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SURGICAL ASPECTS OF ALBUMIN METABOLISM
SURGICAL ASPECTS OF ALBUMIN METABOLISM JOHN J. SKILLMAN,
M.D.
The Department of Surgery, Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts 02215
CONTENTS I. Introduction II. Transcapillary Fluid Exchange of Water, Sodium and Protein with Particular Reference to the Lung HI. Observations of Albumin Metabolism in Man A. Patients in acute respiratory failure B. Depletion of intravascular albumin during operation C. Deposition of albumin in skin, muscle and lung during operation D. Randomized trial of albumin vs. electrolyte solutions during abdominal aortic operations IV. Discussion V. Summary References
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I. INTRODUCTION Fluid replacement of patients following episodes of traumatic, hemorrhagic and septic shock or during major operative procedures has traditionally involved the use of salt and water regimens of varying amounts and composition. (1~5) Controversy concerning the precise magnitude of the extracellular volume deficits arising in these clinical situations (6~8) was originally based largely on differences in interpretation of the isotope dilution curves from which the volume deficits are believed to exist. Recent differences of opinion among various investigators interested in this field have focused on the pulmonary effects of electrolyte or colloid regimens for the treatment of hemorrhagic shock and for fluid replacement during or after a major operative procedure. (9~18) Because we are living in an era of soaring hospital costs, concern regarding the increased use of solutions of albumin for hospitalized patients has been voiced by physicians and hospital administrative personnel. The substantial increase in costs of processing plasma has been noted by one supplier to be primarily due to increasing procurement cost for domestic plasma supplies and higher costs associated with plasma donor center functions. Tn 1973 the Beth Israel Hospital in Boston, Massachusetts, purchased 11,032 units of albumin at an average cost of S22.00 for a total expenditure of $242,704, which was approximately 30% of the entire pharmacy budget. Tn one Boston hospital, the cost of a month's usage of albumin exceeded 350,000. These sobering statistics suggest a need for critical assessment of the utility of this material in the clinical practice of medicine and surgery. 333
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It is the intent of this brief review to outline the physiological basis for fluid and protein movement across capillary membranes, especially in relation to the lung. Emphasis is placed on the response of the lung because of the central role this organ plays in producing important dysfunction and death in critically ill patients. Observations made in operated and critically ill patients (Section III) form the basis for the use of albumin solutions in the clinical practice of surgery.
II. TRANSCAPILLARY FLUID EXCHANGE OF WATER, SODIUM AND PROTEIN WITH PARTICULAR REFERENCE TO THE LUNG The classic description of fluid movement across capillary membranes was originally described by Ernest Starling in 1896 (19) and can be expressed as: (20) Jr = Kf(Pc
-
PiH)
— (ττ ρ 1 -
TTi.s.),
where Jr = rate of net liquid movement across unit surface area of capillary, Kf = the capillary filtration coefficient, Pc and P{ s = the hydrostatic pressures (P) in the capillary (c) and interstitial space (i.s.), π ρ1 and TTJ s = the plasma (pi) and interstitial space (i.s.) oncotic (77) pressures. Although there may be reason to question the validity of this simplified statement of capillary permeability,(21) the experimental evidence in support of which was provided largely by the isogravimetric experiments of Pappenheimer and SotoRivera,(22,23) this concept appears at the very least to serve as an extremely useful model of capillary fluid movement. With regard to the lung, it would appear that edema formation cannot be defined solely in terms of intravascular forces, as previously suggested by Guyton and Lindsey. (24) Pericapillary forces in the pulmonary interstitium have an appreciable effect on exchange of fluid through the capillary membrane. (25) In an isolated, dog-lung lobe preparation perfused in vivo with solutions of horseradish peroxidase or hemoglobin (molecular weight 64,500 and diameter of approximately 60 Ä), a perfusion pressure of greater than 50 mm Hg for 5 to 10 minutes was required before intraalveolar edema occurred. (2e) From these latter experiments it was concluded that the pulmonary alveolar epithelium, and not the vascular endothelium, represents the major barrier to the passage of water from the capillaries into the alveolar space. Since greater degrees of perfusion pressure were associated with a heightened permeability, it seems likely that increased intravascular pressure may widen the caliber of pulmonary capillary endothelial pores. These experiments also support the concept of a system of labile pores for systemic and pulmonary capillaries(27) and suggest the possibility that the traditional distinction between "hemodynamic" and "permeability" types of pulmonary edema may not be valid. However, other recent experimental evidence in favor of a difference between hydrostatic and permeability types of pulmonary edema was presented by Brigham and coworkers. (28) These investigators studied the responses of lung lymph flow and lymph and plasma protein concentrations in awake sheep to steady-state elevations of pulmonary vascular pressures made by inflating a left atrial balloon with those after an
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intravenous infusion of 105—1010 Pseudomonas aeruginosa bacteria. Their data showed that the intravenous infusion of Pseudomonas aeruginosa bacteria into the awake sheep causes a dramatic, prolonged, but reversible increase in pulmonary transvascular fluid and protein flow which was out of proportion to changes in vascular pressure. Even though two groups suggested that pore size may increase with increased vascular pressure (2729) and another group suggested that increased pressure decreases pore size,(30) Brigham and his coworkers did not find either change necessary to predict the effects of increased pressure on lymph-plasma protein ratios. The latter group found that a fixed vascular membrane structure with a large number of small pores, which completely exclude albumin per one intermediate pore of 125 A radius, would predict experimentally measured lymph-plasma albumin and globulin concentration ratios over a wide range of microvascular pressures. (3l) They concluded that large changes in fluid and protein filtration may result from small changes in the structure of exchanging vessels. Another important conclusion from Brigham's study is that the lesion induced by Pseudomonas infusion is entirely reversible in most sheep, a finding which suggests that severe pulmonary edema in humans occurring in the absence of heart failure may not necessarily result in extensive, irreversible damage to the lung's vascular endothelium. It may be important, therefore, as suggested by these investigators, to keep left atrial pressures low in clinical situations where increased vascular permeability is suspected. A further implication of this labile pore theory is that increases of pulmonary intravascular pressure, as might result from a rapid rise in left atrial pressure, will increase the capillary permeability to albumin, a tendency which would increase water movement into the pulmonary interstitium. It would appear that the degree of restriction to exchange of solutes across the pulmonary capillary endothelium is quite similar to that which is observed in the endothelium of heart and skeletal muscle capillaries. <32) In addition, electron micrographs indicate great similarity of these capillaries. (26) Calculations of pore size indicate that the pores of the pulmonary capillary endothelial membrane (40-50 Ä) are approximately 7-10 times larger than those of the alveolar epithelial membrane (6-10 Ä), a finding which is consistent with the differences in permeability at these two sites. (26) Pulmonary intraalveolar edema is prevented not only by the restrictive effect of the alveolar epithelial membrane, but also by the collection of fluid in the pulmonary interstitium which eventually results in increased lymphatic flow. Obstruction to increased lymph flow by a rise in left atrial pressure increases the likelihood of the development of pulmonary edema (33) and, as noted above, might be expected to be especially hazardous in association with a major septic focus. Chronic heart failure induced in animals is associated with a large functional expansion of pulmonary lymphatic drainage,(34) a compensatory mechanism which may be of great importance in the prevention of pulmonary edema in patients with a failing myocardium. Although pulmonary capillaries have a high permeability to water and other solutes,(20) relatively high molecular weight substances, such as proteins, are much less capable of diffusing across these cells. (32*35) When the alveoli of dogs are filled with saline for hours, (20) even large molecules (such as dextran—70,000 molecular weight) may be found in the alveolar fluid. This work suggests that the longer that fluid stays in pulmonary alveoli, the greater are the chances for increased alveolar capillary permeability to occur. These experimental observations support the clinical relevance
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of early aggressive reversal of acute pulmonary edema by diuretic therapy to prevent sustained fluid accumulations in the pulmonary interstitial and alveolar spaces. (17) Colloid osmotic pressure (25-28 mm Hg) normally acts to retain water within the capillary. Pulmonary hydrostatic pressure (10 mm Hg) drives fluid into the interstitial space. The magnitude of the pulmonary interstitial oncotic and hydrostatic pressures are much less certain, although work by Meyer et al.(36) and Levine and coworkers <25) suggests that pulmonary interstitial pressure is normally about minus 10-15 mm Hg (subatmospheric). it is presumed that lymph pumping and the physical motion of lung tissue may be causally related to the development of the negative pressure. (20) Pulmonary interstitial oncotic pressure depends on chemical binding of water, exclusion of plasma proteins, and the contribution of substances such as hyaluronic acid. (37~39) It has been estimated by Staub that the interstitial oncotic pressure is high enough that movement of fluid from pulmonary capillaries may occur even in the absence of a negative interstitial pressure. (40) Alveolar surface tension forces tend to promote a movement of fluid from pulmonary capillaries into the alveoli. (41) Robin has suggested that the major function of the lymphatic system in the lung may involve selective uptake of protein from the pulmonary interstitial space. (20) Even though the graphic experiments of Guyton (24) and Gaar (42) indicate the importance of protein concentration to prevention of pulmonary water accumulation, Robin has suggested that these experiments may merely reflect the point at which formation of capillary ultrafiltrate exceeds the capacity for lymphatic removal of this fluid. It appears that the net result of the Starling forces acting across pulmonary capillary walls is somewhat positive.(40) This conclusion is consistent with a liquid layer coating the surface of the alveolar lining in the normal lung and would also explain the origin of normal pulmonary lymphatic flow. Certainly much is not yet known about the precise magnitude of the various physical forces capable of influencing fluid movement across the alveolar-capillary membrane. (43) Although Starling's hypothesis of transcapillary fluid exchange does not provide a complete description of these forces, the pulmonary intravascular and interstitial oncotic and hydrostatic forces are nevertheless extremely important determinants of net fluid flow in the lungs.
