein transport remained constant with a decreased fluid transport (6). As the shock period progressed, lymph flow returned toward base line with a decreasing lymph-to-plasma protein ratio while pulmonary vascular resistance continued to increase (Fig. 2). The increasing QL with a decreasing lymph-to-plasma ratio can be explained by an increase in microvascular pressure in the areas of the lung being perfused. This would be possible in the presence of a decreased left atria1 pressure if a large portion of the increase in total pulmonary vascular resistance occurred on the venous side. The presence of pulmonary venoconstriction has been implicated by others (16,19) as a cause of the injury to the lung seen after severe shock and resuscitation. Lung water measurements after hemorrhagic shock were unchanged from the base-line value. This finding has been reported by others (6, 20). The maintenance of pulmonary blood volume during shock by an increased pulmonary venous resistance would explain this finding. The large increase in lung lymph flow during resuscitation appeared to be due to an accentuation of the process seen during late shock. The lymph-to-plasma protein ratio was significantly decreased with increasing lymph flow. We reanalyzed the data of Erdmann et al. (9) to quantitate the response in the lymph-to-plasma ratio to increases in lymph flow secondary to increased vascular pressure. The regression line is shown in Fig. 3. A 40% decrease in the lymph plasma protein ratio was noted with a twofol .d increase in lymph flow. This can be compared with a 9% decrease in lymph-to-plasma ratio with a greater than fivefold increase in QL after a Pseu-
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502 domonas-induced protein permeability change (3). We noted a 32% mean decrease in lymph-to-plasma ratio with the 110% increase in QL in our data. The relationship between QL and lymph-to-plasma ratio in our studies is compared with that due to elevated pressure (9) (Fig. 3), in the same m .odel. As indicated, our results are very similar to that of Erdmann and strongly suggest an increase in pressure as the met hanism for the increase in QL. The larie decrease in the lymph-to-plasma ratio we noted does not appear compatible with an increase in protein permeability. The increased vascular pressure is probably unevenly distributed throughout the lung so that some areas may be subject to very high pressure, producing capillary disruptions. This would explain the presence of bloody lymph in five of nine animals and also explain the focal lung hemorrhages described in the literature (1). An increase in the membrane fluid filtration coefficient or a change in interstitial pressure that was not measured are also possible explanations for our findings. The significant decrease in arterial oxygen tension during resuscitation can be best explained by an increase in ventilation to perfusion mismatch. The 110% increase in lymph flow with a normal lung water during resuscitation demonstrates the efficiency of the lung
DEMLING,
NIEHAUS,
AND
WILL
lymphatics in preventing edema (26). The increased fluid filtration rate and interstitial hemorrhage were very transient as all parameters returned toward base line during the recovery period. Part of the discrepancy as to the severity of lung damage caused by shock can be explained by the fact that many studies were terminated during or immediately after resuscitation, and what we found to be a temporary injury may have been interpreted by others as being progressive, eventually producing respiratory failure (16, 22, 31). The seizure activity present in three animals during recovery remains unexplained. No pulmonary damage was evidenced during the recovery period and postmortem lung water measurements were normal. We can conclude that hemorrhagic shock to the degree produced in our protocol produces a transient increase in transvascular fluid filtration rate manifested during the resuscitation period with no evidence of a generalized permeability change to protein. We thank Sue Retzlaff and Gordon Johnson for their technical assistance. This work was supported by National Institutes of Health Grant HL-21076 and the College of Agriculture and Life Sciences. Received
10 July
1978; accepted
in final
form
5 October
1978.
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14. HOVIG, T., A. NICOLAYSEN, AND G. NICOLAYSEN. Ultrastructureal studies of the alveolar-capillary barrier in isolated plasma-perfused rabbit lungs. Effects of EDTA and of increased capillary pressure. Acta PhysioZ. Stand. 82: 417-432, 1971. 15. HYDE, D. M. A freeze-fraction study of oxone-induced morphological changes in primate lung. Proc. Electron Microscopy Sot. Am. (Abstract). 31: 394, 1973. 16. KELLER, C. A., R. J. SCHRAMEL, AND A. L. HYMAN. The cause of acute congestive lesions of the lung. J. Thorac. Cardiovasc. Surg. 53: 743-753, 1967. 17. MCLAUGHLIN, R. F., W. S. TYLER, AND R. 0. CANADA. A study of the subgross pulmonary anatomy in various mammals. Am. J. Anat. 108: 149-165, 1961. 18. MEYERS, J. R., J. S. MEYERS, AND A. W. BAUE. Does shock damage the lung? J. Trauma 13: 509-519, 1973. 19. Moss, G., C. STAUNTON, AND A. STEIN. Cerebral etiology of the “shock lung syndrome.” J. Trauma 12: 885-890, 1972. 20. NORTHRUP, W. F., AND E. W. HUMPHREY. The effect of hemorrhagic shock on pulmonary vascular permeability to plasma proteins. Surgery 83: 264-273, 1978. 21. PEARCE, M. L., J. YAMASHITA, AND J. BEASELL. Measurement of pulmonary edema. Circ. Res. 16: 482-488, 1965. 22. RATLIFF, N. B., J. W. WILSON, D. B. HACKEL, AND A. M. MARTIN. The lung in hemorrhagic shock. II. Observation on alveolar and vascular ultrastructure. Am. J. PathoZ. 58: 353-373, 1970. 23. SMITH, N. T. Circulatory effects of modern anesthetic agents in modern inhalation anesthetic agents. In: Heffters Handbook of Experimental Pharmacology edited by M. B. Chenoweth. Berlin: Springer-Verlag, 1972, p. 149-241. 24. STAUB, N. C. Steady state pulmonary transvascular water filtration in unanesthetized sheep. Circ. Res. 28: 135-139, 1971. 25. STAUB, N. C., R. D. BLAND, K. L. BRIGHAM, R. H. DEMLING, A. J. ERDMANN, AND W. C. WOOLVERTON. Preparation of chronic lung lymph fistulas in sheep. J. Surg. Res. 19: 315-320, 1975. 26. STAUB, N. C., T. R. VAUGHN JR., A. J. ERDMANN III, K. L. BRIGHMAN, AND W. C. WOOLVERTON. Evidence for high efficiency and sensitivity of the lungs lymph pump in unanesthetized sheep (Abstract). Microvasc. Res. 4: 431, 1972. 27. TIEFENBRUN, J., AND W. C. SHOEMAKER. Sequential changes in pulmonary blood flow distribution in hemorrhagic shock. Ann. Surg. 174: 727-733, 1971.
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LUNG
FLUID
AND
PROTEIN
TRANSPORT
AFTER
SHOCK
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