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Lung lavage (alveolar washing) in alveolar proteinosis
Lung Lavage (Alveolar Washing) in Alveolar Proteinosis* KARLMAN
WASSERMAN,
PH.D.,
M.D.,?
NORMAN
BLANK,
M.D.
and GRANT
FLETCHER,
~I.D.
Palo Alto, California A young woman suffering from pulmonary alveolar proteinosis was treated by a method of pulmonary lavage. This form of treatment resulted in striking clinical, physiologic and roentgenologic improvement. The serial changes in clinical course, pulmonary physiology and roentgenographic manifestations of the disease process are described. tried without success, but treatment by means of a modification of the lung lavage procedure described by Ramirez-R et al. [S] resulted in striking improvement. This form of therapy yielded such pertinent physiologic and roentgenographic information that we believed a detailed description of the procedure and its results is warranted.
proteinosis is a disorder in which an amorphous proteinaceous material, rich in lipids, fills alveoli and bronchioles. The pathologic features have been described in detail by Rosen et al. [7]. Reviews by Summers [2] and Bala and Snidal [3] have recently appeared. The symptomatology [3,4] of this disorder is variable. At least two cases have been reported in asymptomatic subjects in whom evidence of the disease was first noted on routine x-ray examination of the chest [4,5]. In the majority of patients, however, there are symptoms of cough (with or without much sputum production), dyspnea, fatigue and malaise. Other symptoms and signs include weight loss, chest pain, hemoptysis, clubbing of fingers and cyanosis. Fever is often present but may be secondary to associated infection. The diagnosis is established by lung biopsy or autopsy. The course of the disorder also is variable-in some patients improvement is spontaneous but in many death occurs from hypoxemia or complicating diseases, especially superimposed infections. There has been a relatively high rate of complicating fungus infection of which nocardiosis is the most common [2,3,5 1. Various forms of therapy for this disorder have been described with inconsistent results. The purpose of this report is to present a case in which inhalation therapy and tracheal instillation of heparin and proteolytic agents had been
A
LVEOLAR
CASE REPORT
This forty-two year old woman complained chiefly of dry cough and shortness of breath. She was in her presumed usual state of health until three months prior to admission when she noted the insidious onset of a nagging dry cough. This cough was originally bothersome only during the day but later also became troublesome at night. Exertional dyspnea progressed until she began having difficulty doing her housework, walking 15 to 20 feet, or climbing five or more stairs. She also had a weight loss of between 10 and 15 pounds. Four weeks prior to admission to Stanford Hospital she was seen by her private physician and hospitalized locally. Thoracotomy and a biopsy of the lingula was performed. The histologic diagnosis of pulmonary alveolar proteinosis was made (Fig. 1) and she was treated with aerosol inhalations and subsequently by transtracheal installation of heparin in saline solution four times daily for seven days. Her condition did not improve and she was transferred to the Stanford Hospital for further therapy. Her additional past history included six episodes of pneumonia over the past twenty years. Each episode was said to be characterized by fever and the production of sputum. She also had had two episodes of
* From The Departments of Medicine, Radiology and Anesthesiology, Stanford University School of Medicine, Palo Alto, California. This study was supported in part by Public Health Grants HE 06591 and HE 03043 and The John A. Hartford Foundation. Requests for reprints should be addressed to Karlman Wasserman, M.D. Manuscript received May 22, 1967. t Present address: Department of Medicine, U.C.L.A. School of Medicine, Respiratory Disease Division, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90502. “01..
44,
APRIL.
1968
611
612
Lung Lavage-
FIG. 1. Periodic acid-Schiff stain of lung biopsy section. Amorphous material in alveolar space is periodic acidSchiff-positive. bronchitis, the last of these occurring six years prior to the present illness. Approximately one month before her present illness she had an episode of chills, fever and sweating which lasted for two days. A chest roentgenogram and pulmonary function studies in 1964 were reportedly normal. She had smoked a package of cigarettes daily for twenty years. There was no history of allergies. The remainder of the past history, system review and family history was not contributory. The physical examination demonstrated a thin, middle-aged woman with normal vital signs and in no apparent distress. The fundi showed minimal scattered hemorrhages with a clear outline of the discs. Examination of the chest revealed normal diaphragmatic excursion with normal breath sounds but a few fine inspiratory basilar and axillary rales. There was a healing left thoracotomy scar. Examination of the heart revealed no enlargement. The second aortic sound was slightly greater than the second pulmonic sound. There were no murmurs, heaves or thrills. The remainder of the examination was within normal limits. Laboratory studies revealed an erythrocyte sedimentation rate of 8 mm. per hour, hemoglobin 17 gm. per 100 ml., hematocrit 54 per cent, white blood cells 9,000 per cu. mm. with a normal differential
-Wasserman
et al.