III. OBSERVATIONS OF ALBUMIN METABOLISM IN MAN A. Patients in Acute Respiratory Failure Hypoalbuminemia and decreased serum oncotic pressure are extremely common abnormalities in patients with acute respiratory failure after major abdominal operations, particularly when these operations are associated with peritonitis. (17-44) In a series of fifty-eight consecutive patients admitted to a respiratory-surgical intensive-care unit after abdominal operations, the mean lowest serum albumin concentration in patients with peritonitis and acute respiratory failure was 2.3 ± 0.1 g/dl (SEM), a value which was significantly lower than in patients in whom peritonitis and respiratory failure were absent (2.8 ± 0.1 g/dl; p < 0.025). Similar findings were reported by Hoye and Ketcham(45) in patients having extensive abdominal operations and by Deysine and coworkers (46) in patients who had septic shock or
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septicemia. The former group (45) also demonstrated that the return of albumin to the intravascular compartment via the thoracic duct was considerably reduced in the intraoperative period. The observation that almost all patients after abdominal operations have significant hypoalbuminemia led to the suggestion that the reduced colloid osmotic pressure of the plasma might, in part, be a contributor to the development of acute respiratory failure by increasing the tendency for water to accumulate in the lung. (24,42) It is clear that an increase in lung water plays a central role in the development and continuation of acute respiratory failure in man. (47 · 48) To assess the possibility that an increase of serum oncotic pressures and diuresis might reduce pulmonary water and improve ventilation perfusion in the lung, (17) sixteen patients in acute respiratory failure with alveolar to arterial oxygen tension differences ( F , 0 2 = 1.0) ranging from 235 to 579 mm Hg (mean—360 mm Hg) were treated with concentrated human salt-poor albumin (25 g) alone or albumin (25 g) plus a potent diuretic (ethacrynic acid—20 to 100 mg) or ethacrynic acid alone (50 mg). improvement in right to left intrapulmonary shunting occurred in only five of the twelve measurement periods in patients receiving albumin alone. However, improvement of shunting occurred in ten of sixteen measurement periods in patients receiving both albumin and ethacrynic acid. The improvement in alveolar-arterial oxygen tension gradients correlated strongly with the magnitude of the diuresis. Albumin infusion prevented the fall in plasma volume which occurred with ethacrynic acid alone and resulted in a significant increase of albumin concentration and serum oncotic pressure. Results of this study suggest that concentrated salt-poor albumin, especially when given with a potent diuretic agent, may remove pulmonary water and improve the pulmonary ventilation-perfusion abnormality in patients with acute respiratory failure.
B. Depletion of Intravascular Albumin during Operation Significant depletion of intravascular albumin occurs intraoperatively in patients who undergo major vascular reconstructive procedures. (49) The mean decrease of intravascular albumin mass in this study was 33.3 g, a decrease which was approximately 20% of the preoperative circulating value. A large part of this albumin depletion can be explained by unreplaced deficits of whole blood. Seven of the twelve patients studied showed an increased disappearance rate of Evans blue from the plasma in the postoperative period, suggesting the possibility that increased capillary permeability to albumin and accumulation of this protein in extravascular tissues might be an additional explanation for intravascular albumin depletion.
C. Deposition of Albumin in Skin, Muscle and Lung during Operation Recent studies of the accumulation of albumin in human tissue during major operative procedures in sixteen patients indicate that there is a significant increase in the total albumin content of skin and muscle tissue at the operative wound site which is almost entirely accounted for by deposition of this protein in the extravascular portion of these tissues. (50) More extravascular albumin and water deposition occurred
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in muscle in comparison to skin. However, nine patients in this study who underwent thoracotomy for suspected bronchogenic carcinoma did not show the expected increase of extravascular albumin deposition in lung biopsies taken from the lobe to be resected when the chest was opened and just before the lobe was removed. Inadequate perfusion of the lung does not appear to explain this finding, since there was a minimum time of 60 minutes between the first biopsy and ligation of the pulmonary artery. The greater extravascular accumulation of albumin in human skin and muscle tissues in comparison to lung suggests that under the conditions imposed by these operative procedures, the capillary membrane of the lung may be less permeable to albumin than skin and muscle at the operative wound site. An alternate explanation is the possibility that lymphatic removal of albumin from the lung may have been significantly greater than that from skin and muscle tissues. Of additional interest in these studies was the finding that the intraoperative loss of circulating albumin was significantly correlated with the duration of operation (r = 0.69, p < 0.01).(51) The decrease in circulating albumin mass was also significantly correlated with the increase in extravascular albumin in muscle tissue (/* = 0.7, p < 0.01). These data suggest that intravascular albumin depletion is greater with longer operative procedures. It seems clear from the data cited above that intravascular albumin depletion occurs during major operative procedures, and is in part causally related to the subsequent development of hypoalbuminemia which is frequently observed in the postoperative period. Sepsis, especially when it occurs in the peritoneal cavity, is particularly likely to be associated with hypoalbuminemia and a decreased serum oncotic pressure. Although a portion of the loss of serum albumin is related to its accumulation in the skin and muscle of operative wounds, a finding which has also been reported by Mouridsen,(52) these sites probably account for only a small fraction of the total intravascular depletion of this osmotically active protein. Unreplaced blood volume deficits, as noted above, make up another important source of this albumin loss. It is unlikely that a generalized increase in vascular permeability occurs after operative procedures, except in situations like portal hypertension where reaccumulation of ascites may be responsible for large intravascular albumin deficits or in clinical situations associated with marked sepsis, where it has been demonstrated that endotoxin may produce a diffuse capillary injury (5354) and where large protein molecules such as fibrinogen (molecular weight = 340,000) may be found in substantial quantities in pulmonary edema fluid. (55)
D. Randomized Trial of Albumin vs. Electrolyte Solutions during Abdominal Aortic Operations A prospective, randomized trial of sixteen patients undergoing operative procedures on the abdominal aorta was recently conducted to assess the comparative effects of an albumin-rich intraoperative fluid regimen to a sodium-rich intraoperative fluid regimen (18) on postoperative pulmonary shunting, serum oncotic pressure, albumin and total protein concentration, plasma volume and creatinine clearance. Patients received either a sodium-rich regimen (prehydration with 5% dextrose in water— 1 litre, 5% dextrose in Ringer's lactate solution—approximately 500 ml per hour of
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METABOLISM
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anesthesia, and blood to replace estimated whole blood losses) or an albumin-rich regimen (25% concentrated salt-poor human albumin—1 gm/kg body weight, 5% albumin in saline—1 liter, and prehydration and blood as in the sodium-rich regimen). Three patients in the electrolyte group received Ringer's lactate in excess of the protocol through an error. The mean alveolar to arterial oxygen tension difference measured in nine patients after 15 minutes of breathing 100% oxygen (AaD0 2 , F ^ = 1.0) was 315 ± 51 mm Hg (SEM) in the sodium-rich group on the first postoperative day in comparison to an AaD0 2 (Fj0 2 = 1.0) of 142 ± 39 mm Hg in seven patients in the albumin-rich group, /; < 0.05. The increase in A a D 0 2 correlated positively with the total sodium intake in the electrolyte group (r = 0.74, p < 0.05), but a significant correlation between A a D 0 2 and sodium intake was not found in the albumin-treated patients (/* = 0.25, p < 0.1). Despite the large fluid load, patients in the sodium-rich group had a significant decrease in the postoperative plasma volume and circulating intravascular albumin mass, findings which were not observed in the albumin group. The gain in body weight was 1.7 times greater in the combined Ringer's lactated patients than in the albumin-treated patients, /; < 0.01. These differences in body weight were reflected by the net mean fluid balance increments on the day of operation in the two groups (p < 0.01). The serum albumin concentration rose significantly on the day of operation in albumin-treated patients (/; < 0.01). The decrease in serum albumin concentration on the day of operation, though statistically significant for the combined Ringer's lactate and excess Ringer's lactate groups (/; < 0.025), was not significant for the individual Ringer's lactate subgroups (Ringer's lactate and excess Ringer's lactate). The albumin concentration was significantly greater in albumin-treated patients than in either of the Ringer's lactate groups on the day of operation, p < 0.005. The changes in serum albumin concentration were reflected by similar