Experimental Pulmonary Edema The Effect of Unilateral PEEP
on
the Accumulation of Lung Water
CARL E. BREDENBERG, M.D.,* WATTS R. WEBB, M.D.t
The effect of PEEP in retarding the development of pulmonary edema produced by elevation of left atrial (LA) pressure to 25cm water was studied in dogs. Using two synchronized volume respirators connected to a double lumen endotracheal tube, 10 or 25cm H20 PEEP was applied to one lung while the contralateral lung was ventilated with an equal tidal volume without PEEP. LA pressure was then elevated by inflating a Foley catheter balloon in the LA until the desired LA pressure was reached. After three hours of pulmonary edema with ventilation of one lung with PEEP lung water was quantitated by wet-to-dry weights. There were no differences in wet to dry weights of PEEP and nonPEEP lungs at either 10 or 25cm H20 level. Additional blood flow studies showed that 25cm H20 of PEEP reduced blood flow to the PEEP lung by 25% and to the nonPEEP lung by 7%. This study shows that PEEP will not mechanically retard the accumulation of lung water due to increased pulmonary capillary hydrostatic pressure.
POSITIVE PRESSURE VENTILATION with positive end
expiratory pressure (PEEP) frequently benefits patients who have wet lungs-from either classic pulmonary edema or from one of the "acute respiratory distress syndromes." It has been suggested that one of the reasons for clinical improvement is that PEEP helps rid the lung of excess water.2'3 In previous work we have used partial left atrial obstruction to create pulmonary edema in dogs'2 and could find no difference in the rate of lung water accumulation during two hours of pulmonary edema between animals ventilated with 10cm of PEEP compared with animals ventilated without PEEP.4 Using the same method of creating pulmonary edema, the present experiments employ a tracheal divider and two ventilators to ventilate one * Department of Surgery, State University of New York, Upstate Medical Center, 750 E. Adams Street, Syracuse, New York 13210.
t Department of Surgery, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112. Reprint requests: Carl E. Bredenberg, M.D., F.A.C.S., Department of Surgery, State University of New York, Upstate Medical Center, 750 E. Adams Street, Syracuse, New York 13210. Submitted for publication: November 6, 1978.
From the Departments of Surgery, State University of New York, Upstate Medical Center, Syracuse, New York, and Tulane University School of Medicine, New Orleans, Louisiana
lung with PEEP and to ventilate the contralateral lung of the same dog with an identical and synchronous tidal volume without PEEP" allowing each animal to serve as its own control. Two levels of PEEP have been used in the present experiments: 10cm H,O and 25cm H20. Methods Adult mongrel dogs with an average weight of 21kg were anesthetized with I.V. pentobarbitol. A Rush #39 tracheal divider tube® was inserted through a tracheostomy and was positioned to ventilate each lung independently. This tracheal divider is a double lumen endotracheal tube designed specifically for dogs (Fig. 1). The two channels diverge at the tip so that each intubates a separate mainstem bronchus. A single cuff is then inflated in the distal trachea which occludes the orifices of both right and left mainstem bronchi assuring independent ventilation of each lung. Positioning of this tube was facilitated by passing it through a tracheostomy rather than orally. Each channel of the tracheal divider was connected to a separate piston respirator (Harvard Instrument Company, Boston, Mass.) and the respirators were synchronized by mechanical linkage of their pistons. Animals were ventilated with room air with a tidal volume of 17cc/kg divided equally between the two lungs. The pressure of each airway was measured by inserting a T piece at the junction of respirator tubing and each channel of the tracheal divider. Each T piece was connected to a Hewlett-Packard 267-B.C. transducers and pressure was recorded on a HewlettPackard recorder.® Transducers were both internally calibrated as well as calibrated against a mercury manometer (with appropriate- arithmetic conversion to
0003-4932/79/0400/0433 $00.80 © J. B. Lippincott Company
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BREDENBERG AND WEBB
FIG. 1. Rush tracheal divider. Note stopcocks attached to proximal end of each lumen for measuring airway pressure in each lumen. Inset shows tracheal occluding balloon deflated and divergence of terminal channels for fitting into mainstem bronchi.
