- Email: [email protected]
The management of interstitial pulmonary edema
The management of interstitial pulmonary edema Significance of hypoproteinemia Joseph M. Giordano, M.D. (by invitation), William L. Joseph, M.D. (by invitation), C. Herman Klingenmaier, M.D. (by invitation), and Paul C. Adkins, M.D., Bethesda, Md., and Washington, D. C.
Xulmonary insufficiency secondary to nonthoracic trauma has become an important clinical problem. Although clinicians have been aware of the association of pulmonary problems with stress since World War II, only recently has the extent and severity of this entity been emphasized. This increased awareness is due to the extensive study of Vietnam casualties and the more sophisticated monitoring of blood gases and other respiratory parameters in civilian practice.1- 2 Although the etiology and pathophysiology of pulmonary insufficiency secondary to nonthoracic trauma remains obscure, the treatment has improved.3 The recognition of the association of depressed pulmonary parameters with excess fluid in the interstitial space has led to the more judicious use of intravenous fluid in the therapy of shock. From the Departments of Surgery and Anesthesia, George Washington University Medical Center, Washington, D. C , and The Clinical Center, The National Institutes of Health, Bethesda, Md. Supported in part by a grant from the Mary Cogswell Kinney Endowment Fund. Read at the Fifty-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., May 1, 2, and 3, 1972. Address for reprints: Dr. Joseph, Department of Surgery, George Washington University Medical Center, 2150 Pennsylvania Ave., N.W., Washington, D. C. 20037.
Potent diuretics such as furosemide and ethacrynic acid have become important adjuncts to therapy. Continuous positive-pressure ventilation (CPPV), by maintaining alveolar patency during expiration, has significantly decreased the pulmonary shunting characteristic of this entity.4-5 Recent reports6- 7 and our own clinical experience have suggested that the administration of massive amounts of intravenous albumin plays a substantial role in reducing the interstitial pulmonary edema (major pathology seen in post-traumatic pulmonary insufficiency) and thereby improving pulmonary function in these patients. Case material and results Nine cases of pulmonary interstitial edema have been reviewed. The criteria for establishing this diagnosis is as follows: (1) a decreased Po, despite high Fi02, (2) normal or decreased Pco2, (3) characteristic roentgenographic appearance of patchy infiltrates throughout both lung fields (Fig. 1), and (4) the absence clinically of cardiac failure, extensive pneumonia, airway problems, or pulmonary contusion that could explain the blood-gas abnormalities. All patients were admitted to the intensive care unit, intubated, and placed on a volume-controlled 739
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Fig. 1. Chest roentgenograms of patient with interstitial pulmonary edema illustrating (A) characteristic bilateral patchy pulmonary infiltrates and (B) complete resolution by 8 days.
respirator. Catheters were inserted into the superior vena cava and radial artery for continuous monitoring of central venous pressure (CPV), blood pressure, and for serial blood-gas determinations. After the diagnosis of pulmonary interstitial edema had been made, patients were given 100 to 200 Gm. per 24 hours of human salt-poor albumin diuretics and were placed on CPPV at 5 to 10 cm. H 2 0 . Some patients did not receive this entire therapeutic regimen at once; instead, each modality was added individually as the clinical situation warranted it. It is our opinion, however, that the addition of albumin to diuretics and CPPV was the major factor in the clinical improvement of these patients. The patients and their primary diagnoses are listed in Table I. Each individual had a number of associated problems at the time of the development of pulmonary interstitial edema. However, the major clinical problems were shock (5 patients), peritonitis (3 patients) and barbiturate overdose (in 1 patient who had prolonged periods of hypotension). Prior to the development of pulmonary problems, 5 of the 9 patients received excessive amounts of intravenous fluid in an attempt to maintain blood pressure and urine output. Initial blood gases and serum albumin prior to treatment are listed in Table II. All patients had a low Po 2 despite high con-
centrations of inspired oxygen while maintained on a volume respirator. The serum albumin, obtained when the Po 2 was low, was less than 50 per cent of normal in all but 1 of the cases. Before the administration of albumin, 4 patients were already receiving diuretics and 1 was on CPPV without significant improvement in arterial Po 2 . The condition of 1 patient improved after administration of albumin and furosemide without CPPV. The substantial improvement in blood gases following the administration of intravenous albumin is apparent in Table II. All patients had a significant diuresis over a relatively short period of time, and this correlated with an improvement in oxygenation. There were 6 long-term survivors. Two individuals subsequently died in gram-negative sepsis despite improvement in pulmonary function, while the remaining patient died of a myocardial infarction. The following case illustrates the syndrome of pulmonary interstitial edema or "shock lung" and the dramatic improvement that can occur if promptly recognized and properly treated. Case report A. L., a 48-year-old woman, underwent pelvic exenteration for recurrent cervical carcinoma. Eight hours postoperatively the arterial systolic pressure fell to 75 mm. Hg. Removal of the
Volume 64
Interstitial pulmonary edema
Number 5 November, 1972
741
Table I Patient
Age (years)
M.J.
29
Delerium tremors, gastrointestinal bleeding, shock, aspiration, fluid overload
Patient initially treated with furosemide, steroids, and digitalis with no improvement; died 20 days after respiratory improvement from gastrointestinal bleeding and gram-negative sepsis
G. B.
30
Caesarian section; developed advanced peritonitis, fluid overload
N o initial response to diuretic and digitalis; discharged
F. L.
48
Cholecystectomy; shock secondary to ruptured spleen, fluid overload
Treated with furosemide and digitalis initially with no response; discharged
M. W.
42
Barbiturate overdose, renal dialysis, hypotension, fluid overload
Patient improved without CPPV; died 5 days later with pneumonia
A.L.
48
Pelvic exenteration for carcinoma, hypo- Initially digitalized without effect; distension, fluid overload charged
L. M.
61
Perforated diverticulum, peritonitis
Initially treated with CPPV and furosemide with no improvement; died 2 days later of myocardial infarction
L. C.
56
Repair of aortic aneurysm, shock
Digitalized before operation; discharged
Z. H.
23
Septic abortion, shock, fluid overload
Discharged
31
Peritonitis secondary to ruptured uterus Discharged
M.J.