count and a platelet count of 353,000 per cu. mm. The urinalysis was normal. Protein electrophoresis was normal. Cold agglutinins and multiple lupus erythematosus preparations were negative. Skin tests, including intermediate strength purified protein derivatives, coccidioidin and histoplasmin were negative. The arm to tongue circulation time with Decholin@ was nine seconds. The serum glutamic oxalacetic transaminase titer was 19 units. Four lactic dehydrogenase measurements ranged between 670 and 890 units (normal range is 100 to 350 units). Zinc turbidity was 62 units (normal range is 30 to 60 units). The lung biopsy sections were reviewed and the diagnosis of pulmonary alveolar proteinosis was confirmed. Previous chest films of August 10, 1964 and August 26, 1965, were obtained. The film made in 1964 showed no pulmonary abnormalities other than a minimal thickening and scalloping of the pleura over both apices associated with a few subjacent linear strands and small nodules. The film obtained in August 1965, however, demonstrated a subtle but definite diffuse bilateral infiltrate consisting of minute nodular densities. This infiltrate was profuse enough to obliterate most of the shadows of the smaller vascular radicals even though casual inspection of the film might lull one into thinking it was negative. In May 1966, after two months of exertional dyspnea, a chest film (Fig. 2) showed an extensive symmetrical alveolar infiltrate with relative sparing of the extreme lung bases and apices. Although the alveolar components of the infiltrate predominated, on this and on several subsequent films there was evidence of an interstitial component manifested by the presence of “septal lines” in the periphery of the bases of both lungs. Inhalation therapy was initiated, consisting of nebulized solutions of heparin, acetylcysteine and pancreatic dornase given alternately as often as every two hours for six days. The patient was also given 10 drops of a saturated solution of potassium iodide for seven days. She did not improve symptomatically nor produce sputum despite vigorous coughing. Several chest roentgenograms obtained up to and including June 8, 1966, showed a remarkably static appearance of the pulmonary abnormalities on both sides. The patient’s respiratory function before the lung lavage therapy (Table I, June 2) demonstrated no significant abnormality in the mechanics of breathing (normal vital capacity and flow rates) but there was marked hypoxemia and reduction in the diffusing capacity measurement. The arterial carbon dioxide tension was reduced. The absence of a defect in lung mechanics and only a mild defect in distribution of inspired gas suggest that the lung parenchyma was relatively intact. However, the large alveolar-arterial oxygen difference of 80 mm. Hg (assuming a gas exchange ratio of 1) demonstrated difficulty in oxygen reaching or passing through perfused alveolae. AMERICAN
JOURNAL
OF
MEDICINE
Lung Lavage-
Wasserman
613
et al.
2
3
2. Chest roentgenogram symmetrical alveolar infiltrate. I-‘IG.
obtained
on -May 11, 1966, showing
cxtrnsivc
FIG. 3. Supine chest film with Carlens catheter in place obtained live minutes following occlusion of the left side. There is marked reduction in gas volume on the left. TABLE RESPIRATORY
I‘UNCTION
CHANGES
IN
A WOMAN
WITH
Test Mechanics Vital capacity (ml.) Expiratory reserve volume (ml.) Inspiratory capacity (ml.) Functional residual capacity (ml.) Total lung capacity (ml.) Residual volume (ml.) Residual volume: total capacity Timed vital capacity 1’ (%) Maximal expiratory flow (L./min.) Maximal inspiratory flow (L./min.) Maximal breathing capacity (L./min.) Distribution-inspired gas Single breath oxygen 7 min. (nitrogen “wash-out”} Arterial blood 02 tension (mm. Hg) 02 saturation (yO) CO? tension (mm. Hg) PH Bicarbonate (mEq./L.) Alveolar-arterial 02 difference (mm. Hg) Diffusion Diffusing capacity carbon monoxide (single breath) ml. carbon monoxide/min./mm. Hg
Predicted
2,890 960 1,930 1,830 3,760 870 0.23 >72 >300 >300 88 <2 <2 >80 >95 38-42 7 .38-7.42 23-25 <20
* Before lavage. t Approximately forty-eight hours after lavage of left lung. # Four days after lavage of right lung. VOL.