centimeters of water for consistency of data collection). In each animal isolation ofthe airways was confirmed prior to the experiment by elevating the end expiratory pressure of one side in 5cm increments to 25cm of water maximum and observing no significant change in the airway pressure in the contralateral lung. This test was then repeated with the opposite lung confirming separate ventilation. PEEP was applied using the Emerson PEEP valve. PEEP was adjusted until the end expiratory pressure as actualiy measured at the orifice of the tracheal divider was at the desired level. Arterial blood gases were drawn from a femoral artery cannula and measured immediately after drawing on heparinized blood using the Corning 165 pH blood gas analyzer.@ The plasma colloid oncotic pressure (COP) was measured on a Critical Care Instrumentation Center Oncometer
Ann. Surg. * April 1979
Model #C- I11. * Microhematocrits were performed by standard techniques on arterial blood. Through a left thoracotomy, a Foley catheter was inserted into the left atrium through the atrial appendage with a separate polyethylene catheter placed for measurement of left atrial pressure. Catheters were led through stab wounds in the chest wall. Pressure recordings were made using the HP 267 B.C. pressure transducer and Hewlett-Packard recorder. The chest was surgically closed, and a chest tube placed to underwater seal without suction and the animal positioned on its back. After expanding the lung on the operated side and ensuring that the two airways were functionally isolated from one another, PEEP was applied to the ventilator of one lung alternating between right and left lungs in successive animals. After application of unilateral PEEP, pulmonary edema was induced by elevating left atrial pressure to an average of 25mmHg by inflating the balloon of the Foley catheter in the left atrium. The animals received an average of 45cc/kg of Ringer's lactate prior to and during surgical procedures and additional 30cc/kg over the three hours of left atrial obstruction. After 3 hours of left atrial obstruction, animals were sacrificed and each lung removed by division of the pulmonary hilum close to the lung parenchyma. Each lung was passively drained of blood then the entire lung weighed on a triple beam balance. After weighing, each lung was placed in the drying oven set at 430 without vacuum and dried to a constant weight (usually 7-10 days). Lung water was quantitated by ratio of wet-to-dry weight of each lung as suggested by Guyton.8 Two groups of animals were studied. In Group I ten dogs had 10cm of water PEEP applied to one lung and no PEEP to the contralateral lung. In Group II thirteen dogs had 25cm of PEEP applied to one lung and none to the contralateral. Statistical comparison was made using a student's t-test. The effect of 25cm H20 unilateral PEEP on lung blood flow was studied in seven additional dogs. Through a left thoracotomy electromagnetic flow probes (Carolina Electronics, King, N.C.) were placed around the main pulmonary artery to measure cardiac output and around the left pulmonary artery to measure left lung blood flow. Right lung flow was calculated as the arithmetic difference between main pulmonary artery and left pulmonary artery flow. Left atrial catheters were then placed as described above and the chest closed. Flows were measured both with normal left atrial pressure and with left atrial pressures elevated by the balloon catheter as described above. After control measurements with a normal left atrial pressure, PEEP * U.S.C. School of Medicine. Shock Research Unit, 1300 Vermont Avenue Los Angeles, California 90027.
VOl. 189 . NO. 4
EXPERIMENTAL PULMONARY EDEMA
was applied to one lung. Blood flows were remeasured. PEEP was then removed and after restabilization a second set of control flows were measured and then PEEP applied to the contralateral lung. After stabilization and measurement PEEP was removed and left atrial pressure was elevated to 25cm H20 by inflating the left atrial balloon. After stabilization a third set of control flows were measured with the elevated left atrial pressure following which PEEP was applied to one lung with repeat flow measurements. PEEP was then removed but the elevated left atrial pressure maintained and a fourth control interval measured following which PEEP was applied to the contralateral lung and a final measurement made. Thus in each animal changes in the distribution of blood flow were studied when unilateral PEEP was applied to the left lung and to the right lung, and at normal and elevated left atrial pressure. Flows were expressed as a per cent change from the immediately preceding control measurement. Results No significant difference between Groups I and II were noted in the results of arterial blood gases, hematocrit and colloid oncotic pressure, and these data are reported for the two groups combined (Table 1 and Fig. 2). Arterial blood gases with mechanical ventilation using room air and pentobarbital anesthesia showed relatively normal oxygenation and ventilation during the control interval with a slight base deficit and low normal pH. Over three hours of pulmonary edema, there was a progressive fall in Po2 and pH. Pco2 remained relatively constant as one would expect on controlled ventilation. An increasing base deficit matched the fall in pH. Over the course of three hours of pulmonary edema an average of 650cc of Ringer's lactate was given for a 21kg dog. Colloid oncotic pressure fell from l9mmHg to 14.5mmHg. Hematocrit in contrast remained fairly stable or rose an insignificant amount throughout the
experiment (Fig. 2). Wet-to-dry weights of the lungs were used to quantitate the accumulation of lung water at the end of the three hours of left atrial obstruction. In our laboratory TABLE 1. Arterial Blood Gases
Po2 PH BE
Pco2
Control
1 Hour
3 Hours
91 ± 5 7.35 ± .02 -5± 1 34 ± 2
75 ± 5 7.29 ± .02 -7± 1 37 ± 3
63 ± 5 7.27 ± .03 -8± 1 38 ± 2
Mean and Standard error of Group I and Group II combined. No significant difference between Groups I and II.
50 r
435
wltI
I I %O 11
f
401-
301-
C.O.P. 20 !^
lo0p
0
CONTROL
2
I
3
HOURS FIG. 2. Course of hematocrit and plasma oncotic pressure over three hours of pulmonary edema. Mean + S.E.