Diagnosis
Comment
Legend: CPPV, Continuous positive-pressure ventilation.
Table II
Patient
PO: (mm. Hg)
Flo, (per cent)
Serum albumin (Gm. per cent)
M.J. G.B. F. L. M. W. A.L. M.J. Z. H. L. C. L. M.
41 42 68 80 40 59 68 51 46
100 100 60 100 100 80 80 100 100
2.5 2.1 1.8 2.2 2.1 1.9 1.7 1.9 1.9
Pretreatment
perineal pack revealed a considerable amount of bleeding. Transfusion of 6 units of blood was required over the next 8 hours. On the following morning, the blood pressure was 135/76 mm. Hg, pulse was normal, and CVP was 10 mm. Hg. Six hours later the patient became cyanotic, restless, and tachypneic. The blood pressure and C V P remained unchanged, and urine output was adequate. The Po 2 was 70 mm. Hg on room air. This gradually fell through the night, and on the next morning (36 hours after the hypotension) the
Post-treatment Po, (mm. Hg)
Flo, (per cent)
Diuresis (c.c/hr.)
93 94 106 180 135 127 125 120 124
80 100 40 100 100 80 80 80 80
3,000/5 3,000/12 5,500/48 4,000/24 1,350/5 4,215/6 4,000/6 2,750/6 2,800/12
Po 2 was 47 mm. Hg on 80 per cent oxygen. Serum albumin was 2.1 Gm. per cent. A chest x-ray film (Fig. 2 ) showed extensive bilateral patchy infiltrates consistent with symptoms of interstitial pulmonary edema. At 1:00 P . M . , the Po 2 was 40 mm. Hg on an F i ^ of 100 per cent in spite of digitalization and diuretics. At 3:00 P.M. 50 Gm. of albumin, furosemide, and C P P V were administered, and the dramatic improvement over the next 5 hours is documented in Table III. The urine output during this period was 1,350 c.c.
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Thoracic and Cardiovascular Surgery
Table III Po, Time
(mm.
Hg)
Flo, (per cent)
Serum alb umin (Gm per cent)
Urine output (c.c.)
2.1 2.0
240
1:00 P . M . 3:00 P.M.
40 40
100 100
4:00 P . M . 5:00 P . M . 7:00 P . M . 8:00 P . M . 8:00 A.M.
71
100
86 135 98
100 100 80
2.5 2.7 2.7 3.1
650
Therapy IPPB, furosemide 50 gr. albumin, furosemide, CPPV 50 gr. of albumin
550 150
the capillaries and the difference in protein oncotic pressure in the intravascular spaces.8 The importance of plasma protein in opposing the loss of fluid from the intravascular space can be seen when one calculates the oncotic pressure by the formula O.P. - 2.1 C + 0.16 C 2 + 0.009 C 3
Fig. 2. The serum albumin gradually rose and by the following morning was 3.1 Gm. per cent. She was eventually discharged with no residual respiratory problems.
Comment. This patient, like the majority of our patients, responded to the administration of albumin over a relatively short period of time. The condition of Patient F. L. (Table II) improved over a 48 hour period during which time she received a total of 175 Gm. of albumin. However, she still required 25 to 50 Gm. of albumin per day to maintain the serum albumin at a normal level and to keep the lungs dry. Some patients may need this daily administration of albumin over a prolonged period. Discussion Starling's law states that the net movement of fluid between the vascular and extravascular compartments is governed by the difference in hydrostatic pressure across
in which c is plasma protein concentration in grams per cent and O.P. is oncotic pressure. Under normal conditions, the hydrostatic pressure of the pulmonary capillary bed is 7 mm. Hg., and the plasma oncotic pressure from a serum protein concentration of 7.3 per cent is 28 mm Hg.9 The net effect is a negative interstitial balance which helps keep the lung dry under normal circumstances. With these factors as a reference point, the sequence of events that occurs in the development of pulmonary interstitial edema can be interpreted as follows: 1. The initial observation is pulmonary capillary congestion.1' - This raises the capillary hydrostatic pressure favoring a flow of fluid into the interstitial space. The greater permeability of the capillary bed of the lung compared to other organs accentuates this transcapillary fluid movement.10 2. Fluid and then protein accumulate in the interstitial space, increasing the distance between the alveolus and capillary and thereby creating an alveolar-capillary block. 3. The fluid and protein enter the alveolus, which further accentuates the block and inactivates surfactant resulting in alveolar collapse. At stages 2 and 3, the patient has considerable pulmonary shunting
Volume 64 Number 5 November, 1972
and is restless, tachypneic, and cyanotic. The flow of fluid into the interstitial space is increased if the plasma oncotic pressure is low in the face of an elevated capillary hydrostatic pressure. Since albumin9 accounts for 70 per cent of the oncotic pressure in plasma, stressful conditions associated with a low serum albumin can cause pulmonary interstitial edema. Recent reports have suggested the relationship of low serum albumin with the development of pulmonary interstitial edema. Gutierrez6 evaluated 19 patients who died with shock and respiratory insufficiency. He noted that a low plasma protein was associated with increased lung weight and edema fluid. Skillman7 was also impressed by the significance of low serum albumin in patients with peritonitis and respiratory failure. The experience with pulmonary interstitial edema at our institution has been similar; 8 of 9 patients had a serum albumin less than 50 per cent of normal. Theoretically, the administration of large amounts of albumin intravenously should, and in fact did, aid in the removal of fluid from the interstitial space back into the intravascular compartment. Our patients showed a rapid improvement of blood gases associated with a brisk diuresis. The CVP of these patients rose, indicating an increased amount of fluid in the intravascular compartment. It is important to emphasize that at this point, although diuretics were used without effect prior to the administration of albumin, it is necessary to administer them in order to remove the mobilized fluid as rapidly as possible. Seven of the 9 patients treated with albumin also had CPPV at the same time. CPPV, by applying a positive pressure during expiration, maintains patency of those alveoli that have become unstable due to the loss of surfactant. There is an improvement in the ventilation-perfusion ratio, and patients generally respond with improvement in pulmonary function. We believe that CPPV plays an important role in the treatment of this entity. In these 9 patients,