44,
APRIL
1968
I
ALVEOLAR
22
PROTEINOSIS
__-____ h/2*
2,770 1.530 lj240 2,380 3,620 850 0.23 69 385 213 96
BEFORE
AND
AFTER
L.UNG
Actual ~_ _~605
t
.
61201
2,930 1,610 1,320 2,650 3,970 1,040 0.26 82 385 192 95
LAVAGE
--.9/8
3,350 1,540 1,810 ... ,.. . ..,
6.0 0.8
. .
3.9 1.4
42 81 28 7.48 20 80
55 89.4 30 7.49 22.5 65
70 94.5 35 7.48 25 45
97 97.4 33 7.48 23.7 20
8.2
11.2
14.0
19.6
614
Lung Lavage-
Chest roentgenogram
FIG. 5.
Chest roentgenogram
et al.
5
4 FIG. 4.
Wasserman
obtained obtained
6
five hours following completion
of left lung lavage.
twenty hours following lavage of right lung. Compare
FIG. 6. Chest roentgenozram obtained two and a half months striking improvement compared to Figure 2. On June 13, 1966, the patient was anesthetized with sodium pentothal in preparation for lavage of the left lung. After bronchoscopy, a Carlens catheter was put in place as described by Ramirez-R et al. [6]. The ventilation of each lung was controlled separately. The patient was ventilated with 100 per cent oxygen for approximately ten minutes. The outlet of the Carlens catheter from the left lung was then clamped for five minutes to permit degassing. Figure 3 is a supine chest film made at that time and demonstrates almost complete atelectasis of the left lung. The patient’s left lung was then filled with saline solution containing 10 gm. of acetylcysteine and 7,500 units of heparin per L., until a pressure of 25 cm. of water was reached. Approximately 1,500 cc. of this fluid was instilled. (During this time, the right lung was continually ventilated with oxygen as it was throughout the lavage procedure.) The left lung was then drained by gravity to 20 cm. water below the patient’s mid-chest level. A thick off white effluent was obtained. The lung was again filled with a fresh solution of the same substances and drained in a similar fashion. This procedure was repeated for a total of eleven times. Each time the wash apeared less opaque. The procedure was stopped after the eleventh lavage because of worsening hypoxemia. A total of approximately 16 L. of irrigating fluid was used for the total procedure. A portable supine film of the chest (Fig. 4) made approximately five hours after completion of the lavage of the left lung showed a moderate reduction in the amount of infiltrate in the left lung. Films made at 8 A.M. on the following morning, fifteen hours after the procedure. and again on June 15, 1966, ap-
following
to Figure 2.
the last lung lavage procedure
showing
proximately forty-eight hours following the procedure, showed striking improvement in the roentgenographic appearance of the left lung. Arterial blood gas measurements made approximately forty-eight hours following the procedure (Table I, June 15) demonstrated an increase in the arterial oxygen tension and a significant decrease in the alveolar-arterial oxygen tension difference. The diffusing capacity measurement (single breath, carbon monoxide) also increased. In view of this gratifying response as measured by functional and roentgenographic studies the entire procedure was then performed on the right side on June 16, 1966. The right lung underwent thirteen lavages at a single session, with the same type of effluent return as had been obtained from the lavage of the left lung. The first three lavages consisted of saline solution alone. We could not visually detect any reduction in the effect of the lavages with the omission of the acetylcysteine and heparin. Addition of these agents to the fourth and subsequent lavages did not result in thicker effluents. A chest film made at 8 A.M. on the following morning, approximately twenty hours following completion of the procedure, showed remarkable reduction of the infiltrate in the right lung (Fig. 5). Before discharge, four days following lavage of the right lung, there was further improvement. Repeat respiratory function tests on June 20, 1966 (Table I), showed considerable further improvement in blood gases and diffusing capacity. The patient was discharged on June 20, 1966 feeling greatly improved but with some persistent physiologic impairment. AMERICAN
JOURNAL
OF
MEDICINE
Lung Lavage-
615
Wasserman Pt al.