differences in serum oncotic pressure (π) on the day of operation and on the first postoperative day. Serum oncotic pressure was maintained in the albumin-treated patients on the day of operation and on the first postoperative day, but fell significantly on the day of operation in the Ringer's lactate-treated patients. A significant correlation between the fall in serum oncotic pressure and sodium intake was observed in the Ringer's lactate-treated patients (r = 0.72, /; < 0.01). Changes in circulating albumin mass were correlated positively with changes in serum oncotic pressure (/· = 0.73, p < 0.01). As the circulating albumin mass increased, the serum oncotic pressure also increased. Conversely, decreases in circulating albumin mass were associated with decreases in serum oncotic pressure. The endogenous creatinine clearance fell similarly on the day of operation in both groups and no apparent differences in this measurement of renal function were observed in the two groups. The concern, therefore, that a colloid-based intraoperative fluid regimen would produce more depression of renal function in the postoperative period than an electrolyte-based regimen was not realized. The changes in pulmonary arteriovenous admixture, plasma volume, weight gain, fluid intake, albumin concentration, circulating albumin mass and serum oncotic pressure of a group of patients undergoing a major but similar operative stress are indicated in considerable detail because the data appear to be pertinent to the question of the optimum choice of fluids for many patients undergoing major operative
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SKILLMAN
procedures. Although Ladegaard-Pedersen found that patients who underwent a variety of major operative procedures showed a decreased plasma volume in the postoperative period, he was able to find only minimally significant changes in the serum oncotic pressure over that which might be expected to occur from differences in posture (bed rest versus ambulatory state). (56) Data obtained from our prospective randomized trial show that even when large volumes of Ringer's lactate are infused intraoperatively, the plasma volume falls significantly despite a large weight gain in patients who do not receive any intraoperative albumin infusion. The colloid osmotic pressure fell to approximately 70% of the control value in these patients. It would appear, therefore, that the tendency for infused fluid to leave the plasma volume follows the laws of transcapillary fluid exchange originally proposed by Starling. The more positive weight gain which was observed in patients who did not receive colloid must, by virtue of the normal distribution of sodium and water, contribute to excess expansion of the interstitial fluid space. Although it has already been pointed out that the contribution of intravenously administered salt and water to pulmonary extravascular water accumulation may not strictly follow Starling's predictions, the marked increase in the alveolar-arterial oxygen tension gradients in those patients receiving excess Ringer's lactate is dramatic evidence in support of the importance of this relationship to the lung. The three patients who received excess Ringer's lactate were in serious difficulty with pulmonary edema on the morning of the first postoperative day and required vigorous diuresis and controlled ventilation with positive endexpiratory pressure to reverse this acute problem. Convincing evidence of a positive relationship between the increase of A a D 0 2 and sodium intake was also observed in this study. These data showed a significant correlation between increasing sodium intake and rises in the alveolar-arterial oxygen tension gradients, a correlation which was not observed in patients receiving albumin. This evidence gives even more support to the conclusion that provision of large amounts of saline without albumin to patients undergoing major operative procedures is undesirable and is likely to contribute to postoperative acute respiratory failure through an increase of pulmonary water content.
IV. DiSCUSSION Although the infusion of colloid into rats following a 50% hemorrhage in an amount equivalent to five times the estimated blood loss was associated with more pulmonary edema than crystalloid infusion in the amount of six times the blood loss,(16) this result is entirely predictable based on the distribution of the infused fluid in these two experimental situations. (57) In the study of hemorrhagic shock performed in rhesus monkeys by Gaisford and coworkers,(10) in which Ringer's lactate solution or 5 % albumin was infused at a rate sufficient to maintain the central venous pressure at 5-6 cm water, pulmonary ultrastructural evidence of pulmonary edema occurred only in those animals treated with Ringer's lactate. The results of this latter study are in conflict with those reported by Moss and coworkers (14) and Siegel and coworkers, (58) who studied pulmonary ultrastructural changes after hemorrhagic shock in the baboon treated by saline infusion and colloid infusion. These latter two studies indicated that saline resuscitation resulted in a disappearance of interstitial pulmonary
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edema, whereas colloid infusion resulted in distortion of alveolar collagen and interstitial edema. These experiments (14 · 58) may be criticized, however, since human albumin was infused into baboons in the colloid resuscitation experiments,(58) a protocol which might, therefore, have led to an immunological reaction in the lung. Although treatment of acute respiratory failure in humans with concentrated salt-poor albumin infusion is not uniformally beneficial in reducing elevated alveolararterial oxygen tension gradients, when this therapy is combined with a rapidly acting diuretic agent, dramatic reversal of pulmonary shunting is often observed.(17) It has been recently demonstrated that lung weight and pulmonary capillary pressure may be dramatically reduced by concentrated albumin (25 g) and urea (10 g in invert sugar) when hydrostatic pulmonary edema is produced by pulmonary venous constriction in an isolated, perfused dog lung model.(59) Similar results have been obtained by others. (60) Uncertainties regarding the application of the colloid-diuretic principle to patients who have acute respiratory failure associated with major sepsis still exist, however, since increased pulmonary capillary permeability to albumin leading to its accumulation in the pulmonary interstitial space may occur in this clinical situation and lead to a decreased oncotic effect of the albumin which is infused. As previously noted, however, the relative tightness of the pulmonary alveolar membrane (26) and the tremendous capacity for an increase of lymphatic removal of salt, water and protein from the lung are two important protective mechanisms which lead to amelioration of persistent fluid accumulations in the lung. As has already been pointed out, the effect of an experimentally induced bacterial insult on the permeability of the pulmonary capillary endothelium to water and protein may also be readily reversible,(28) although the mortality rate of patients in acute respiratory failure rises precipitously when gram negative pneumonia supervenes.(61) Clinical experience in the management of patients in acute respiratory failure suggests that early agressive treatment of atelectasis and pulmonary edema by controlled ventilation, chest physical therapy, fluid restriction, albumin infusion and diuresis are all extremely important therapeutic measures. V. SUMMARY Patients who undergo major operative procedures lose albumin from the intravascular compartment through unreplaced deficits of blood volume. There is also a significant extravascular accumulation of albumin in skin and muscle, but not in lung, during operative procedures in man. Although sepsis may alter capillary permeability and result in further losses of albumin from the intravascular compartment into the interstitial fluid space, this possibility should not necessarily be interpreted as a reason to withhold albumin in hypoalbuminemic patients. When hypovolemia occurs in post-operative patients it is almost always associated with a gain of weight and a large increase in body water and sodium content. Further sodium intake, in the absence of an osmotic force to hold it within the intravascular compartment, will only increase the tendency for interstitial fluid volume expansion. As the interstitial fluid space of the lung shares in the accumulation of sodium and water, the tendency for eventual pulmonary edema and subsequent acute respiratory failure to occur is also increased. Evidence presented in the prospective randomized trial of patients receiving an albumin-rich versus a sodium-rich inträoperative fluid
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regimen suggests that albumin replacement may have advantages over conventional salt and water-based fluid regimens. Patients treated with albumin in this study had less pulmonary arteriovenous admixture in the post-operative period, with better maintenance of the circulating albumin mass, serum oncotic pressure and plasma volume than patients who were treated with Ringer's lactate. Although these data should not be interpreted to indicate that salt should be withheld during major operative procedures, they do suggest a more moderate position with regard to sodium administration. The tendency for "third space losses" to occur following major operative procedures may be partly an iatrogenic abnormality, since the administration of excess salt and water can only result in an increase of the interstitial fluid volume. It would appear that the tendency to third space fluid accumulation may be minimized by the provision of albumin in the operative and early postoperative periods in patients who have major operative procedures.