Interstitial
pulmonary
edema
74 3
however, the association of improved blood gases with a brisk diuresis would indicate that it was the administration of albumin, by elevating plasma oncotic pressure, that substantially reduced the interstitial pulmonary edema. Summary Nine patients with clinical pictures characteristic of pulmonary interstitial edema are presented. Eight of these patients had a serum albumin less than 50 per cent of normal. Initially these patients were treated with intermittent positive-pressure breathing, diuretics, and intubation with no significant change in blood gases. The administration of massive amounts of intravenous albumin was accompanied by a brisk diuresis and a substantial improvement in Po 2 . The low serum albumin decreases the plasma oncotic pressure, favoring a flow of fluid into the interstitial space. The administration of intravenous albumin rapidly mobilizes the interstitial fluid, forcing fluid back into the intravascular compartment and thereby decreasing the interstitial edema and improving oxygenation. REFERENCES 1 Moore, F. D., Lyons, J. H., Pierce, E. C , Morgan, A. P., Drinker, P. A., MacArthur, J. D., and Dammin, G. J.: Post-traumatic Pulmonary Insufficiency, Philadelphia, 1968, W. B. Saunders Company. 2 Webb, W. R.: Pulmonary Complications of Non-thoracic Trauma: Summary of The National Research Council Conference, J. Trauma 9: 700, 1969. 3 Proctor, H. J., Ballantine, T. V. N., and Broussard, N. D.: An Analysis of Pulmonary Function Following Non-thoracic Trauma, With Recommendations for Therapy, Ann. Surg. 172: 180, 1970. 4 Ashbaugh, D. G., Petty, T. L., Bigelow, D. B., and Harris, T. M.: Continuous Positivepressure Breathing (CPPB) in Adult Respiratory Distress Syndrome, J. THORAC. CARDIOVASC. SURG. 57: 31,
1969.
5 Kumar, A., Ialke, K. J., Geffrin, B., Aldredge, C. F., Laver, M. B., Louenstein, E., and Pontoppidan, H.: Continuous Positive-Pressure Ventilation in Acute Respiratory Failure, N. Engl. J. Med. 283: 1430, 1970. 6 Gutierrez, V. S., Berman I. R., Soloway, H.
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8 9 10
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B., and Hamit, H. F.: Relationship of Hypoproteinemia and Prolonged Mechanical Ventilation to the Development of Pulmonary Insufficiency in Shock, Ann. Surg. 171: 385, 1970. Skillman, J. J., Bushnell, L. S., and Whyte, J. H.: Peritonitis and Respiratory Failure After Abdominal Operations, Ann. Surg. 170: 122, 1969. Starling, E. H.: On the Absorption of Fluids From the Connective Tissue Spaces, J. Physiol. (London) 19: 312, 1896. Guyton, A. C : Textbook of Medical Physiology, Philadelphia, 1971, W. B. Saunders Company, p. 237. Motsay, G. J., Alho, A. V., Schultz, L. S., Dretzman, R. H., and Lillehei, R. C : Pulmonary Capillary Permeability in the Post-traumatic Pulmonary Insufficiency Syndrome, Ann. Surg. 173: 244, 1971.
Discussion DR. J E F F RAY New
York, N.
Thoracic and Cardiovascular
Y.
I congratulate the authors on an excellent study. Four papers so far, and some to follow, address themselves to treatment of interstitial pulmonary edema, an important component of pulmonary insufficiency. I should like to draw your attention to the role of patient immobility as a critical factor, abetting interstitial edema, pulmonary arteriovenous shunting, and hypoxemia. [Slide] This slide shows low Pao2 in 7 patients after 3V2 to 8 hours of immobility in the supine position during anesthesia and operation. Turning each patient to one lateral position raised the Paoz to the physiologically acceptable tension of 80 mm. Hg or higher, without changing the pressure and volume settings of the respirator or altering the Fioj. Nondependent portions of lung have no interstitial edema and are available for instant use with optimal ventilation-perfusion relationships. I wish to report observations made at New York Medical College with Drs. Clauss and Moallem. The observations were made in laterally positioned, anesthetized, overhydrated dogs; some were immobile and others were turned. [Slide] Blood samples drawn from pulmonary veins in this laterally positioned, immobile dog disclosed normal Po8 in blood from the antidependent (up) lung. In the dependent lung (the repository of the bulk of pulmonary blood flow and volume), PpVo, was low—suboptimal. [Slide] In this dog, turning into alternate lateral positions hourly drains the blood and interstitial edema and allows alveoli to expand despite
massive overhydration. Gas exchange is more effective at once. Po, rises in pulmonary veins and in systemic arteries. [Slide] This is the same phenomenon in a man. [Slide] To prevent and to relieve interstitial edema and suboptimal ventilation-perfusion relationships, frequent turning (for example, at halfhour intervals) may have to be done. The per cent pulmonary arteriovenous shunt decreases, allowing Flo, to be lowered. The "stir-up regimen" has merit. It should be used systematically to complement protein infusion, diuresis, and respirator treatment with continuous positive end-expiratory pressure. DR. W I L L I A M H. F L E M I N G Atlanta,
Ga.