TABLE II CHANGES
IN
ARTERIAL OXYGEN
TENSION
RESULTING
RIGHT LUNG P (mm%,)
pl 1
~______ 7.59 7.56 7.62 7.55 7.60 7.56 7.57 7.53 7.57 7.54 7.48
425 225 445 185 560 64 515 51 475 51 315
OF INTRAPULMONARY
CHANGES
ON VENOUS
DURING
LUNG
FROM FILLING FLUID
pcoz (mm. Hg)
Venous Admixture (% of cardiac output)
26 26 22 27 24 25 25 29 24 30 32
14 27 13 30 6 43 9 52 12 52 21
The patient was seen at a clinic visit two and a half months later. At that time respiratory function studies were within normal limits (Table I). Chest films showed a striking sustained reduction in the amount of pulmonary infiltrate, so much so that the smaller ramifications of the pulmonary vascular tree could be identified easily (Fig. 6). Thus complete removal of the physiological abnormalities as well as remarkable roentgenographic clearing of the disease process was apparent two and a half months following the lung lavages. The patient was without symptoms at that time. EFFECT
WITH
PRESSURE
ADMIXTURE
LAVAGE
The arterial oxygen tension during 100 per cent oxygen breathing should be reduced in proportion to the admixture of venous and pulmonary capillary blood. If venous admixture is not present, the systemic arterial blood oxygen tension should equal the alveolar tension since there is apparent diffusion equilibrium across the normal alveolar-capillary membrane [7,8]. The
Sodium (mEq./L.) Potassium (mEq./L.) Carbon dioxide capacity (mM/L.) Chloride (mEq./L.) Blood urea nitrogen (mg.%) Packed cell volume (70)
Hemoglobin
(pm. ‘%)
139 4.1 24 103 9
54.5 17.7
* Four hours after left lung lavage (16 L.). 1 Four hours after right lung lavage (20 L.). VOL.
44,
APRIL
1968
When
Oh
Measured
Before lung degassing After lung degassing 1st wash, lung full 1st wash, lung empty 3rd wash, lung full 3rd wash, lung empty 7th wash, lung full 7th wash, lung empty 11 th wash, lung full 11 th wash, lung empty 20 minutes after regassing
FOLLOWING
6113
6/13*
(P.M.)
6/14
138 4.3 22.5 104
144 4.1 19 109
48’.;
136 4.0 21.5 106 4
‘47
(A.M.)
EMPTYING
oxygen and carbon dioxide tensions in the radial artery blood were monitored during filling and draining of the lungs, and the venous admixture was calculated assuming a systemic arterialvenous oxygen difference of 4.5 volumes per cent. The results of these measurements during the lavage of the right lung are given in Table II. When the right lung was filled with solution to a pressure of 25 cm. of water, the blood shunted away from this lung. Calculations of venous admixture indicate that only 6 to 13 per cent of the cardiac output could be perfusing this lung at the time of maximal filling with lavage fluid (Table II). However, when the alveolar pressure of the lavaged lung was decreased to -20 cm. of water during the emptying phase, the venous admixture increased to 30 to 52 per cent of the cardiac output. The amount of venous admixture during the emptying phase increased as the lavages progressed. In fact, the large amount of venous admixture during the eleventh lavage on the left side limited continuation of the procedure.
TABLE III HEMODILUTION AND ELECTROLYTE CHANGES
6/l
AND
L”NG
LAVAGE
6/16 (A.M.)
6/16t (P.M.)