normal wet-to-dry weight in dog lungs is 4.3: 14 and the experimental values reported here indicate moderately severe pulmonary edema for both groups.12 Group I lungs receiving 10cm of PEEP had an average wet-todry weight of 6.37 + 0.56 (standard error). The average wet-to-dry weight for Group I lungs without PEEP was 6.25 ± 0.55 (Fig. 3). No significant difference is present between the experimental groups with and without PEEP but both are significantly higher than the wet-to-dry weight in our laboratory of normal dog lungs. Group II lungs receiving 25cm of PEEP had an average wet-to-dry weight after three hours of pulmonary edema of 7.03 ± 0.27 compared with average wet-to-dry weight of Group II lungs without PEEP of 7.39 ± 0.28 (Fig. 3). Although these figures show slightly drier lungs on the side receiving PEEP, this difference is not significant at the 95% confidence level. Simply averaging the wet-to-dry weights of the lungs in each group however, fails to take advantage of the fact that each animal serves as its own control. In order to specifically compare the lung receiving PEEP with
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BREDENBERG AND WEBB
the contralateral lung of the same dog, the ratio of the wet-to-dry weight of the PEEP lung divided by wet-todry weight of the lung without PEEP was calculated individually in each dog and then summarized for the
Ann. Surg. * April 1979
8r
739 ±028
703 i0.27 6.37 ±056 6.25 ±0.55
T
group:
Wet/dry PEEP Wet/dry 0 PEEP A ratio of one signifies equal lung water in both lungs. A ratio of greater than 1 indicates the lung receiving PEEP was wetter than the contralateral lung in the same dog. A ratio of less than 1 indicates the lung receiving PEEP was drier than the lung without PEEP. In Group I the average ratio of the wet-to-dry weight of the lung receiving 10cm PEEP divided by that of the lung without PEEP was 1.03 + 0.04 (S.E.). This represents no statistical difference in water accumulation over three hours pulmonary edema. In Group II the average ratio of the wet-to-dry weight of the lung receiving 25 cm PEEP over the lung without PEEP was 0.96 + 0.02. This indicates that lungs receiving 25cm PEEP were slightly drier than the contralateral lungs in the same dogs without PEEP. This difference, however, is not significant at the 95% level. Thus at 10cm of PEEP there is no difference in lung water accumulation between the lungs. At 25cm of water there was a slight tendency for the lung with PEEP to be drier but this difference did not reach statistical significance. Blood Flow Studies Unilateral PEEP had the same effect on lung flow at both normal left atrial pressures and at left atrial pressures elevated by balloon obstruction of the mitral valve. With the application of 25cm unilateral PEEP cardiac output fell an average of 14%. In the lung without PEEP, applying 25cm of PEEP to the contralateral lung reduced blood flow by an average of 7%. Flow to the lung with PEEP was reduced by an average of 25%. Changes in cardiac output were significant at p < 0.01 and the reduction in flow to the lung with PEEP is significant at p < 0.05. The reduction in flow to the lung without PEEP is not significant at the 0.05 level. These changes in flows were the same whether PEEP was applied to the left or to the right lung and were the same with normal and with elevated left atrial pressures.
Discussion It is a frequent clinical observation that positive pressure ventilation improves oxygenation and ventilation in patients with severe pulmonary edema. In most instances addition of PEEP further improves oxygenation. There is, however, disagreement as to the mech-
61-
4
21-
0I
iucm
u
PEEP
25cm
U
PEEP
FIG. 3. Wet-to-dry weights of lungs with PEEP and lungs without PEEP mean + S.E. No statistically significant difference between the wet-to-dry weights of lungs with or without PEEP in either group.
anism which explains the clinical improvement in patients ventilated with positive pressure and PEEP. It has been suggested that positive pressure with PEEP actually dries out the lungs, reducing lung water and thereby improves gas exchange across the alveolar capillary membrane.2'3 While it is now generally concluded that positive pressure ventilation without PEEP does not physically dry out the lung,13 the question remains as to the effect on lung water of the addition of PEEP to positive pressure ventilation. In our own laboratory, we have previously compared two groups of animals with pulmonary edema induced in fashion similar to that of the present experiments. One group had 10cm of PEEP applied to the ventilator, the second group was ventilated with zero end expiratory pressure. No difference in lung water was found between the two groups after two hours of pulmonary edema.4 The present study was designed to look at the effect of higher levels of PEEP (25cm H20)
and to use each animal as its own control. The divided trachea model used in the present work has the advantage that the systemic response to pulmonary edema is constant for both lungs in any given animal
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EXPERIMENTAL PULMONARY EDEMA
and in particular, blood constituents are identical for each lung. Hence although colloid oncotic pressure and blood gases do not remain constant, the variance is the same for each pair of lungs. The divergence between the fall in colloid oncotic pressure compared with the relative stability of the hematocrit is an intriguing but unexplained observation. If we were observing simple hemodilution from the infusion of Ringer's lactate one would expect the relative concentration of both blood constituents to decrease in parallel fashion. The fall in colloid oncotic pressure may represent an actual loss in protein from the circulation, either in pulmonary edema fluid or in response to surgery as has been described.10 This divergence between colloid oncotic pressure and hematocrit has also been observed in our previous work.4 The major disadvantage of the split tracheal model is that at high levels of PEEP there is a relative reduction in blood flow to the lung ventilated with PEEP. Previous work has shown that with 10cm PEEP there is approximately a 5-10% reduction in flow to the lung with PEEP.'1 In the present work we looked at the effect on pulmonary blood flow of a higher level of PEEP comparable to that of Group II experiments. As one might anticipate, there was an even greater reduction in flow to the lung with PEEP, approximately 25%. However, the effect of reduction in blood flow to the lung would be to reduce the rate of lung water accumulation. Had