I would like to compliment the authors on their study. When we saw similar problems in Vietnam, we had the feeling, as they obviously did, that this is probably an iatrogenic disease. Without fluid overload, it doesn't seem to develop. [Slide] Our criteria for making the diagnosis were essentially the same as theirs. Because these patients were in another prospective study, we had the advantage of having some antecedent data on them: (1) significant decline in arterial Po2; (2) significant decline in pulmonary compliance; (3) x-ray evidence of increased pulmonary interstitial fluid bilaterally; and (4) no other evident cause, such as fat embolism or respirator changes. [Slide] Dr. Giordano mentioned in his abstract the changes in compliance. Our 10 patients went from a mean of 32.8 ml. per centimeter of water the day before the diagnosis of wet lung syndrome to the mean low point of 21.0 at the time of diagnosis. They were treated with diuretics and fluid restriction alone, and in \¥z hours, pulmonary compliance came back up appreciably to a mean of 32.9 ml. per centimeter of water. [Slide] There were similar changes at similar times in the arterial Po2, the day before, at the low point, and Wi hours later. Again, the only therapy on these patients was diuretics and fluid restriction. [Slide] Fluid balances in the 5 patients on whom we could get valid figures show that they were in distinctly positive fluid balance. [Slide] These patients excreted an average of 2,165 ml. of urine in 2 hours with a diuretic dose of 40 to 80 mg. of intravenous furosemide. This is a higher average than you may note in civilian practice because the patients were younger men, and I think it may have taken more fluid to get them into this difficulty. I would like to ask Dr. Giordano if he used the albumen therapy on people who did not receive diuretics. There certainly is a greater intellectual appeal to adding an osmotic agent, but I wonder
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Interstitial pulmonary edema
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November, 1972
whether that alone would be sufficient or whether perhaps the combination would be better than either alone.
or perhaps others have considered measurements of these factors in their problems.
DR. J A M E S G E I G E R
Santa Barbara, Calif.
DR. T H O M A S O'BRIEN
San Francisco, Calif.
I would like to compliment the authors for calling our attention to another important factor in this problem of pulmonary insufficiency. I would emphasize that this is not a simple problem. There are many complicated factors in the etiology, and, therefore, many times there are mixed modalities of therapy which are applicable. I suggest two things that should also be considered: One is an endocrine response to stress, and the second is metabolic water production. In a group of 30 patients who I treated successfully with a complicated therapeutic regimen, there were several common denominators. All were hypoalbuminic and hyponatremic, and most were anemic; these observations are consistent with hyperaldosteronism. I would like to discuss metabolic water production with the aid of a slide on a young man of 23 years. [Slide] This man had a gunshot wound through the lung and spine. He was paraplegic and was received after 6 weeks of continuous ventilatory support. This represents 1 day during his 3 months on the ventilator. He received Lasix and albumin twice a day for a week and then at least every day for the ensuing 10 days. These films were taken on the same day, approximately 8 hours apart, and represent the dynamics of this problem. We were careful to restrict his intake of fluid and sodium. However, in spite of this, the water became mobilized, and he developed pulmonary edema. I might also mention that he had a marked need for inspiratory pressure support (70 cm. H-O), initially. The patient lost approximately 55 pounds during the course of his injury in spite of hyperalimentation. I think it was first pointed out by Dr. Francis Moore that breakdown of 1 kilogram of tissue will produce 1 L. of water. Much of this is never taken into account in the fluid management of these patients. I also have some preliminary data which indicate that a number of the casualties do have markedly elevated levels of aldosterone. A very important factor in this entity is vascular damage. The role of a humoral factor was first delineated by Dr. Blaisdale of San Francisco. It has been shown that aldosterone and vasoactive amines, in combination, are extremely vasculotoxic. They may contribute to the permeability of the pulmonary circulation. I would like to ask the authors whether they
I would like to express my congratulations to the authors on a very significant contribution and also to comment about our experience with this form of therapy. It appears that most forms of acute respiratory failure are associated with inappropriate water retention. In the clinical setting, this can be demonstrated by the presence of hyponatremia, hypoalbuminemia, lowered serum osmolality, and so forth. Van De Water and others, using impedance plethysmography, have demonstrated that much of this fluid is finally deposited in the lungs. It is not surprising then that patients with acute respiratory failure, whether they have posttraumatic respiratory insufficiency, viral pneumonia, or whatever, will benefit from a program of fluid restriction and intensive dehydration with the utilization of albumin and other agents to improve serum oncotic pressure. The regimen that we have used consists of albumin, 100 to 200 Gm. a day, Lasix, 100 to 200 mg. a day, or Edecrin, 100 to 1,000 mg. a day; we usually use methylprednisone sodium succinate as well because of the fact that this drug appears to enhance certain cellular characteristics of an injured lung. This particular regimen is not original with us. We have plagiarized it in toto from Dr. Robert Bartlett of the University of California at Irvine. We recently had the opportunity to treat a patient with preterminal shock lung by means of this regimen. At the start of therapy, he had a calculated negative fluid balance of 1 L. Over the course of the first 48 hours of therapy, a further negative fluid balance of 10 L. was accomplished. Improvement in gas exchange was impressive as water was removed from the lungs. However, the patient eventually required the services of Dr. Hill and Mr. Bramson with the membrane oxygenator and was on bypass for perhaps 75 hours. Ultimately he survived. I am quite sure that one of the reasons this patient's pulmonary pathology was reversible was related to the marked state of negative fluid balance that had been achieved before bypass. Finally, in our community, during the past several months, there has been a significant problem with acute respiratory failure caused by viral pneumonitis. Patients with this disease have responded very dramatically to the same program of marked water restriction and intensive dehydration. I would like to add one word of caution to those who utilize this form of therapy. If it is
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7 4 6 Giordano et al.
Thoracic and Cardiovascular Surgery
pushed hard enough, a very dangerous state of hypernatremia and hyperosmolality can be induced. This can have severe, if not lethal, effects on the central nervous system and on the urinary tract. I believe that it is inadvisable to use this therapy to the point where the serum osmolality exceeds 330 or the serum sodium exceeds 160. DR. J O S E P H M. G I O R D A N O
(Closing)
I would like to thank the discussers for their comments. I think Dr. Ray's point that the dependent portions of the lung are most severely affected is important. Continual movement of the patient
every half hour, as he suggested, may play a significant role in treatment. Regarding Dr. Fleming's question as to whether albumin could be used alone, we believe that diuretics should always be given with the albumin. Once the fluid is mobilized, it should be excreted as rapidly as possible, because the albumin itself does not remain in the intravascular compartment more than 6 or 8 hours. Regarding Dr. Geiger's point, we did not measure aldosterone in these patients. I think we should pay more attention to aldosterone and to the amount of water contributed by the metabolic breakdown of protein.