REFERENCES 1. Shires, T., J. Williams and F. Brown (1961) Acute change in extracellular fluids associated with major surgical procedures. Ann. Surg. 154, 803-810. 2. Shires, T., D. Cohn, J. Carrico and S. Lightfoot (1964) Fluid therapy in hemorrhagic shock. Arch. Surg. 88, 688-693. 3. Thompson, J. E., R. W. Vollman, D. J. Austin and M. M. Kartchner (1968) Prevention of hypotensive and renal complications of aortic surgery using balanced salt solution: thirteen years experience with 670 cases. Ann. Surg. 167, 767-778. 4. Wheeler, C. G., J. E. Thompson, M. M. Kartchner,' D. J. Austin and R. D. Patman (1966) Massive fluid requirement in surgery of the abdominal aorta. New Engl. J. Med. 275, 320-322. 5. Cohn, L. H., M. R. Powell, L. Seidlitz, W. K. Hamilton and E. J. Wylie (1970) Fluid requirements and shifts after reconstruction of the aorta. Am. J. Surg. 120, 182-186. 6. Roth, E., L. C. Lax and J. V. Maloney, Jr. (1969) Ringer's lactate solution and extracellular fluid volume in the surgical patient. A critical analysis. Ann. Surg. 169, 149-164. 7. Gutelius, J. R., H. M. Shizgal and G. Lopez (1968) The effect of trauma on extracellular water volume. Arch. Surg. 97, 206-214. 8. Hutchin, P., R. G. Terzi, L. C. Hollandsworth, G. Johnson, Jr. and R. M. Peters (1969) The influence of intravenous fluid administration on post-operative urinary water and electrolyte excretion in thoracic surgical patients. Ann. Surg. 170, 813-823. 9. Collins, J. A., A. Braitberg and H. R. Butcher (1973) Changes in lung and body weight and lung water content in rats treated for hemorrhagic shock with various fluids. Surgery 73, 401-411. 10. Gaisford, W. D., N. Pandey and C. G. Jensen (1972) Pulmonary changes in treated hemorrhagic shock. Am. J. Surg. 124, 738-743. 11. Giordano, J. M., D. A. Campbell and W. L. Joseph (1973) The effect of intravenously administered albumin on dogs with interstitial pulmonary edema. Surg., Gynec. and Obstet. 137, 593-596. 12. Holcroft, J. W. and D. D. Trunkey (1974) Extra vascular lung water following hemorrhagic shock in the baboon: Comparison between resuscitation with Ringer's lactate and plasmanate. Ann. Surg. 180,408-417. 13. Johansen, S. H., P. Bech-Jansen and O. Beck (1972) Alveolar-arterial oxygen tension gradients during preoperative replacement of fluid loss by physiological saline. Acta Anaesth. Scand. 16, 127-131. 14. Moss, G. S., T. K. Das Gupta, B. Newson and L. M. Nyhus (1973) The effect of saline solution resuscitation on pulmonary sodium and water distribution. Surg., Gynec. and Obstet. 136, 934-940. 15. Moss, G. S., D. C. Siegel, A. Cochin and V. Fresquez (1971) Effects of saline and colloid solutions on pulmonary function in hemorrhagic shock. Surg., Gynec. and Obstet. 133, 53-58. 16. Schloerb, P. R., P. T. Hunt, J. A. Plummer and G. K. Cage (1972) Pulmonary edema after replacement of blood loss by electrolyte solutions. Surg., Gynec. and Obstet. 135, 893-896. 17. Skillman, J. J., B. M. Parikh and B. J. Tanenbaum (1970) Pulmonary arteriovenous admixture— improvement with albumin and diuretics. Am. J. Surg. 119,440-447.