we shown a reduction in lung water with high levels of unilateral PEEP the conclusion would have had to be tempered by a realization that any reduction in the accumulation of lung water could in part be due to reduction of blood flow. However, since in actual fact there was no significant reduction in lung water with high levels of PEEP despite a 25% reduction in lung flow, the conclusion that PEEP has no demonstrable effect on the accumulation of lung water remains valid. In the face of an elevated LA pressure, all lungs-with or without PEEP, 10cm H20 on 25cm H20 PEEP-accumulated significant and equal volumes of edema fluid. Lung water rose from a normal of77% to between 84% and 87% in the experimental group. The fact that despite the reduction in blood flow, PEEP lungs were not significantly drier than nonPEEP only underlines the inability of PEEP to mechanically prevent accumulation of water in the lung. Recent work in several laboratories confirms these observations. Alexander et al.I found no effect of 10cm of PEEP on the rate of lung water accumulation after two hours of pulmonary edema caused by constriction of the ascending aorta. Hopewell and Murray9 measured lung water both by indicator dilution methods and gravimetric techniques during pulmonary edema in dogs induced by left atrial obstruction and hemodilu-
437
tion. They demonstrated no difference in the increase in lung water between animals ventilated without PEEP and those ventilated with 10cm of PEEP. Caldini et al.5 also studying pulmonary edema in dogs caused by increased hydrostatic pressure and hemodilution both in the intact dog and in the isolated perfused lobe preparation demonstrated no difference in the rate of fluid transfer across the alveolar membrane between animals with and without PEEP. They did however note that with PEEP above 20 Torr pulmonary fluid was held in the alveoli and prevented from accumulating in the larger airways. They also noted that high levels of PEEP tended to favor the accumulation of fluid in the extravascular space of the lung. Demling et al.6'7 studied pulmonary edema in dogs caused by lobar venous occlusion. They found that at comparable intravascular filtration pressures dogs ventilated at an end expiratory pressure 10cm of water accumulated in fact somewhat more extravascular lung water than those ventilated without PEEP. Staub has quantitated the rate of water filtration across the pulmonary capillary membrane in unanesthetized sheep by measuring lung lymph flow. Lung lymph flow increased with elevated left atrial pressure but there was no difference in the rate of increase between sheep breathing spontaneously with 10cm of continuous positive airway pressure versus those breathing normally.'4 They also observed an increase in FRC and a decrease in intrapulmonary shunting in animals breathing against positive pressure similar to results obtained in our own earlier work with mechanical ventilation. It appears clear that positive end expiratory pressure on the airway is transmitted equally to the intravascular hydrostatic pressure as well as to the intrapleural pressure. The observation from multiple laboratories" 4-7'9"14 that increasing airway pressure has no effect on the rate of water transfer across the pulmonary capillary membrane confirms that the increase in airway pressure is transmitted also to the perimicrovascular interstitial fluid pressure to the same extent as it is to the microvascular intraluminal hydrostatic pressure.'4 Staub has quantitated this increase to be approximately 50% of the increase in airway pressure'4 al-
though this will vary with lung compliance. Hence an increase in airway pressure causes no change in the net filtration forces across the capillary membrane. These conclusions are similar to those reached concerning intermittent positive pressure breathing in the past.'3 Positive end expiratory pressure does not mechanically retard the accumulation of lung water caused by an increase in hydrostatic pressure. The benefit of
continuous positive pressure ventilation either spontaneously or with a ventilator derives from the increase in FRC and the recruitment of previously col-
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lapsed nonperfused alveoli which thereby reduce intrapulmonary shunting improving oxygen delivery. References 1. Alexander, L. G., Devries, W. C. and Anderson, R. W.: Airway Pressures and Pulmonary Edema Formation. Surg. Forum, 24:231, 1973. 2. Ashbaugh, D. G., Petty, T. L., Bigelow, D. B. and Harris, T. W.: Continuous Positive-Pressure Breathing (CPPB) in Adult Respiratory Distress Syndrome. J. Thorac. Cardiovasc. Surg., 57:31, 1969. 3. Aviado, D. M., Jr. and Schmidt, C. F.: Physiologic Basis for Treatment of Pulmonary Edema. J. Chronic Dis., 9:495, 1959. 4. Bredenberg, C. E., Kazui, T. and Webb, W. R.: Experimental Pulmonary Edema: The Effect of Positive End Expiratory Pressure on Lung Water. Ann. Thor. Surg., 26:62, 1978. 5. Caldini, P., Leith, J. D. and Brennan, M. J.: Effect of Continuous Positive-pressure Ventilation (CPPV) on Edema Formation in Dog Lung. J. Appl. Physiol., 39:672, 1975. 6. Demling, R. H. and Edmunds, L. H.: Effect of Continous Positive Airway Pressure on Extravascular Lung Water. Surg. Forum., 24:226, 1973.
Ann. Surg. * April 1979
7. Demling, R. H., Staub, N. C. and Edmunds, L. H., Jr.: Effect of End-expiratory Airway Pressure on Accumulation of Extravascular Lung Water. J. Appl. Physiol., 38:907, 1975. 8. Guyton, A. C. and Lindsey, A. W.: Effect of Elevated Left Atrial Pressure and Decreased Plasma Protein Concentration on the Development of Pulmonary Edema. Circ. Res., 7: 649, 1959. 9. Hopewell, P. C. and Murray, J. F.: Effects of Continous Positive-pressure Ventilation in Experimental Pulmonary Edema. J. Appl. Physiol., 40:568, 1976. 10. Hoye, R. C., Paulson, D. F. and Ketchum, A. S.: Total Circulating Albumin Deficits Occuring with Extensive Surgical Procedures. Surg. Gynecol. Obstet., 131:943, 1970. 11. Kusajima, K., Webb, W. R., Parker, F. B., Jr., et al.: Pulmonary Responses of Unilateral Positive End Expiratory Pressure (PEEP) on Experimental Fat Embolism. Ann. Surg., 181:676, 1975. 12. Levine, 0. R., Mellins, R. B., Senior, R. M. and Fishman, A. P.: The Application of Starling's Law of Capillary Exchange to the Lungs. J. Clin. Invest., 46:934, 1967. 13. Visscher, M. B., Haddy, F. J. and Stephens, G.: The Physiology and Pharmacology of Lung Edema. Pharm. Rev., 8:388, 1956. 14. Woolverton, W. C., Brigham, K. L. and Staub, N. C.: Effect of Positive Pressure Breathing on Lung Lymph Flow and Water Content in Sheep. Circ. Res., 42:550, 1977.