Xulmonary insufficiency secondary to nonthoracic trauma has become an important clinical problem. Although clinicians have been aware of the association of pulmonary problems with stress since World War II, only recently has the extent and severity of this entity been emphasized. This increased awareness is due to the extensive study of Vietnam casualties and the more sophisticated monitoring of blood gases and other respiratory parameters in civilian practice.1- 2 Although the etiology and pathophysiology of pulmonary insufficiency secondary to nonthoracic trauma remains obscure, the treatment has improved.3 The recognition of the association of depressed pulmonary parameters with excess fluid in the interstitial space has led to the more judicious use of intravenous fluid in the therapy of shock. From the Departments of Surgery and Anesthesia, George Washington University Medical Center, Washington, D. C , and The Clinical Center, The National Institutes of Health, Bethesda, Md. Supported in part by a grant from the Mary Cogswell Kinney Endowment Fund. Read at the Fifty-second Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., May 1, 2, and 3, 1972. Address for reprints: Dr. Joseph, Department of Surgery, George Washington University Medical Center, 2150 Pennsylvania Ave., N.W., Washington, D. C. 20037.
Potent diuretics such as furosemide and ethacrynic acid have become important adjuncts to therapy. Continuous positive-pressure ventilation (CPPV), by maintaining alveolar patency during expiration, has significantly decreased the pulmonary shunting characteristic of this entity.4-5 Recent reports6- 7 and our own clinical experience have suggested that the administration of massive amounts of intravenous albumin plays a substantial role in reducing the interstitial pulmonary edema (major pathology seen in post-traumatic pulmonary insufficiency) and thereby improving pulmonary function in these patients. Case material and results Nine cases of pulmonary interstitial edema have been reviewed. The criteria for establishing this diagnosis is as follows: (1) a decreased Po, despite high Fi02, (2) normal or decreased Pco2, (3) characteristic roentgenographic appearance of patchy infiltrates throughout both lung fields (Fig. 1), and (4) the absence clinically of cardiac failure, extensive pneumonia, airway problems, or pulmonary contusion that could explain the blood-gas abnormalities. All patients were admitted to the intensive care unit, intubated, and placed on a volume-controlled 739
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The Journal of
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Thoracic and Cardiovascular Surgery
Fig. 1. Chest roentgenograms of patient with interstitial pulmonary edema illustrating (A) characteristic bilateral patchy pulmonary infiltrates and (B) complete resolution by 8 days.
respirator. Catheters were inserted into the superior vena cava and radial artery for continuous monitoring of central venous pressure (CPV), blood pressure, and for serial blood-gas determinations. After the diagnosis of pulmonary interstitial edema had been made, patients were given 100 to 200 Gm. per 24 hours of human salt-poor albumin diuretics and were placed on CPPV at 5 to 10 cm. H 2 0 . Some patients did not receive this entire therapeutic regimen at once; instead, each modality was added individually as the clinical situation warranted it. It is our opinion, however, that the addition of albumin to diuretics and CPPV was the major factor in the clinical improvement of these patients. The patients and their primary diagnoses are listed in Table I. Each individual had a number of associated problems at the time of the development of pulmonary interstitial edema. However, the major clinical problems were shock (5 patients), peritonitis (3 patients) and barbiturate overdose (in 1 patient who had prolonged periods of hypotension). Prior to the development of pulmonary problems, 5 of the 9 patients received excessive amounts of intravenous fluid in an attempt to maintain blood pressure and urine output. Initial blood gases and serum albumin prior to treatment are listed in Table II. All patients had a low Po 2 despite high con-
centrations of inspired oxygen while maintained on a volume respirator. The serum albumin, obtained when the Po 2 was low, was less than 50 per cent of normal in all but 1 of the cases. Before the administration of albumin, 4 patients were already receiving diuretics and 1 was on CPPV without significant improvement in arterial Po 2 . The condition of 1 patient improved after administration of albumin and furosemide without CPPV. The substantial improvement in blood gases following the administration of intravenous albumin is apparent in Table II. All patients had a significant diuresis over a relatively short period of time, and this correlated with an improvement in oxygenation. There were 6 long-term survivors. Two individuals subsequently died in gram-negative sepsis despite improvement in pulmonary function, while the remaining patient died of a myocardial infarction. The following case illustrates the syndrome of pulmonary interstitial edema or "shock lung" and the dramatic improvement that can occur if promptly recognized and properly treated. Case report A. L., a 48-year-old woman, underwent pelvic exenteration for recurrent cervical carcinoma. Eight hours postoperatively the arterial systolic pressure fell to 75 mm. Hg. Removal of the
Volume 64
Interstitial pulmonary edema
Number 5 November, 1972
741
Table I Patient
Age (years)
M.J.
29
Delerium tremors, gastrointestinal bleeding, shock, aspiration, fluid overload
Patient initially treated with furosemide, steroids, and digitalis with no improvement; died 20 days after respiratory improvement from gastrointestinal bleeding and gram-negative sepsis
G. B.
30
Caesarian section; developed advanced peritonitis, fluid overload
N o initial response to diuretic and digitalis; discharged
F. L.
48
Cholecystectomy; shock secondary to ruptured spleen, fluid overload
Treated with furosemide and digitalis initially with no response; discharged
M. W.
42
Barbiturate overdose, renal dialysis, hypotension, fluid overload
Patient improved without CPPV; died 5 days later with pneumonia
A.L.
48
Pelvic exenteration for carcinoma, hypo- Initially digitalized without effect; distension, fluid overload charged
L. M.
61
Perforated diverticulum, peritonitis
Initially treated with CPPV and furosemide with no improvement; died 2 days later of myocardial infarction
L. C.
56
Repair of aortic aneurysm, shock
Digitalized before operation; discharged
Z. H.
23
Septic abortion, shock, fluid overload
Discharged
31
Peritonitis secondary to ruptured uterus Discharged
M.J.