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18. Skillman, J. J., D. S. Restall and E. W. Salzman (1975) Randomized trial of albumin vs. electrolyte solutions during abdominal aortic operations. Surgery 78, 291-303. 19. Starling, E. H. (1896) On the absorption of fluids from the connective tissue spaces. J. Physiol. (Lond.) 19,312-326. 20. Robin, E. D., C. E. Cross and R. Zelis (1973) Pulmonary edema. New Engt. J. Med. 288,239-246, 292-304. 21. Weiderhelm, C. A. (1966) Analysis of small vessel function (abstract). In: Physical Basis of Circulatory Transport: Regulation and Exchange. Aspen, Colorado. 22. Pappenheimer, J. R. and A. Soto-Rivera (1948) Effective osmotic pressure of the plasma proteins and other quantities associated with the capillary circulation in the hindlimbs of cats and dogs. Am. J. Physiol. 152, 471-491. 23. Landis, E. M. and J. R. Pappenheimer (1963) Exchange of substances through capillary walls. In: Handbook of Physiology, Sect. 2, Vol. 2. Circulation, W. F. Hamilton and P. Dow, editors. Washington, D.C., American Physiological Society. 24. Guyton, A. C. and A. W. Lindsey (1959) Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circulation Res. 7, 649-657. 25. Levine, O. R., R. B. Mellins, R. M. Senior and A. P. Fishman (1967) The application of Starling's law of capillary exchange to the lungs. J. Clin. Invest. 46, 934-944. 26. Szidon, J. P., G. G. Pietra and A. P. Fishman (1972) The alveolar-capillary membrane and pulmonary edema. New Engl. J. Med. 286, 1200-1204. 27. Shirley, H. H., Jr., C. G. Wolfram, K. Wasserman and H. S. Mayerson (1957) Capillary permeability to macromolecules: stretched pore phenomenon. Am. J. Physiol. 190, 189-193. 28. Brigham, K. L., W. C. Woolverton, L. H. Blake and N. C. Staub (1974) Increased sheep lung vascular permeability caused by Pseudomonas bacteria. J. Clin. Invest. 54, 729-804. 29. Pietra, G. G., J. P. Szidon, M. M. Leventhal and A. P. Fishman (1969) Hemoglobin as a tracer in hemodynamic pulmonary edema. Science (Washington, D.C.) 166, 189-197. 30. Arturson, G., T. Groth and G. Grotte (1972) The functional ultrastructure of the blood-lymph barrier. Computer analysis of data from dog heart-lymph experiments using theoretical models. Act a Physiol. Scand. Suppl. 374, 1-30. 31. Blake, L. H. and N. C. Staub (1972) Modeling of steady state pulmonary transvascular fluid and protein exchange in unanesthetized sheep. Physiologist 15, 88 (Abstr.). 32. Taylor, A. E. and K. A. Gaar, Jr. (1967) Estimation of equivalent pore radii of pulmonary capillary and alveolar membranes. Am. J. Physiol. 213, 94-101. 33. Wegria, R., R. W. Entrup, J. Jue and M. Hughes (1967) A new factor in pathogenesis of edema of cardiac origin. Am. J. Physiol. 213, 94-101. 34. Uhley, H. N., S. E. Leeds, J. J. Sampson and M. Friedman (1962) Role of pulmonary lymphatics in chronic pulmonary edema. Circulation Res. 11, 966-970. 35. Chinard, F. P. (1966) The permeability characteristics of the pulmonary blood-gas barrier. Advances in Respiratory Physiology, C. G. Caro, editor, pp. 106-147. London, England, Arnold Ltd. 36. Meyer, B. J., A. Meyer and A. C. Guyton (1968) Interstitial fluid pressure v. negative pressure in lungs. Circulation Res. 22, 263-271. 37. Guyton, A. C , H. T. Granger and A. E. Taylor (1971) Interstitial fluid pressure. Physiol. Rev. 51, 527-563. 38. Weiderhelm, C. A. (1968) Dynamics of transcapillary fluid exchange. / . Gen. Physiol. 52, Suppl. 29-63. 39. Weiderhelm, C. A. (1969) The interstitial space and lymphatic pressures in the bat wing—the pulmonary circulation and interstitial space. A. P. Fishman and H. H. Hecht, editors, pp. 29-41. Chicago, University of Chicago Press. 40. Staub, N. C. (1971) Steady state pulmonary transvascular water filtration in unanesthetized sheep. Circ. Res. 28, Suppl. 1, 135-139. 41. Mead, J., T. Takishima and D. Leith (1970) Stress distribution in lungs: a model of pulmonary elasticity. J. Appl. Physiol. 28, 596-608. 42. Gaar, K. A., Jr., A. E. Taylor, L. J. Owens and A. C. Guyton (1967) Effect of capillary pressure and plasma protein concentration on development of pulmonary edema. Am. J. Physiol. 213, 79-82. 43. Staub, N. C. (1970) The pathophysiology of pulmonary edema. Hum. Pathol. 1, 419-432. 44. Skillman, J. J., L. S. Bushnell and J. Hedley-Whyte (1969) Peritonitis and respiratory failure after abdominal operations. Ann. Surg. 170, 122-127. 45. Hoye, R. C. and A. S. Ketcham (1967) Shifts in body fluids during radical surgery. Cancer 20, 1827-1831.
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46. Deysine, M., N. Lieblich and A. H. Aufses, Jr. (1973) Albumin changes during clinical septic shock. Surg., Gynec, and Obstet. 137, 475-478. 47. Martin, A. M., Jr., R. L. Simmons and C. A. Heistercamp (1969) Respiratory insufficiency in combat casualties 1. Pathologic changes in lungs of patients dying of wounds. Ann. Surg. 170, 30-38. 48. Sladen, A., M. B. Laver and H. Pontopiddan (1968) Pulmonary complications and water retention in prolonged mechanical ventilation. New Engt. J. Med. 279, 448-453. 49. Skillman, J. J. and B. J. Tanenbaum (1970) Unrecognized losses of albumin, plasma and red cells during abdominal vascular operations. Current Topics in Surg. Res. 2, 523-533. 50. Smith, P. C , H. A. Frank and J. J. Skillman (1975) Albumin deposition in human lung, skin and skeletal muscle during operation. Surg. Forum 26, 91-93. 51. Smith, P. C , E. C. Dearborn, H. A. Frank and J. J. Skillman (1976) Deposition of albumin in human lung, skin and skeletal muscle during operation and in patients dying of acute respiratory failure. (Manuscript in preparation.) 52. Mouridsen, H. T. (1968) The extravascular retention of serum albumin in the operative wound. Acta Chir. Scand. 134, 417-421. 53. Riordan, J. F. and G. Walters (1968) Pulmonary edema in bacterial shock. Lancet 1, 719-721. 54. Clarkson, B., D. Thompson, M. Horwith and E. H. Luckey (1960) Cyclical edema and shock due to increased capillary permeability. Am. J. Med. 29, 193-216. 55. Robin, E. D., L. C. Carey, A. Grenvik, F. Glauser and R. Gaudio (1972) Capillary leak syndrome with pulmonary edema. Arch. Intern. Med. 130, 66-71. 56. Ladegaard-Pedersen, H. J. (1969) Post-operative changes in blood volume and colloid osmotic pressure. Acta Chir. Scand. 135, 95-104. 57. Skillman, J. J. and P. R. Schloerb (1973) Surgical pros and cons. Surg., Gynec, and Obstet. 137, 279. 58. Siegel, D. C , G. S. Moss, A. Cochin and T. K. Das Gupta (1970) Pulmonary changes following treatment for hemorrhagic shock: saline versus colloid infusion. Surgical Forum 21, 17-19. 59. Brown, P. P., J. R. McCurdy, R. C. Elkins and L. J. Greenfield (1973) Effects of albumin and urea on hydrostatic pulmonary edema in the perfused lung. J. Surg. Res. 14, 359-366. 60. Williams, G. D., K. Ozment and R. W. Baggett (1972) Hyperosmolar perfusion for removal of pulmonary edema. / . Surg. Res. 12, 105-113. 61. Stevens, R. M., D. Teres, J. J. Skillman and D. S. Feingold (1974) Pneumonia in an intensive care unit: a thirty month experience. Arch, intern. Med. 134, 106-111.
M.D.
The Department of Surgery, Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts 02215
CONTENTS I. Introduction II. Transcapillary Fluid Exchange of Water, Sodium and Protein with Particular Reference to the Lung HI. Observations of Albumin Metabolism in Man A. Patients in acute respiratory failure B. Depletion of intravascular albumin during operation C. Deposition of albumin in skin, muscle and lung during operation D. Randomized trial of albumin vs. electrolyte solutions during abdominal aortic operations IV. Discussion V. Summary References
333 334 336 336 337 337 338 340 341 342
I. INTRODUCTION Fluid replacement of patients following episodes of traumatic, hemorrhagic and septic shock or during major operative procedures has traditionally involved the use of salt and water regimens of varying amounts and composition. (1~5) Controversy concerning the precise magnitude of the extracellular volume deficits arising in these clinical situations (6~8) was originally based largely on differences in interpretation of the isotope dilution curves from which the volume deficits are believed to exist. Recent differences of opinion among various investigators interested in this field have focused on the pulmonary effects of electrolyte or colloid regimens for the treatment of hemorrhagic shock and for fluid replacement during or after a major operative procedure. (9~18) Because we are living in an era of soaring hospital costs, concern regarding the increased use of solutions of albumin for hospitalized patients has been voiced by physicians and hospital administrative personnel. The substantial increase in costs of processing plasma has been noted by one supplier to be primarily due to increasing procurement cost for domestic plasma supplies and higher costs associated with plasma donor center functions. Tn 1973 the Beth Israel Hospital in Boston, Massachusetts, purchased 11,032 units of albumin at an average cost of S22.00 for a total expenditure of $242,704, which was approximately 30% of the entire pharmacy budget. Tn one Boston hospital, the cost of a month's usage of albumin exceeded 350,000. These sobering statistics suggest a need for critical assessment of the utility of this material in the clinical practice of medicine and surgery. 333
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It is the intent of this brief review to outline the physiological basis for fluid and protein movement across capillary membranes, especially in relation to the lung. Emphasis is placed on the response of the lung because of the central role this organ plays in producing important dysfunction and death in critically ill patients. Observations made in operated and critically ill patients (Section III) form the basis for the use of albumin solutions in the clinical practice of surgery.