on
the Accumulation of Lung Water
CARL E. BREDENBERG, M.D.,* WATTS R. WEBB, M.D.t
The effect of PEEP in retarding the development of pulmonary edema produced by elevation of left atrial (LA) pressure to 25cm water was studied in dogs. Using two synchronized volume respirators connected to a double lumen endotracheal tube, 10 or 25cm H20 PEEP was applied to one lung while the contralateral lung was ventilated with an equal tidal volume without PEEP. LA pressure was then elevated by inflating a Foley catheter balloon in the LA until the desired LA pressure was reached. After three hours of pulmonary edema with ventilation of one lung with PEEP lung water was quantitated by wet-to-dry weights. There were no differences in wet to dry weights of PEEP and nonPEEP lungs at either 10 or 25cm H20 level. Additional blood flow studies showed that 25cm H20 of PEEP reduced blood flow to the PEEP lung by 25% and to the nonPEEP lung by 7%. This study shows that PEEP will not mechanically retard the accumulation of lung water due to increased pulmonary capillary hydrostatic pressure.
POSITIVE PRESSURE VENTILATION with positive end
expiratory pressure (PEEP) frequently benefits patients who have wet lungs-from either classic pulmonary edema or from one of the "acute respiratory distress syndromes." It has been suggested that one of the reasons for clinical improvement is that PEEP helps rid the lung of excess water.2'3 In previous work we have used partial left atrial obstruction to create pulmonary edema in dogs'2 and could find no difference in the rate of lung water accumulation during two hours of pulmonary edema between animals ventilated with 10cm of PEEP compared with animals ventilated without PEEP.4 Using the same method of creating pulmonary edema, the present experiments employ a tracheal divider and two ventilators to ventilate one * Department of Surgery, State University of New York, Upstate Medical Center, 750 E. Adams Street, Syracuse, New York 13210.
t Department of Surgery, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, Louisiana 70112. Reprint requests: Carl E. Bredenberg, M.D., F.A.C.S., Department of Surgery, State University of New York, Upstate Medical Center, 750 E. Adams Street, Syracuse, New York 13210. Submitted for publication: November 6, 1978.
From the Departments of Surgery, State University of New York, Upstate Medical Center, Syracuse, New York, and Tulane University School of Medicine, New Orleans, Louisiana
lung with PEEP and to ventilate the contralateral lung of the same dog with an identical and synchronous tidal volume without PEEP" allowing each animal to serve as its own control. Two levels of PEEP have been used in the present experiments: 10cm H,O and 25cm H20. Methods Adult mongrel dogs with an average weight of 21kg were anesthetized with I.V. pentobarbitol. A Rush #39 tracheal divider tube® was inserted through a tracheostomy and was positioned to ventilate each lung independently. This tracheal divider is a double lumen endotracheal tube designed specifically for dogs (Fig. 1). The two channels diverge at the tip so that each intubates a separate mainstem bronchus. A single cuff is then inflated in the distal trachea which occludes the orifices of both right and left mainstem bronchi assuring independent ventilation of each lung. Positioning of this tube was facilitated by passing it through a tracheostomy rather than orally. Each channel of the tracheal divider was connected to a separate piston respirator (Harvard Instrument Company, Boston, Mass.) and the respirators were synchronized by mechanical linkage of their pistons. Animals were ventilated with room air with a tidal volume of 17cc/kg divided equally between the two lungs. The pressure of each airway was measured by inserting a T piece at the junction of respirator tubing and each channel of the tracheal divider. Each T piece was connected to a Hewlett-Packard 267-B.C. transducers and pressure was recorded on a HewlettPackard recorder.® Transducers were both internally calibrated as well as calibrated against a mercury manometer (with appropriate- arithmetic conversion to
0003-4932/79/0400/0433 $00.80 © J. B. Lippincott Company
433
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BREDENBERG AND WEBB
FIG. 1. Rush tracheal divider. Note stopcocks attached to proximal end of each lumen for measuring airway pressure in each lumen. Inset shows tracheal occluding balloon deflated and divergence of terminal channels for fitting into mainstem bronchi.