Diagnosis
Comment
Legend: CPPV, Continuous positive-pressure ventilation.
Table II
Patient
PO: (mm. Hg)
Flo, (per cent)
Serum albumin (Gm. per cent)
M.J. G.B. F. L. M. W. A.L. M.J. Z. H. L. C. L. M.
41 42 68 80 40 59 68 51 46
100 100 60 100 100 80 80 100 100
2.5 2.1 1.8 2.2 2.1 1.9 1.7 1.9 1.9
Pretreatment
perineal pack revealed a considerable amount of bleeding. Transfusion of 6 units of blood was required over the next 8 hours. On the following morning, the blood pressure was 135/76 mm. Hg, pulse was normal, and CVP was 10 mm. Hg. Six hours later the patient became cyanotic, restless, and tachypneic. The blood pressure and C V P remained unchanged, and urine output was adequate. The Po 2 was 70 mm. Hg on room air. This gradually fell through the night, and on the next morning (36 hours after the hypotension) the
Post-treatment Po, (mm. Hg)
Flo, (per cent)
Diuresis (c.c/hr.)
93 94 106 180 135 127 125 120 124
80 100 40 100 100 80 80 80 80
3,000/5 3,000/12 5,500/48 4,000/24 1,350/5 4,215/6 4,000/6 2,750/6 2,800/12
Po 2 was 47 mm. Hg on 80 per cent oxygen. Serum albumin was 2.1 Gm. per cent. A chest x-ray film (Fig. 2 ) showed extensive bilateral patchy infiltrates consistent with symptoms of interstitial pulmonary edema. At 1:00 P . M . , the Po 2 was 40 mm. Hg on an F i ^ of 100 per cent in spite of digitalization and diuretics. At 3:00 P.M. 50 Gm. of albumin, furosemide, and C P P V were administered, and the dramatic improvement over the next 5 hours is documented in Table III. The urine output during this period was 1,350 c.c.
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Table III Po, Time
(mm.
Hg)
Flo, (per cent)
Serum alb umin (Gm per cent)
Urine output (c.c.)
2.1 2.0
240
1:00 P . M . 3:00 P.M.
40 40
100 100
4:00 P . M . 5:00 P . M . 7:00 P . M . 8:00 P . M . 8:00 A.M.
71
100
86 135 98
100 100 80
2.5 2.7 2.7 3.1
650
Therapy IPPB, furosemide 50 gr. albumin, furosemide, CPPV 50 gr. of albumin
550 150
the capillaries and the difference in protein oncotic pressure in the intravascular spaces.8 The importance of plasma protein in opposing the loss of fluid from the intravascular space can be seen when one calculates the oncotic pressure by the formula O.P. - 2.1 C + 0.16 C 2 + 0.009 C 3
Fig. 2. The serum albumin gradually rose and by the following morning was 3.1 Gm. per cent. She was eventually discharged with no residual respiratory problems.
Comment. This patient, like the majority of our patients, responded to the administration of albumin over a relatively short period of time. The condition of Patient F. L. (Table II) improved over a 48 hour period during which time she received a total of 175 Gm. of albumin. However, she still required 25 to 50 Gm. of albumin per day to maintain the serum albumin at a normal level and to keep the lungs dry. Some patients may need this daily administration of albumin over a prolonged period. Discussion Starling's law states that the net movement of fluid between the vascular and extravascular compartments is governed by the difference in hydrostatic pressure across
in which c is plasma protein concentration in grams per cent and O.P. is oncotic pressure. Under normal conditions, the hydrostatic pressure of the pulmonary capillary bed is 7 mm. Hg., and the plasma oncotic pressure from a serum protein concentration of 7.3 per cent is 28 mm Hg.9 The net effect is a negative interstitial balance which helps keep the lung dry under normal circumstances. With these factors as a reference point, the sequence of events that occurs in the development of pulmonary interstitial edema can be interpreted as follows: 1. The initial observation is pulmonary capillary congestion.1' - This raises the capillary hydrostatic pressure favoring a flow of fluid into the interstitial space. The greater permeability of the capillary bed of the lung compared to other organs accentuates this transcapillary fluid movement.10 2. Fluid and then protein accumulate in the interstitial space, increasing the distance between the alveolus and capillary and thereby creating an alveolar-capillary block. 3. The fluid and protein enter the alveolus, which further accentuates the block and inactivates surfactant resulting in alveolar collapse. At stages 2 and 3, the patient has considerable pulmonary shunting
Volume 64 Number 5 November, 1972
and is restless, tachypneic, and cyanotic. The flow of fluid into the interstitial space is increased if the plasma oncotic pressure is low in the face of an elevated capillary hydrostatic pressure. Since albumin9 accounts for 70 per cent of the oncotic pressure in plasma, stressful conditions associated with a low serum albumin can cause pulmonary interstitial edema. Recent reports have suggested the relationship of low serum albumin with the development of pulmonary interstitial edema. Gutierrez6 evaluated 19 patients who died with shock and respiratory insufficiency. He noted that a low plasma protein was associated with increased lung weight and edema fluid. Skillman7 was also impressed by the significance of low serum albumin in patients with peritonitis and respiratory failure. The experience with pulmonary interstitial edema at our institution has been similar; 8 of 9 patients had a serum albumin less than 50 per cent of normal. Theoretically, the administration of large amounts of albumin intravenously should, and in fact did, aid in the removal of fluid from the interstitial space back into the intravascular compartment. Our patients showed a rapid improvement of blood gases associated with a brisk diuresis. The CVP of these patients rose, indicating an increased amount of fluid in the intravascular compartment. It is important to emphasize that at this point, although diuretics were used without effect prior to the administration of albumin, it is necessary to administer them in order to remove the mobilized fluid as rapidly as possible. Seven of the 9 patients treated with albumin also had CPPV at the same time. CPPV, by applying a positive pressure during expiration, maintains patency of those alveoli that have become unstable due to the loss of surfactant. There is an improvement in the ventilation-perfusion ratio, and patients generally respond with improvement in pulmonary function. We believe that CPPV plays an important role in the treatment of this entity. In these 9 patients,