140 4.9 24 106
148 4.0 17.5 114
46 15.3
.41
14.2
6117 138 4.5 24 105 5
39.5 13.4
Lung Lavage-
FIG. 7. Histiocyte acid-Schiff-positive placed nucleus. ELECTROLYTE
from lavage fluid showing periodic staining cytoplasm and eccentrically
CHANGES
FOLLOWING
AND HEMODILUTION
LUNG
LAVAGE
Because of the large volumes of the lavage fluid, we assumed that there would be a certain amount of solute redistribution between body fluids and lavage fluid as well as hemodilution. Therefore, the hematocrit and electrolytes were measured just before the lavage and approximately four hours following the completion of the lavage (Table III). In addition, the blood urea nitrogen was measured at intervals. Sodium and chloride increased following the lavages, whereas potassium and the carbon dioxide capacity decreased. However, these measurements returned to their original values by the next day. The blood urea nitrogen was reduced and hemodilution occurred following both lavage procedures. However, the hemodilution occurred to a relatively small degree on the left. The right side lavage might have been associated with more hemodilution than the left because of the longer procedure associated with the larger volume used. COMMENTS
As yet, no specific agent has been found to be effective in the management of patients with
Wasserman et al. pulmonary alveolar proteinosis. Indeed, it is difficult to evaluate therapy in this disorder because of the factor of spontaneous improvement. According to Summers [2], most patients with pulmonary alveolar proteinosis who are still alive have had no special therapy. It is feared that the use of steroids is dangerous because of the threat of fungus infections. Nevertheless, patients have been treated with steroids apparently with little consistent improvement. Saturated solutions of potassium iodide have been used in several cases as well as oral and parenteral forms of trypsin and chymoptrysin. A variety of preparations have been used for administration by intermittent positive pressure nebulization. Among these have been solutions containing streptokinase, streptodornase, trypsin and varidase. The results in all forms of treatment have been variable [3 3. Ramirez-R and collaborators [9] first utilized repeated washings of segments of the lungs by means of an indwelling catheter passed into the trachea via a subglottic approach. Subsequently, however, it was concluded that this method was relatively inefficient since only small amounts of alveolar material were removed with each treatment and the severely hypoxic patients were unable to tolerate the marked coughing caused by the infusions. Consequently, a technic was described by Ramirez-R et al. [6] for lavaging one whole lung at a time. They employed this form of treatment in four patients with alveolar proteinosis [6] but used no more than 3.0 L. of lavage fluid at any session. The technic used for the patient described in this report differed from the latter studies only in that a much larger total volume of lavage solution was used for each treatment. The results demonstrated significant early improvement. Smears made from the sediment of the lavage effluent revealed a great deal of pink granular material which stained with periodic acid-S&8 stain. Other than large histiocytes filled with periodic acid-Schiff positive material (Fig. 7), no inflammatory cells were present. It would appear that the major benefit from this form of treatment lies in the mechanical removal of inspissated material from the finer ramifications of the tracheobronchial tree. It is unlikely that there is any basic alteration of the underlying disease process. Nevertheless, it is anticipated that this technic, employed judiciously, might provide relief for the patients with severe hypoxemia due to a variety of diseases in which filling
Lung of the alveoli tracheobronchial factor.
and small tree is
Lavage-
ramifications of the a major pathologic
Acknowledgment: We wish to thank Dr. George Gordon of San Jo&, California for referring the patient to the Stanford Medical Service.
FVu.sxerman pt al. 4.
5.
6.
REFERENCES
S. H., CASTLEMAN, B. and LIEBOW, A. ,4. Pulmonary alveolar proteinosis. New England J. Med., 258: 1123, 1958. 2. SUMMERS, J. E. Pulmonary alveolar proteinosis. Review of the literature with follow-up studies and report of two cases. Calif. Med., 104: 428, 1966. 3. BALA, R. M. and SNIDAL, D. P. Pulmonary alveolar proteinosis. A case report and review of the literature. Dir. Chest, 49: 643, 1966. 1.
ROSEN,
VOL.
44,
APRIL
1968
7.
8.
9.