centimeters of water for consistency of data collection). In each animal isolation ofthe airways was confirmed prior to the experiment by elevating the end expiratory pressure of one side in 5cm increments to 25cm of water maximum and observing no significant change in the airway pressure in the contralateral lung. This test was then repeated with the opposite lung confirming separate ventilation. PEEP was applied using the Emerson PEEP valve. PEEP was adjusted until the end expiratory pressure as actualiy measured at the orifice of the tracheal divider was at the desired level. Arterial blood gases were drawn from a femoral artery cannula and measured immediately after drawing on heparinized blood using the Corning 165 pH blood gas analyzer.@ The plasma colloid oncotic pressure (COP) was measured on a Critical Care Instrumentation Center Oncometer
Ann. Surg. * April 1979
Model #C- I11. * Microhematocrits were performed by standard techniques on arterial blood. Through a left thoracotomy, a Foley catheter was inserted into the left atrium through the atrial appendage with a separate polyethylene catheter placed for measurement of left atrial pressure. Catheters were led through stab wounds in the chest wall. Pressure recordings were made using the HP 267 B.C. pressure transducer and Hewlett-Packard recorder. The chest was surgically closed, and a chest tube placed to underwater seal without suction and the animal positioned on its back. After expanding the lung on the operated side and ensuring that the two airways were functionally isolated from one another, PEEP was applied to the ventilator of one lung alternating between right and left lungs in successive animals. After application of unilateral PEEP, pulmonary edema was induced by elevating left atrial pressure to an average of 25mmHg by inflating the balloon of the Foley catheter in the left atrium. The animals received an average of 45cc/kg of Ringer's lactate prior to and during surgical procedures and additional 30cc/kg over the three hours of left atrial obstruction. After 3 hours of left atrial obstruction, animals were sacrificed and each lung removed by division of the pulmonary hilum close to the lung parenchyma. Each lung was passively drained of blood then the entire lung weighed on a triple beam balance. After weighing, each lung was placed in the drying oven set at 430 without vacuum and dried to a constant weight (usually 7-10 days). Lung water was quantitated by ratio of wet-to-dry weight of each lung as suggested by Guyton.8 Two groups of animals were studied. In Group I ten dogs had 10cm of water PEEP applied to one lung and no PEEP to the contralateral lung. In Group II thirteen dogs had 25cm of PEEP applied to one lung and none to the contralateral. Statistical comparison was made using a student's t-test. The effect of 25cm H20 unilateral PEEP on lung blood flow was studied in seven additional dogs. Through a left thoracotomy electromagnetic flow probes (Carolina Electronics, King, N.C.) were placed around the main pulmonary artery to measure cardiac output and around the left pulmonary artery to measure left lung blood flow. Right lung flow was calculated as the arithmetic difference between main pulmonary artery and left pulmonary artery flow. Left atrial catheters were then placed as described above and the chest closed. Flows were measured both with normal left atrial pressure and with left atrial pressures elevated by the balloon catheter as described above. After control measurements with a normal left atrial pressure, PEEP * U.S.C. School of Medicine. Shock Research Unit, 1300 Vermont Avenue Los Angeles, California 90027.
VOl. 189 . NO. 4
EXPERIMENTAL PULMONARY EDEMA
was applied to one lung. Blood flows were remeasured. PEEP was then removed and after restabilization a second set of control flows were measured and then PEEP applied to the contralateral lung. After stabilization and measurement PEEP was removed and left atrial pressure was elevated to 25cm H20 by inflating the left atrial balloon. After stabilization a third set of control flows were measured with the elevated left atrial pressure following which PEEP was applied to one lung with repeat flow measurements. PEEP was then removed but the elevated left atrial pressure maintained and a fourth control interval measured following which PEEP was applied to the contralateral lung and a final measurement made. Thus in each animal changes in the distribution of blood flow were studied when unilateral PEEP was applied to the left lung and to the right lung, and at normal and elevated left atrial pressure. Flows were expressed as a per cent change from the immediately preceding control measurement. Results No significant difference between Groups I and II were noted in the results of arterial blood gases, hematocrit and colloid oncotic pressure, and these data are reported for the two groups combined (Table 1 and Fig. 2). Arterial blood gases with mechanical ventilation using room air and pentobarbital anesthesia showed relatively normal oxygenation and ventilation during the control interval with a slight base deficit and low normal pH. Over three hours of pulmonary edema, there was a progressive fall in Po2 and pH. Pco2 remained relatively constant as one would expect on controlled ventilation. An increasing base deficit matched the fall in pH. Over the course of three hours of pulmonary edema an average of 650cc of Ringer's lactate was given for a 21kg dog. Colloid oncotic pressure fell from l9mmHg to 14.5mmHg. Hematocrit in contrast remained fairly stable or rose an insignificant amount throughout the
experiment (Fig. 2). Wet-to-dry weights of the lungs were used to quantitate the accumulation of lung water at the end of the three hours of left atrial obstruction. In our laboratory TABLE 1. Arterial Blood Gases
Po2 PH BE
Pco2
Control
1 Hour
3 Hours
91 ± 5 7.35 ± .02 -5± 1 34 ± 2
75 ± 5 7.29 ± .02 -7± 1 37 ± 3
63 ± 5 7.27 ± .03 -8± 1 38 ± 2
Mean and Standard error of Group I and Group II combined. No significant difference between Groups I and II.
50 r
435
wltI
I I %O 11
f
401-
301-
C.O.P. 20 !^
lo0p
0
CONTROL
2
I
3
HOURS FIG. 2. Course of hematocrit and plasma oncotic pressure over three hours of pulmonary edema. Mean + S.E.