Interstitial
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edema
74 3
however, the association of improved blood gases with a brisk diuresis would indicate that it was the administration of albumin, by elevating plasma oncotic pressure, that substantially reduced the interstitial pulmonary edema. Summary Nine patients with clinical pictures characteristic of pulmonary interstitial edema are presented. Eight of these patients had a serum albumin less than 50 per cent of normal. Initially these patients were treated with intermittent positive-pressure breathing, diuretics, and intubation with no significant change in blood gases. The administration of massive amounts of intravenous albumin was accompanied by a brisk diuresis and a substantial improvement in Po 2 . The low serum albumin decreases the plasma oncotic pressure, favoring a flow of fluid into the interstitial space. The administration of intravenous albumin rapidly mobilizes the interstitial fluid, forcing fluid back into the intravascular compartment and thereby decreasing the interstitial edema and improving oxygenation. REFERENCES 1 Moore, F. D., Lyons, J. H., Pierce, E. C , Morgan, A. P., Drinker, P. A., MacArthur, J. D., and Dammin, G. J.: Post-traumatic Pulmonary Insufficiency, Philadelphia, 1968, W. B. Saunders Company. 2 Webb, W. R.: Pulmonary Complications of Non-thoracic Trauma: Summary of The National Research Council Conference, J. Trauma 9: 700, 1969. 3 Proctor, H. J., Ballantine, T. V. N., and Broussard, N. D.: An Analysis of Pulmonary Function Following Non-thoracic Trauma, With Recommendations for Therapy, Ann. Surg. 172: 180, 1970. 4 Ashbaugh, D. G., Petty, T. L., Bigelow, D. B., and Harris, T. M.: Continuous Positivepressure Breathing (CPPB) in Adult Respiratory Distress Syndrome, J. THORAC. CARDIOVASC. SURG. 57: 31,
1969.
5 Kumar, A., Ialke, K. J., Geffrin, B., Aldredge, C. F., Laver, M. B., Louenstein, E., and Pontoppidan, H.: Continuous Positive-Pressure Ventilation in Acute Respiratory Failure, N. Engl. J. Med. 283: 1430, 1970. 6 Gutierrez, V. S., Berman I. R., Soloway, H.
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8 9 10
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B., and Hamit, H. F.: Relationship of Hypoproteinemia and Prolonged Mechanical Ventilation to the Development of Pulmonary Insufficiency in Shock, Ann. Surg. 171: 385, 1970. Skillman, J. J., Bushnell, L. S., and Whyte, J. H.: Peritonitis and Respiratory Failure After Abdominal Operations, Ann. Surg. 170: 122, 1969. Starling, E. H.: On the Absorption of Fluids From the Connective Tissue Spaces, J. Physiol. (London) 19: 312, 1896. Guyton, A. C : Textbook of Medical Physiology, Philadelphia, 1971, W. B. Saunders Company, p. 237. Motsay, G. J., Alho, A. V., Schultz, L. S., Dretzman, R. H., and Lillehei, R. C : Pulmonary Capillary Permeability in the Post-traumatic Pulmonary Insufficiency Syndrome, Ann. Surg. 173: 244, 1971.
Discussion DR. J E F F RAY New
York, N.
Thoracic and Cardiovascular
Y.
I congratulate the authors on an excellent study. Four papers so far, and some to follow, address themselves to treatment of interstitial pulmonary edema, an important component of pulmonary insufficiency. I should like to draw your attention to the role of patient immobility as a critical factor, abetting interstitial edema, pulmonary arteriovenous shunting, and hypoxemia. [Slide] This slide shows low Pao2 in 7 patients after 3V2 to 8 hours of immobility in the supine position during anesthesia and operation. Turning each patient to one lateral position raised the Paoz to the physiologically acceptable tension of 80 mm. Hg or higher, without changing the pressure and volume settings of the respirator or altering the Fioj. Nondependent portions of lung have no interstitial edema and are available for instant use with optimal ventilation-perfusion relationships. I wish to report observations made at New York Medical College with Drs. Clauss and Moallem. The observations were made in laterally positioned, anesthetized, overhydrated dogs; some were immobile and others were turned. [Slide] Blood samples drawn from pulmonary veins in this laterally positioned, immobile dog disclosed normal Po8 in blood from the antidependent (up) lung. In the dependent lung (the repository of the bulk of pulmonary blood flow and volume), PpVo, was low—suboptimal. [Slide] In this dog, turning into alternate lateral positions hourly drains the blood and interstitial edema and allows alveoli to expand despite
massive overhydration. Gas exchange is more effective at once. Po, rises in pulmonary veins and in systemic arteries. [Slide] This is the same phenomenon in a man. [Slide] To prevent and to relieve interstitial edema and suboptimal ventilation-perfusion relationships, frequent turning (for example, at halfhour intervals) may have to be done. The per cent pulmonary arteriovenous shunt decreases, allowing Flo, to be lowered. The "stir-up regimen" has merit. It should be used systematically to complement protein infusion, diuresis, and respirator treatment with continuous positive end-expiratory pressure. DR. W I L L I A M H. F L E M I N G Atlanta,
Ga.