II. TRANSCAPILLARY FLUID EXCHANGE OF WATER, SODIUM AND PROTEIN WITH PARTICULAR REFERENCE TO THE LUNG The classic description of fluid movement across capillary membranes was originally described by Ernest Starling in 1896 (19) and can be expressed as: (20) Jr = Kf(Pc
-
PiH)
— (ττ ρ 1 -
TTi.s.),
where Jr = rate of net liquid movement across unit surface area of capillary, Kf = the capillary filtration coefficient, Pc and P{ s = the hydrostatic pressures (P) in the capillary (c) and interstitial space (i.s.), π ρ1 and TTJ s = the plasma (pi) and interstitial space (i.s.) oncotic (77) pressures. Although there may be reason to question the validity of this simplified statement of capillary permeability,(21) the experimental evidence in support of which was provided largely by the isogravimetric experiments of Pappenheimer and SotoRivera,(22,23) this concept appears at the very least to serve as an extremely useful model of capillary fluid movement. With regard to the lung, it would appear that edema formation cannot be defined solely in terms of intravascular forces, as previously suggested by Guyton and Lindsey. (24) Pericapillary forces in the pulmonary interstitium have an appreciable effect on exchange of fluid through the capillary membrane. (25) In an isolated, dog-lung lobe preparation perfused in vivo with solutions of horseradish peroxidase or hemoglobin (molecular weight 64,500 and diameter of approximately 60 Ä), a perfusion pressure of greater than 50 mm Hg for 5 to 10 minutes was required before intraalveolar edema occurred. (2e) From these latter experiments it was concluded that the pulmonary alveolar epithelium, and not the vascular endothelium, represents the major barrier to the passage of water from the capillaries into the alveolar space. Since greater degrees of perfusion pressure were associated with a heightened permeability, it seems likely that increased intravascular pressure may widen the caliber of pulmonary capillary endothelial pores. These experiments also support the concept of a system of labile pores for systemic and pulmonary capillaries(27) and suggest the possibility that the traditional distinction between "hemodynamic" and "permeability" types of pulmonary edema may not be valid. However, other recent experimental evidence in favor of a difference between hydrostatic and permeability types of pulmonary edema was presented by Brigham and coworkers. (28) These investigators studied the responses of lung lymph flow and lymph and plasma protein concentrations in awake sheep to steady-state elevations of pulmonary vascular pressures made by inflating a left atrial balloon with those after an
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intravenous infusion of 105—1010 Pseudomonas aeruginosa bacteria. Their data showed that the intravenous infusion of Pseudomonas aeruginosa bacteria into the awake sheep causes a dramatic, prolonged, but reversible increase in pulmonary transvascular fluid and protein flow which was out of proportion to changes in vascular pressure. Even though two groups suggested that pore size may increase with increased vascular pressure (2729) and another group suggested that increased pressure decreases pore size,(30) Brigham and his coworkers did not find either change necessary to predict the effects of increased pressure on lymph-plasma protein ratios. The latter group found that a fixed vascular membrane structure with a large number of small pores, which completely exclude albumin per one intermediate pore of 125 A radius, would predict experimentally measured lymph-plasma albumin and globulin concentration ratios over a wide range of microvascular pressures. (3l) They concluded that large changes in fluid and protein filtration may result from small changes in the structure of exchanging vessels. Another important conclusion from Brigham's study is that the lesion induced by Pseudomonas infusion is entirely reversible in most sheep, a finding which suggests that severe pulmonary edema in humans occurring in the absence of heart failure may not necessarily result in extensive, irreversible damage to the lung's vascular endothelium. It may be important, therefore, as suggested by these investigators, to keep left atrial pressures low in clinical situations where increased vascular permeability is suspected. A further implication of this labile pore theory is that increases of pulmonary intravascular pressure, as might result from a rapid rise in left atrial pressure, will increase the capillary permeability to albumin, a tendency which would increase water movement into the pulmonary interstitium. It would appear that the degree of restriction to exchange of solutes across the pulmonary capillary endothelium is quite similar to that which is observed in the endothelium of heart and skeletal muscle capillaries. <32) In addition, electron micrographs indicate great similarity of these capillaries. (26) Calculations of pore size indicate that the pores of the pulmonary capillary endothelial membrane (40-50 Ä) are approximately 7-10 times larger than those of the alveolar epithelial membrane (6-10 Ä), a finding which is consistent with the differences in permeability at these two sites. (26) Pulmonary intraalveolar edema is prevented not only by the restrictive effect of the alveolar epithelial membrane, but also by the collection of fluid in the pulmonary interstitium which eventually results in increased lymphatic flow. Obstruction to increased lymph flow by a rise in left atrial pressure increases the likelihood of the development of pulmonary edema (33) and, as noted above, might be expected to be especially hazardous in association with a major septic focus. Chronic heart failure induced in animals is associated with a large functional expansion of pulmonary lymphatic drainage,(34) a compensatory mechanism which may be of great importance in the prevention of pulmonary edema in patients with a failing myocardium. Although pulmonary capillaries have a high permeability to water and other solutes,(20) relatively high molecular weight substances, such as proteins, are much less capable of diffusing across these cells. (32*35) When the alveoli of dogs are filled with saline for hours, (20) even large molecules (such as dextran—70,000 molecular weight) may be found in the alveolar fluid. This work suggests that the longer that fluid stays in pulmonary alveoli, the greater are the chances for increased alveolar capillary permeability to occur. These experimental observations support the clinical relevance
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of early aggressive reversal of acute pulmonary edema by diuretic therapy to prevent sustained fluid accumulations in the pulmonary interstitial and alveolar spaces. (17) Colloid osmotic pressure (25-28 mm Hg) normally acts to retain water within the capillary. Pulmonary hydrostatic pressure (10 mm Hg) drives fluid into the interstitial space. The magnitude of the pulmonary interstitial oncotic and hydrostatic pressures are much less certain, although work by Meyer et al.(36) and Levine and coworkers <25) suggests that pulmonary interstitial pressure is normally about minus 10-15 mm Hg (subatmospheric). it is presumed that lymph pumping and the physical motion of lung tissue may be causally related to the development of the negative pressure. (20) Pulmonary interstitial oncotic pressure depends on chemical binding of water, exclusion of plasma proteins, and the contribution of substances such as hyaluronic acid. (37~39) It has been estimated by Staub that the interstitial oncotic pressure is high enough that movement of fluid from pulmonary capillaries may occur even in the absence of a negative interstitial pressure. (40) Alveolar surface tension forces tend to promote a movement of fluid from pulmonary capillaries into the alveoli. (41) Robin has suggested that the major function of the lymphatic system in the lung may involve selective uptake of protein from the pulmonary interstitial space. (20) Even though the graphic experiments of Guyton (24) and Gaar (42) indicate the importance of protein concentration to prevention of pulmonary water accumulation, Robin has suggested that these experiments may merely reflect the point at which formation of capillary ultrafiltrate exceeds the capacity for lymphatic removal of this fluid. It appears that the net result of the Starling forces acting across pulmonary capillary walls is somewhat positive.(40) This conclusion is consistent with a liquid layer coating the surface of the alveolar lining in the normal lung and would also explain the origin of normal pulmonary lymphatic flow. Certainly much is not yet known about the precise magnitude of the various physical forces capable of influencing fluid movement across the alveolar-capillary membrane. (43) Although Starling's hypothesis of transcapillary fluid exchange does not provide a complete description of these forces, the pulmonary intravascular and interstitial oncotic and hydrostatic forces are nevertheless extremely important determinants of net fluid flow in the lungs.