normal wet-to-dry weight in dog lungs is 4.3: 14 and the experimental values reported here indicate moderately severe pulmonary edema for both groups.12 Group I lungs receiving 10cm of PEEP had an average wet-todry weight of 6.37 + 0.56 (standard error). The average wet-to-dry weight for Group I lungs without PEEP was 6.25 ± 0.55 (Fig. 3). No significant difference is present between the experimental groups with and without PEEP but both are significantly higher than the wet-to-dry weight in our laboratory of normal dog lungs. Group II lungs receiving 25cm of PEEP had an average wet-to-dry weight after three hours of pulmonary edema of 7.03 ± 0.27 compared with average wet-to-dry weight of Group II lungs without PEEP of 7.39 ± 0.28 (Fig. 3). Although these figures show slightly drier lungs on the side receiving PEEP, this difference is not significant at the 95% confidence level. Simply averaging the wet-to-dry weights of the lungs in each group however, fails to take advantage of the fact that each animal serves as its own control. In order to specifically compare the lung receiving PEEP with
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the contralateral lung of the same dog, the ratio of the wet-to-dry weight of the PEEP lung divided by wet-todry weight of the lung without PEEP was calculated individually in each dog and then summarized for the
Ann. Surg. * April 1979
8r
739 ±028
703 i0.27 6.37 ±056 6.25 ±0.55
T
group:
Wet/dry PEEP Wet/dry 0 PEEP A ratio of one signifies equal lung water in both lungs. A ratio of greater than 1 indicates the lung receiving PEEP was wetter than the contralateral lung in the same dog. A ratio of less than 1 indicates the lung receiving PEEP was drier than the lung without PEEP. In Group I the average ratio of the wet-to-dry weight of the lung receiving 10cm PEEP divided by that of the lung without PEEP was 1.03 + 0.04 (S.E.). This represents no statistical difference in water accumulation over three hours pulmonary edema. In Group II the average ratio of the wet-to-dry weight of the lung receiving 25 cm PEEP over the lung without PEEP was 0.96 + 0.02. This indicates that lungs receiving 25cm PEEP were slightly drier than the contralateral lungs in the same dogs without PEEP. This difference, however, is not significant at the 95% level. Thus at 10cm of PEEP there is no difference in lung water accumulation between the lungs. At 25cm of water there was a slight tendency for the lung with PEEP to be drier but this difference did not reach statistical significance. Blood Flow Studies Unilateral PEEP had the same effect on lung flow at both normal left atrial pressures and at left atrial pressures elevated by balloon obstruction of the mitral valve. With the application of 25cm unilateral PEEP cardiac output fell an average of 14%. In the lung without PEEP, applying 25cm of PEEP to the contralateral lung reduced blood flow by an average of 7%. Flow to the lung with PEEP was reduced by an average of 25%. Changes in cardiac output were significant at p < 0.01 and the reduction in flow to the lung with PEEP is significant at p < 0.05. The reduction in flow to the lung without PEEP is not significant at the 0.05 level. These changes in flows were the same whether PEEP was applied to the left or to the right lung and were the same with normal and with elevated left atrial pressures.
Discussion It is a frequent clinical observation that positive pressure ventilation improves oxygenation and ventilation in patients with severe pulmonary edema. In most instances addition of PEEP further improves oxygenation. There is, however, disagreement as to the mech-
61-
4
21-
0I
iucm
u
PEEP
25cm
U
PEEP
FIG. 3. Wet-to-dry weights of lungs with PEEP and lungs without PEEP mean + S.E. No statistically significant difference between the wet-to-dry weights of lungs with or without PEEP in either group.
anism which explains the clinical improvement in patients ventilated with positive pressure and PEEP. It has been suggested that positive pressure with PEEP actually dries out the lungs, reducing lung water and thereby improves gas exchange across the alveolar capillary membrane.2'3 While it is now generally concluded that positive pressure ventilation without PEEP does not physically dry out the lung,13 the question remains as to the effect on lung water of the addition of PEEP to positive pressure ventilation. In our own laboratory, we have previously compared two groups of animals with pulmonary edema induced in fashion similar to that of the present experiments. One group had 10cm of PEEP applied to the ventilator, the second group was ventilated with zero end expiratory pressure. No difference in lung water was found between the two groups after two hours of pulmonary edema.4 The present study was designed to look at the effect of higher levels of PEEP (25cm H20)
and to use each animal as its own control. The divided trachea model used in the present work has the advantage that the systemic response to pulmonary edema is constant for both lungs in any given animal
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and in particular, blood constituents are identical for each lung. Hence although colloid oncotic pressure and blood gases do not remain constant, the variance is the same for each pair of lungs. The divergence between the fall in colloid oncotic pressure compared with the relative stability of the hematocrit is an intriguing but unexplained observation. If we were observing simple hemodilution from the infusion of Ringer's lactate one would expect the relative concentration of both blood constituents to decrease in parallel fashion. The fall in colloid oncotic pressure may represent an actual loss in protein from the circulation, either in pulmonary edema fluid or in response to surgery as has been described.10 This divergence between colloid oncotic pressure and hematocrit has also been observed in our previous work.4 The major disadvantage of the split tracheal model is that at high levels of PEEP there is a relative reduction in blood flow to the lung ventilated with PEEP. Previous work has shown that with 10cm PEEP there is approximately a 5-10% reduction in flow to the lung with PEEP.'1 In the present work we looked at the effect on pulmonary blood flow of a higher level of PEEP comparable to that of Group II experiments. As one might anticipate, there was an even greater reduction in flow to the lung with PEEP, approximately 25%. However, the effect of reduction in blood flow to the lung would be to reduce the rate of lung water accumulation. Had we shown a reduction in lung water with