I would like to compliment the authors on their study. When we saw similar problems in Vietnam, we had the feeling, as they obviously did, that this is probably an iatrogenic disease. Without fluid overload, it doesn't seem to develop. [Slide] Our criteria for making the diagnosis were essentially the same as theirs. Because these patients were in another prospective study, we had the advantage of having some antecedent data on them: (1) significant decline in arterial Po2; (2) significant decline in pulmonary compliance; (3) x-ray evidence of increased pulmonary interstitial fluid bilaterally; and (4) no other evident cause, such as fat embolism or respirator changes. [Slide] Dr. Giordano mentioned in his abstract the changes in compliance. Our 10 patients went from a mean of 32.8 ml. per centimeter of water the day before the diagnosis of wet lung syndrome to the mean low point of 21.0 at the time of diagnosis. They were treated with diuretics and fluid restriction alone, and in \¥z hours, pulmonary compliance came back up appreciably to a mean of 32.9 ml. per centimeter of water. [Slide] There were similar changes at similar times in the arterial Po2, the day before, at the low point, and Wi hours later. Again, the only therapy on these patients was diuretics and fluid restriction. [Slide] Fluid balances in the 5 patients on whom we could get valid figures show that they were in distinctly positive fluid balance. [Slide] These patients excreted an average of 2,165 ml. of urine in 2 hours with a diuretic dose of 40 to 80 mg. of intravenous furosemide. This is a higher average than you may note in civilian practice because the patients were younger men, and I think it may have taken more fluid to get them into this difficulty. I would like to ask Dr. Giordano if he used the albumen therapy on people who did not receive diuretics. There certainly is a greater intellectual appeal to adding an osmotic agent, but I wonder
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Interstitial pulmonary edema
745
November, 1972
whether that alone would be sufficient or whether perhaps the combination would be better than either alone.
or perhaps others have considered measurements of these factors in their problems.
DR. J A M E S G E I G E R
Santa Barbara, Calif.
DR. T H O M A S O'BRIEN
San Francisco, Calif.
I would like to compliment the authors for calling our attention to another important factor in this problem of pulmonary insufficiency. I would emphasize that this is not a simple problem. There are many complicated factors in the etiology, and, therefore, many times there are mixed modalities of therapy which are applicable. I suggest two things that should also be considered: One is an endocrine response to stress, and the second is metabolic water production. In a group of 30 patients who I treated successfully with a complicated therapeutic regimen, there were several common denominators. All were hypoalbuminic and hyponatremic, and most were anemic; these observations are consistent with hyperaldosteronism. I would like to discuss metabolic water production with the aid of a slide on a young man of 23 years. [Slide] This man had a gunshot wound through the lung and spine. He was paraplegic and was received after 6 weeks of continuous ventilatory support. This represents 1 day during his 3 months on the ventilator. He received Lasix and albumin twice a day for a week and then at least every day for the ensuing 10 days. These films were taken on the same day, approximately 8 hours apart, and represent the dynamics of this problem. We were careful to restrict his intake of fluid and sodium. However, in spite of this, the water became mobilized, and he developed pulmonary edema. I might also mention that he had a marked need for inspiratory pressure support (70 cm. H-O), initially. The patient lost approximately 55 pounds during the course of his injury in spite of hyperalimentation. I think it was first pointed out by Dr. Francis Moore that breakdown of 1 kilogram of tissue will produce 1 L. of water. Much of this is never taken into account in the fluid management of these patients. I also have some preliminary data which indicate that a number of the casualties do have markedly elevated levels of aldosterone. A very important factor in this entity is vascular damage. The role of a humoral factor was first delineated by Dr. Blaisdale of San Francisco. It has been shown that aldosterone and vasoactive amines, in combination, are extremely vasculotoxic. They may contribute to the permeability of the pulmonary circulation. I would like to ask the authors whether they
I would like to express my congratulations to the authors on a very significant contribution and also to comment about our experience with this form of therapy. It appears that most forms of acute respiratory failure are associated with inappropriate water retention. In the clinical setting, this can be demonstrated by the presence of hyponatremia, hypoalbuminemia, lowered serum osmolality, and so forth. Van De Water and others, using impedance plethysmography, have demonstrated that much of this fluid is finally deposited in the lungs. It is not surprising then that patients with acute respiratory failure, whether they have posttraumatic respiratory insufficiency, viral pneumonia, or whatever, will benefit from a program of fluid restriction and intensive dehydration with the utilization of albumin and other agents to improve serum oncotic pressure. The regimen that we have used consists of albumin, 100 to 200 Gm. a day, Lasix, 100 to 200 mg. a day, or Edecrin, 100 to 1,000 mg. a day; we usually use methylprednisone sodium succinate as well because of the fact that this drug appears to enhance certain cellular characteristics of an injured lung. This particular regimen is not original with us. We have plagiarized it in toto from Dr. Robert Bartlett of the University of California at Irvine. We recently had the opportunity to treat a patient with preterminal shock lung by means of this regimen. At the start of therapy, he had a calculated negative fluid balance of 1 L. Over the course of the first 48 hours of therapy, a further negative fluid balance of 10 L. was accomplished. Improvement in gas exchange was impressive as water was removed from the lungs. However, the patient eventually required the services of Dr. Hill and Mr. Bramson with the membrane oxygenator and was on bypass for perhaps 75 hours. Ultimately he survived. I am quite sure that one of the reasons this patient's pulmonary pathology was reversible was related to the marked state of negative fluid balance that had been achieved before bypass. Finally, in our community, during the past several months, there has been a significant problem with acute respiratory failure caused by viral pneumonitis. Patients with this disease have responded very dramatically to the same program of marked water restriction and intensive dehydration. I would like to add one word of caution to those who utilize this form of therapy. If it is
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7 4 6 Giordano et al.
Thoracic and Cardiovascular Surgery
pushed hard enough, a very dangerous state of hypernatremia and hyperosmolality can be induced. This can have severe, if not lethal, effects on the central nervous system and on the urinary tract. I believe that it is inadvisable to use this therapy to the point where the serum osmolality exceeds 330 or the serum sodium exceeds 160. DR. J O S E P H M. G I O R D A N O
(Closing)
I would like to thank the discussers for their comments. I think Dr. Ray's point that the dependent portions of the lung are most severely affected is important. Continual movement of the patient
every half hour, as he suggested, may play a significant role in treatment. Regarding Dr. Fleming's question as to whether albumin could be used alone, we believe that diuretics should always be given with the albumin. Once the fluid is mobilized, it should be excreted as rapidly as possible, because the albumin itself does not remain in the intravascular compartment more than 6 or 8 hours. Regarding Dr. Geiger's point, we did not measure aldosterone in these patients. I think we should pay more attention to aldosterone and to the amount of water contributed by the metabolic breakdown of protein.