III. OBSERVATIONS OF ALBUMIN METABOLISM IN MAN A. Patients in Acute Respiratory Failure Hypoalbuminemia and decreased serum oncotic pressure are extremely common abnormalities in patients with acute respiratory failure after major abdominal operations, particularly when these operations are associated with peritonitis. (17-44) In a series of fifty-eight consecutive patients admitted to a respiratory-surgical intensive-care unit after abdominal operations, the mean lowest serum albumin concentration in patients with peritonitis and acute respiratory failure was 2.3 ± 0.1 g/dl (SEM), a value which was significantly lower than in patients in whom peritonitis and respiratory failure were absent (2.8 ± 0.1 g/dl; p < 0.025). Similar findings were reported by Hoye and Ketcham(45) in patients having extensive abdominal operations and by Deysine and coworkers (46) in patients who had septic shock or
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septicemia. The former group (45) also demonstrated that the return of albumin to the intravascular compartment via the thoracic duct was considerably reduced in the intraoperative period. The observation that almost all patients after abdominal operations have significant hypoalbuminemia led to the suggestion that the reduced colloid osmotic pressure of the plasma might, in part, be a contributor to the development of acute respiratory failure by increasing the tendency for water to accumulate in the lung. (24,42) It is clear that an increase in lung water plays a central role in the development and continuation of acute respiratory failure in man. (47 · 48) To assess the possibility that an increase of serum oncotic pressures and diuresis might reduce pulmonary water and improve ventilation perfusion in the lung, (17) sixteen patients in acute respiratory failure with alveolar to arterial oxygen tension differences ( F , 0 2 = 1.0) ranging from 235 to 579 mm Hg (mean—360 mm Hg) were treated with concentrated human salt-poor albumin (25 g) alone or albumin (25 g) plus a potent diuretic (ethacrynic acid—20 to 100 mg) or ethacrynic acid alone (50 mg). improvement in right to left intrapulmonary shunting occurred in only five of the twelve measurement periods in patients receiving albumin alone. However, improvement of shunting occurred in ten of sixteen measurement periods in patients receiving both albumin and ethacrynic acid. The improvement in alveolar-arterial oxygen tension gradients correlated strongly with the magnitude of the diuresis. Albumin infusion prevented the fall in plasma volume which occurred with ethacrynic acid alone and resulted in a significant increase of albumin concentration and serum oncotic pressure. Results of this study suggest that concentrated salt-poor albumin, especially when given with a potent diuretic agent, may remove pulmonary water and improve the pulmonary ventilation-perfusion abnormality in patients with acute respiratory failure.
B. Depletion of Intravascular Albumin during Operation Significant depletion of intravascular albumin occurs intraoperatively in patients who undergo major vascular reconstructive procedures. (49) The mean decrease of intravascular albumin mass in this study was 33.3 g, a decrease which was approximately 20% of the preoperative circulating value. A large part of this albumin depletion can be explained by unreplaced deficits of whole blood. Seven of the twelve patients studied showed an increased disappearance rate of Evans blue from the plasma in the postoperative period, suggesting the possibility that increased capillary permeability to albumin and accumulation of this protein in extravascular tissues might be an additional explanation for intravascular albumin depletion.
C. Deposition of Albumin in Skin, Muscle and Lung during Operation Recent studies of the accumulation of albumin in human tissue during major operative procedures in sixteen patients indicate that there is a significant increase in the total albumin content of skin and muscle tissue at the operative wound site which is almost entirely accounted for by deposition of this protein in the extravascular portion of these tissues. (50) More extravascular albumin and water deposition occurred
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in muscle in comparison to skin. However, nine patients in this study who underwent thoracotomy for suspected bronchogenic carcinoma did not show the expected increase of extravascular albumin deposition in lung biopsies taken from the lobe to be resected when the chest was opened and just before the lobe was removed. Inadequate perfusion of the lung does not appear to explain this finding, since there was a minimum time of 60 minutes between the first biopsy and ligation of the pulmonary artery. The greater extravascular accumulation of albumin in human skin and muscle tissues in comparison to lung suggests that under the conditions imposed by these operative procedures, the capillary membrane of the lung may be less permeable to albumin than skin and muscle at the operative wound site. An alternate explanation is the possibility that lymphatic removal of albumin from the lung may have been significantly greater than that from skin and muscle tissues. Of additional interest in these studies was the finding that the intraoperative loss of circulating albumin was significantly correlated with the duration of operation (r = 0.69, p < 0.01).(51) The decrease in circulating albumin mass was also significantly correlated with the increase in extravascular albumin in muscle tissue (/* = 0.7, p < 0.01). These data suggest that intravascular albumin depletion is greater with longer operative procedures. It seems clear from the data cited above that intravascular albumin depletion occurs during major operative procedures, and is in part causally related to the subsequent development of hypoalbuminemia which is frequently observed in the postoperative period. Sepsis, especially when it occurs in the peritoneal cavity, is particularly likely to be associated with hypoalbuminemia and a decreased serum oncotic pressure. Although a portion of the loss of serum albumin is related to its accumulation in the skin and muscle of operative wounds, a finding which has also been reported by Mouridsen,(52) these sites probably account for only a small fraction of the total intravascular depletion of this osmotically active protein. Unreplaced blood volume deficits, as noted above, make up another important source of this albumin loss. It is unlikely that a generalized increase in vascular permeability occurs after operative procedures, except in situations like portal hypertension where reaccumulation of ascites may be responsible for large intravascular albumin deficits or in clinical situations associated with marked sepsis, where it has been demonstrated that endotoxin may produce a diffuse capillary injury (5354) and where large protein molecules such as fibrinogen (molecular weight = 340,000) may be found in substantial quantities in pulmonary edema fluid. (55)
D. Randomized Trial of Albumin vs. Electrolyte Solutions during Abdominal Aortic Operations A prospective, randomized trial of sixteen patients undergoing operative procedures on the abdominal aorta was recently conducted to assess the comparative effects of an albumin-rich intraoperative fluid regimen to a sodium-rich intraoperative fluid regimen (18) on postoperative pulmonary shunting, serum oncotic pressure, albumin and total protein concentration, plasma volume and creatinine clearance. Patients received either a sodium-rich regimen (prehydration with 5% dextrose in water— 1 litre, 5% dextrose in Ringer's lactate solution—approximately 500 ml per hour of
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METABOLISM
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anesthesia, and blood to replace estimated whole blood losses) or an albumin-rich regimen (25% concentrated salt-poor human albumin—1 gm/kg body weight, 5% albumin in saline—1 liter, and prehydration and blood as in the sodium-rich regimen). Three patients in the electrolyte group received Ringer's lactate in excess of the protocol through an error. The mean alveolar to arterial oxygen tension difference measured in nine patients after 15 minutes of breathing 100% oxygen (AaD0 2 , F ^ = 1.0) was 315 ± 51 mm Hg (SEM) in the sodium-rich group on the first postoperative day in comparison to an AaD0 2 (Fj0 2 = 1.0) of 142 ± 39 mm Hg in seven patients in the albumin-rich group, /; < 0.05. The increase in A a D 0 2 correlated positively with the total sodium intake in the electrolyte group (r = 0.74, p < 0.05), but a significant correlation between A a D 0 2 and sodium intake was not found in the albumin-treated patients (/* = 0.25, p < 0.1). Despite the large fluid load, patients in the sodium-rich group had a significant decrease in the postoperative plasma volume and circulating intravascular albumin mass, findings which were not observed in the albumin group. The gain in body weight was 1.7 times greater in the combined Ringer's lactated patients than in the albumin-treated patients, /; < 0.01. These differences in body weight were reflected by the net mean fluid balance increments on the day of operation in the two groups (p < 0.01). The serum albumin concentration rose significantly on the day of operation in albumin-treated patients (/; < 0.01). The decrease in serum albumin concentration on the day of operation, though statistically significant for the combined Ringer's lactate and excess Ringer's lactate groups (/; < 0.025), was not significant for the individual Ringer's lactate subgroups (Ringer's lactate and excess Ringer's lactate). The albumin concentration was significantly greater in albumin-treated patients than in either of the Ringer's lactate groups on the day of operation, p < 0.005. The changes in serum albumin concentration were reflected by similar differences in serum oncotic