6 17
K. K. and GORDINIER. K. Pulmonq alvrolar proteinosis, report of six cases, review of the literature and formulation of d Ned theory. ilnn. Int. Med., 62: 292, 1965. FURST, \‘V. E., BELL, B. M. and IRONS, G. V., .JR. .%ymptomatic pulmonary al\-rolar protcinosis. Am. J. Med., 28: 453, 1960. RAMIRE%-R, J., KIEFPER, R. F., JR. and BALL. [V. C. Bronchopulmonary lavagr in man. :lrrn. In/. &fed., 63: 813, 1965. COMROE, J. H. Physiology of Respiration, p. 140. Chicago, 1965. Yearbook Medical Publishers, Inc. HOLMGREN,:\. and MCILROY, M. B. Effect of temperature on arterial blood gas tensions and pH during exercise. J. Ap,bl. P/p&l., 19: 243, 1964.. RAMIREZ-R, J., NYKA, W. and MCLAUGHLIN, J. Pulmonary alveolar proteinosis. New England J. Med., 268: 453, 1960.
IARSON,
WASSERMAN,
PH.D.,
M.D.,?
NORMAN
BLANK,
M.D.
and GRANT
FLETCHER,
~I.D.
Palo Alto, California A young woman suffering from pulmonary alveolar proteinosis was treated by a method of pulmonary lavage. This form of treatment resulted in striking clinical, physiologic and roentgenologic improvement. The serial changes in clinical course, pulmonary physiology and roentgenographic manifestations of the disease process are described. tried without success, but treatment by means of a modification of the lung lavage procedure described by Ramirez-R et al. [S] resulted in striking improvement. This form of therapy yielded such pertinent physiologic and roentgenographic information that we believed a detailed description of the procedure and its results is warranted.
proteinosis is a disorder in which an amorphous proteinaceous material, rich in lipids, fills alveoli and bronchioles. The pathologic features have been described in detail by Rosen et al. [7]. Reviews by Summers [2] and Bala and Snidal [3] have recently appeared. The symptomatology [3,4] of this disorder is variable. At least two cases have been reported in asymptomatic subjects in whom evidence of the disease was first noted on routine x-ray examination of the chest [4,5]. In the majority of patients, however, there are symptoms of cough (with or without much sputum production), dyspnea, fatigue and malaise. Other symptoms and signs include weight loss, chest pain, hemoptysis, clubbing of fingers and cyanosis. Fever is often present but may be secondary to associated infection. The diagnosis is established by lung biopsy or autopsy. The course of the disorder also is variable-in some patients improvement is spontaneous but in many death occurs from hypoxemia or complicating diseases, especially superimposed infections. There has been a relatively high rate of complicating fungus infection of which nocardiosis is the most common [2,3,5 1. Various forms of therapy for this disorder have been described with inconsistent results. The purpose of this report is to present a case in which inhalation therapy and tracheal instillation of heparin and proteolytic agents had been
A
LVEOLAR
CASE REPORT
This forty-two year old woman complained chiefly of dry cough and shortness of breath. She was in her presumed usual state of health until three months prior to admission when she noted the insidious onset of a nagging dry cough. This cough was originally bothersome only during the day but later also became troublesome at night. Exertional dyspnea progressed until she began having difficulty doing her housework, walking 15 to 20 feet, or climbing five or more stairs. She also had a weight loss of between 10 and 15 pounds. Four weeks prior to admission to Stanford Hospital she was seen by her private physician and hospitalized locally. Thoracotomy and a biopsy of the lingula was performed. The histologic diagnosis of pulmonary alveolar proteinosis was made (Fig. 1) and she was treated with aerosol inhalations and subsequently by transtracheal installation of heparin in saline solution four times daily for seven days. Her condition did not improve and she was transferred to the Stanford Hospital for further therapy. Her additional past history included six episodes of pneumonia over the past twenty years. Each episode was said to be characterized by fever and the production of sputum. She also had had two episodes of
* From The Departments of Medicine, Radiology and Anesthesiology, Stanford University School of Medicine, Palo Alto, California. This study was supported in part by Public Health Grants HE 06591 and HE 03043 and The John A. Hartford Foundation. Requests for reprints should be addressed to Karlman Wasserman, M.D. Manuscript received May 22, 1967. t Present address: Department of Medicine, U.C.L.A. School of Medicine, Respiratory Disease Division, Harbor General Hospital, 1000 West Carson Street, Torrance, California 90502. “01..
44,
APRIL.