high levels of unilateral PEEP the conclusion would have had to be tempered by a realization that any reduction in the accumulation of lung water could in part be due to reduction of blood flow. However, since in actual fact there was no significant reduction in lung water with high levels of PEEP despite a 25% reduction in lung flow, the conclusion that PEEP has no demonstrable effect on the accumulation of lung water remains valid. In the face of an elevated LA pressure, all lungs-with or without PEEP, 10cm H20 on 25cm H20 PEEP-accumulated significant and equal volumes of edema fluid. Lung water rose from a normal of77% to between 84% and 87% in the experimental group. The fact that despite the reduction in blood flow, PEEP lungs were not significantly drier than nonPEEP only underlines the inability of PEEP to mechanically prevent accumulation of water in the lung. Recent work in several laboratories confirms these observations. Alexander et al.I found no effect of 10cm of PEEP on the rate of lung water accumulation after two hours of pulmonary edema caused by constriction of the ascending aorta. Hopewell and Murray9 measured lung water both by indicator dilution methods and gravimetric techniques during pulmonary edema in dogs induced by left atrial obstruction and hemodilu-
437
tion. They demonstrated no difference in the increase in lung water between animals ventilated without PEEP and those ventilated with 10cm of PEEP. Caldini et al.5 also studying pulmonary edema in dogs caused by increased hydrostatic pressure and hemodilution both in the intact dog and in the isolated perfused lobe preparation demonstrated no difference in the rate of fluid transfer across the alveolar membrane between animals with and without PEEP. They did however note that with PEEP above 20 Torr pulmonary fluid was held in the alveoli and prevented from accumulating in the larger airways. They also noted that high levels of PEEP tended to favor the accumulation of fluid in the extravascular space of the lung. Demling et al.6'7 studied pulmonary edema in dogs caused by lobar venous occlusion. They found that at comparable intravascular filtration pressures dogs ventilated at an end expiratory pressure 10cm of water accumulated in fact somewhat more extravascular lung water than those ventilated without PEEP. Staub has quantitated the rate of water filtration across the pulmonary capillary membrane in unanesthetized sheep by measuring lung lymph flow. Lung lymph flow increased with elevated left atrial pressure but there was no difference in the rate of increase between sheep breathing spontaneously with 10cm of continuous positive airway pressure versus those breathing normally.'4 They also observed an increase in FRC and a decrease in intrapulmonary shunting in animals breathing against positive pressure similar to results obtained in our own earlier work with mechanical ventilation. It appears clear that positive end expiratory pressure on the airway is transmitted equally to the intravascular hydrostatic pressure as well as to the intrapleural pressure. The observation from multiple laboratories" 4-7'9"14 that increasing airway pressure has no effect on the rate of water transfer across the pulmonary capillary membrane confirms that the increase in airway pressure is transmitted also to the perimicrovascular interstitial fluid pressure to the same extent as it is to the microvascular intraluminal hydrostatic pressure.'4 Staub has quantitated this increase to be approximately 50% of the increase in airway pressure'4 al-
though this will vary with lung compliance. Hence an increase in airway pressure causes no change in the net filtration forces across the capillary membrane. These conclusions are similar to those reached concerning intermittent positive pressure breathing in the past.'3 Positive end expiratory pressure does not mechanically retard the accumulation of lung water caused by an increase in hydrostatic pressure. The benefit of
continuous positive pressure ventilation either spontaneously or with a ventilator derives from the increase in FRC and the recruitment of previously col-
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lapsed nonperfused alveoli which thereby reduce intrapulmonary shunting improving oxygen delivery. References 1. Alexander, L. G., Devries, W. C. and Anderson, R. W.: Airway Pressures and Pulmonary Edema Formation. Surg. Forum, 24:231, 1973. 2. Ashbaugh, D. G., Petty, T. L., Bigelow, D. B. and Harris, T. W.: Continuous Positive-Pressure Breathing (CPPB) in Adult Respiratory Distress Syndrome. J. Thorac. Cardiovasc. Surg., 57:31, 1969. 3. Aviado, D. M., Jr. and Schmidt, C. F.: Physiologic Basis for Treatment of Pulmonary Edema. J. Chronic Dis., 9:495, 1959. 4. Bredenberg, C. E., Kazui, T. and Webb, W. R.: Experimental Pulmonary Edema: The Effect of Positive End Expiratory Pressure on Lung Water. Ann. Thor. Surg., 26:62, 1978. 5. Caldini, P., Leith, J. D. and Brennan, M. J.: Effect of Continuous Positive-pressure Ventilation (CPPV) on Edema Formation in Dog Lung. J. Appl. Physiol., 39:672, 1975. 6. Demling, R. H. and Edmunds, L. H.: Effect of Continous Positive Airway Pressure on Extravascular Lung Water. Surg. Forum., 24:226, 1973.
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7. Demling, R. H., Staub, N. C. and Edmunds, L. H., Jr.: Effect of End-expiratory Airway Pressure on Accumulation of Extravascular Lung Water. J. Appl. Physiol., 38:907, 1975. 8. Guyton, A. C. and Lindsey, A. W.: Effect of Elevated Left Atrial Pressure and Decreased Plasma Protein Concentration on the Development of Pulmonary Edema. Circ. Res., 7: 649, 1959. 9. Hopewell, P. C. and Murray, J. F.: Effects of Continous Positive-pressure Ventilation in Experimental Pulmonary Edema. J. Appl. Physiol., 40:568, 1976. 10. Hoye, R. C., Paulson, D. F. and Ketchum, A. S.: Total Circulating Albumin Deficits Occuring with Extensive Surgical Procedures. Surg. Gynecol. Obstet., 131:943, 1970. 11. Kusajima, K., Webb, W. R., Parker, F. B., Jr., et al.: Pulmonary Responses of Unilateral Positive End Expiratory Pressure (PEEP) on Experimental Fat Embolism. Ann. Surg., 181:676, 1975. 12. Levine, 0. R., Mellins, R. B., Senior, R. M. and Fishman, A. P.: The Application of Starling's Law of Capillary Exchange to the Lungs. J. Clin. Invest., 46:934, 1967. 13. Visscher, M. B., Haddy, F. J. and Stephens, G.: The Physiology and Pharmacology of Lung Edema. Pharm. Rev., 8:388, 1956. 14. Woolverton, W. C., Brigham, K. L. and Staub, N. C.: Effect of Positive Pressure Breathing on Lung Lymph Flow and Water Content in Sheep. Circ. Res., 42:550, 1977.