pressure (π) on the day of operation and on the first postoperative day. Serum oncotic pressure was maintained in the albumin-treated patients on the day of operation and on the first postoperative day, but fell significantly on the day of operation in the Ringer's lactate-treated patients. A significant correlation between the fall in serum oncotic pressure and sodium intake was observed in the Ringer's lactate-treated patients (r = 0.72, /; < 0.01). Changes in circulating albumin mass were correlated positively with changes in serum oncotic pressure (/· = 0.73, p < 0.01). As the circulating albumin mass increased, the serum oncotic pressure also increased. Conversely, decreases in circulating albumin mass were associated with decreases in serum oncotic pressure. The endogenous creatinine clearance fell similarly on the day of operation in both groups and no apparent differences in this measurement of renal function were observed in the two groups. The concern, therefore, that a colloid-based intraoperative fluid regimen would produce more depression of renal function in the postoperative period than an electrolyte-based regimen was not realized. The changes in pulmonary arteriovenous admixture, plasma volume, weight gain, fluid intake, albumin concentration, circulating albumin mass and serum oncotic pressure of a group of patients undergoing a major but similar operative stress are indicated in considerable detail because the data appear to be pertinent to the question of the optimum choice of fluids for many patients undergoing major operative
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SKILLMAN
procedures. Although Ladegaard-Pedersen found that patients who underwent a variety of major operative procedures showed a decreased plasma volume in the postoperative period, he was able to find only minimally significant changes in the serum oncotic pressure over that which might be expected to occur from differences in posture (bed rest versus ambulatory state). (56) Data obtained from our prospective randomized trial show that even when large volumes of Ringer's lactate are infused intraoperatively, the plasma volume falls significantly despite a large weight gain in patients who do not receive any intraoperative albumin infusion. The colloid osmotic pressure fell to approximately 70% of the control value in these patients. It would appear, therefore, that the tendency for infused fluid to leave the plasma volume follows the laws of transcapillary fluid exchange originally proposed by Starling. The more positive weight gain which was observed in patients who did not receive colloid must, by virtue of the normal distribution of sodium and water, contribute to excess expansion of the interstitial fluid space. Although it has already been pointed out that the contribution of intravenously administered salt and water to pulmonary extravascular water accumulation may not strictly follow Starling's predictions, the marked increase in the alveolar-arterial oxygen tension gradients in those patients receiving excess Ringer's lactate is dramatic evidence in support of the importance of this relationship to the lung. The three patients who received excess Ringer's lactate were in serious difficulty with pulmonary edema on the morning of the first postoperative day and required vigorous diuresis and controlled ventilation with positive endexpiratory pressure to reverse this acute problem. Convincing evidence of a positive relationship between the increase of A a D 0 2 and sodium intake was also observed in this study. These data showed a significant correlation between increasing sodium intake and rises in the alveolar-arterial oxygen tension gradients, a correlation which was not observed in patients receiving albumin. This evidence gives even more support to the conclusion that provision of large amounts of saline without albumin to patients undergoing major operative procedures is undesirable and is likely to contribute to postoperative acute respiratory failure through an increase of pulmonary water content.
IV. DiSCUSSION Although the infusion of colloid into rats following a 50% hemorrhage in an amount equivalent to five times the estimated blood loss was associated with more pulmonary edema than crystalloid infusion in the amount of six times the blood loss,(16) this result is entirely predictable based on the distribution of the infused fluid in these two experimental situations. (57) In the study of hemorrhagic shock performed in rhesus monkeys by Gaisford and coworkers,(10) in which Ringer's lactate solution or 5 % albumin was infused at a rate sufficient to maintain the central venous pressure at 5-6 cm water, pulmonary ultrastructural evidence of pulmonary edema occurred only in those animals treated with Ringer's lactate. The results of this latter study are in conflict with those reported by Moss and coworkers (14) and Siegel and coworkers, (58) who studied pulmonary ultrastructural changes after hemorrhagic shock in the baboon treated by saline infusion and colloid infusion. These latter two studies indicated that saline resuscitation resulted in a disappearance of interstitial pulmonary
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edema, whereas colloid infusion resulted in distortion of alveolar collagen and interstitial edema. These experiments (14 · 58) may be criticized, however, since human albumin was infused into baboons in the colloid resuscitation experiments,(58) a protocol which might, therefore, have led to an immunological reaction in the lung. Although treatment of acute respiratory failure in humans with concentrated salt-poor albumin infusion is not uniformally beneficial in reducing elevated alveolararterial oxygen tension gradients, when this therapy is combined with a rapidly acting diuretic agent, dramatic reversal of pulmonary shunting is often observed.(17) It has been recently demonstrated that lung weight and pulmonary capillary pressure may be dramatically reduced by concentrated albumin (25 g) and urea (10 g in invert sugar) when hydrostatic pulmonary edema is produced by pulmonary venous constriction in an isolated, perfused dog lung model.(59) Similar results have been obtained by others. (60) Uncertainties regarding the application of the colloid-diuretic principle to patients who have acute respiratory failure associated with major sepsis still exist, however, since increased pulmonary capillary permeability to albumin leading to its accumulation in the pulmonary interstitial space may occur in this clinical situation and lead to a decreased oncotic effect of the albumin which is infused. As previously noted, however, the relative tightness of the pulmonary alveolar membrane (26) and the tremendous capacity for an increase of lymphatic removal of salt, water and protein from the lung are two important protective mechanisms which lead to amelioration of persistent fluid accumulations in the lung. As has already been pointed out, the effect of an experimentally induced bacterial insult on the permeability of the pulmonary capillary endothelium to water and protein may also be readily reversible,(28) although the mortality rate of patients in acute respiratory failure rises precipitously when gram negative pneumonia supervenes.(61) Clinical experience in the management of patients in acute respiratory failure suggests that early agressive treatment of atelectasis and pulmonary edema by controlled ventilation, chest physical therapy, fluid restriction, albumin infusion and diuresis are all extremely important therapeutic measures. V. SUMMARY Patients who undergo major operative procedures lose albumin from the intravascular compartment through unreplaced deficits of blood volume. There is also a significant extravascular accumulation of albumin in skin and muscle, but not in lung, during operative procedures in man. Although sepsis may alter capillary permeability and result in further losses of albumin from the intravascular compartment into the interstitial fluid space, this possibility should not necessarily be interpreted as a reason to withhold albumin in hypoalbuminemic patients. When hypovolemia occurs in post-operative patients it is almost always associated with a gain of weight and a large increase in body water and sodium content. Further sodium intake, in the absence of an osmotic force to hold it within the intravascular compartment, will only increase the tendency for interstitial fluid volume expansion. As the interstitial fluid space of the lung shares in the accumulation of sodium and water, the tendency for eventual pulmonary edema and subsequent acute respiratory failure to occur is also increased. Evidence presented in the prospective randomized trial of patients receiving an albumin-rich versus a sodium-rich inträoperative fluid
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regimen suggests that albumin replacement may have advantages over conventional salt and water-based fluid regimens. Patients treated with albumin in this study had less pulmonary arteriovenous admixture in the post-operative period, with better maintenance of the circulating albumin mass, serum oncotic pressure and plasma volume than patients who were treated with Ringer's lactate. Although these data should not be interpreted to indicate that salt should be withheld during major operative procedures, they do suggest a more moderate position with regard to sodium administration. The tendency for "third space losses" to occur following major operative procedures may be partly an iatrogenic abnormality, since the administration of excess salt and water can only result in an increase of the interstitial fluid volume. It would appear that the tendency to third space fluid accumulation may be minimized by the provision of albumin in the operative and early postoperative periods in patients who have major operative procedures.
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