1968
611
612
Lung Lavage-
FIG. 1. Periodic acid-Schiff stain of lung biopsy section. Amorphous material in alveolar space is periodic acidSchiff-positive. bronchitis, the last of these occurring six years prior to the present illness. Approximately one month before her present illness she had an episode of chills, fever and sweating which lasted for two days. A chest roentgenogram and pulmonary function studies in 1964 were reportedly normal. She had smoked a package of cigarettes daily for twenty years. There was no history of allergies. The remainder of the past history, system review and family history was not contributory. The physical examination demonstrated a thin, middle-aged woman with normal vital signs and in no apparent distress. The fundi showed minimal scattered hemorrhages with a clear outline of the discs. Examination of the chest revealed normal diaphragmatic excursion with normal breath sounds but a few fine inspiratory basilar and axillary rales. There was a healing left thoracotomy scar. Examination of the heart revealed no enlargement. The second aortic sound was slightly greater than the second pulmonic sound. There were no murmurs, heaves or thrills. The remainder of the examination was within normal limits. Laboratory studies revealed an erythrocyte sedimentation rate of 8 mm. per hour, hemoglobin 17 gm. per 100 ml., hematocrit 54 per cent, white blood cells 9,000 per cu. mm. with a normal differential
-Wasserman
et al.
count and a platelet count of 353,000 per cu. mm. The urinalysis was normal. Protein electrophoresis was normal. Cold agglutinins and multiple lupus erythematosus preparations were negative. Skin tests, including intermediate strength purified protein derivatives, coccidioidin and histoplasmin were negative. The arm to tongue circulation time with Decholin@ was nine seconds. The serum glutamic oxalacetic transaminase titer was 19 units. Four lactic dehydrogenase measurements ranged between 670 and 890 units (normal range is 100 to 350 units). Zinc turbidity was 62 units (normal range is 30 to 60 units). The lung biopsy sections were reviewed and the diagnosis of pulmonary alveolar proteinosis was confirmed. Previous chest films of August 10, 1964 and August 26, 1965, were obtained. The film made in 1964 showed no pulmonary abnormalities other than a minimal thickening and scalloping of the pleura over both apices associated with a few subjacent linear strands and small nodules. The film obtained in August 1965, however, demonstrated a subtle but definite diffuse bilateral infiltrate consisting of minute nodular densities. This infiltrate was profuse enough to obliterate most of the shadows of the smaller vascular radicals even though casual inspection of the film might lull one into thinking it was negative. In May 1966, after two months of exertional dyspnea, a chest film (Fig. 2) showed an extensive symmetrical alveolar infiltrate with relative sparing of the extreme lung bases and apices. Although the alveolar components of the infiltrate predominated, on this and on several subsequent films there was evidence of an interstitial component manifested by the presence of “septal lines” in the periphery of the bases of both lungs. Inhalation therapy was initiated, consisting of nebulized solutions of heparin, acetylcysteine and pancreatic dornase given alternately as often as every two hours for six days. The patient was also given 10 drops of a saturated solution of potassium iodide for seven days. She did not improve symptomatically nor produce sputum despite vigorous coughing. Several chest roentgenograms obtained up to and including June 8, 1966, showed a remarkably static appearance of the pulmonary abnormalities on both sides. The patient’s respiratory function before the lung lavage therapy (Table I, June 2) demonstrated no significant abnormality in the mechanics of breathing (normal vital capacity and flow rates) but there was marked hypoxemia and reduction in the diffusing capacity measurement. The arterial carbon dioxide tension was reduced. The absence of a defect in lung mechanics and only a mild defect in distribution of inspired gas suggest that the lung parenchyma was relatively intact. However, the large alveolar-arterial oxygen difference of 80 mm. Hg (assuming a gas exchange ratio of 1) demonstrated difficulty in oxygen reaching or passing through perfused alveolae. AMERICAN
JOURNAL
OF
MEDICINE
Lung Lavage-
Wasserman
613
et al.
2
3
2. Chest roentgenogram symmetrical alveolar infiltrate. I-‘IG.
obtained
on -May 11, 1966, showing
cxtrnsivc
FIG. 3. Supine chest film with Carlens catheter in place obtained live minutes following occlusion of the left side. There is marked reduction in gas volume on the left. TABLE RESPIRATORY
I‘UNCTION
CHANGES
IN
A WOMAN
WITH
Test Mechanics Vital capacity (ml.) Expiratory reserve volume (ml.) Inspiratory capacity (ml.) Functional residual capacity (ml.) Total lung capacity (ml.) Residual volume (ml.) Residual volume: total capacity Timed vital capacity 1’ (%) Maximal expiratory flow (L./min.) Maximal inspiratory flow (L./min.) Maximal breathing capacity (L./min.) Distribution-inspired gas Single breath oxygen 7 min. (nitrogen “wash-out”} Arterial blood 02 tension (mm. Hg) 02 saturation (yO) CO? tension (mm. Hg) PH Bicarbonate (mEq./L.) Alveolar-arterial 02 difference (mm. Hg) Diffusion Diffusing capacity carbon monoxide (single breath) ml. carbon monoxide/min./mm. Hg
Predicted
2,890 960 1,930 1,830 3,760 870 0.23 >72 >300 >300 88 <2 <2 >80 >95 38-42 7 .38-7.42 23-25 <20
* Before lavage. t Approximately forty-eight hours after lavage of left lung. # Four days after lavage of right lung. VOL.
44,
APRIL
1968
I
ALVEOLAR
22
PROTEINOSIS
__-____ h/2*
2,770 1.530 lj240 2,380 3,620 850 0.23 69 385 213 96
BEFORE
AND
AFTER
L.UNG
Actual ~_ _~605
t
.
61201
2,930 1,610 1,320 2,650 3,970 1,040 0.26 82 385 192 95
LAVAGE
--.9/8
3,350 1,540 1,810 ... ,.. . ..,
6.0 0.8
. .
3.9 1.4
42 81 28 7.48 20 80
55 89.4 30 7.49 22.5 65
70 94.5 35 7.48 25 45
97 97.4 33 7.48 23.7 20
8.2
11.2
14.0
19.6
614
Lung Lavage-
Chest roentgenogram
FIG. 5.
Chest roentgenogram
et al.
5
4 FIG. 4.
Wasserman
obtained obtained
6
five hours following completion
of left lung lavage.
twenty hours following lavage of right lung. Compare
FIG. 6. Chest roentgenozram obtained two and a half months striking improvement compared to Figure 2. On June 13, 1966, the patient was anesthetized with sodium pentothal in preparation for lavage of the left lung. After bronchoscopy, a Carlens catheter was put in place as described by Ramirez-R et al. [6]. The ventilation of each lung was controlled separately. The patient was ventilated with 100 per cent oxygen for approximately ten minutes. The outlet of the Carlens catheter from the left lung was then clamped for five minutes to permit degassing. Figure 3 is a supine chest film made at that time and demonstrates almost complete atelectasis of the left lung. The patient’s left lung was then filled with saline solution containing 10 gm. of acetylcysteine and 7,500 units of heparin per L., until a pressure of 25 cm. of water was reached. Approximately 1,500 cc. of this fluid was instilled. (During this time, the right lung was continually ventilated with oxygen as it was throughout the lavage procedure.) The left lung was then drained by gravity to 20 cm. water below the patient’s mid-chest level. A thick off white effluent was obtained. The lung was again filled with a fresh solution of the same substances and drained in a similar fashion. This procedure was repeated for a total of eleven times. Each time the wash apeared less opaque. The procedure was stopped after the eleventh lavage because of worsening hypoxemia. A total of approximately 16 L. of irrigating fluid was used for the total procedure. A portable supine film of the chest (Fig. 4) made approximately five hours after completion of the lavage of the left lung showed a moderate reduction in the amount of infiltrate in the left lung. Films made at 8 A.M. on the following morning, fifteen hours after the procedure. and again on June 15, 1966, ap-
following
to Figure 2.
the last lung lavage procedure
showing
proximately forty-eight hours following the procedure, showed striking improvement in the roentgenographic appearance of the left lung. Arterial blood gas measurements made approximately forty-eight hours following the procedure (Table I, June 15) demonstrated an increase in the arterial oxygen tension and a significant decrease in the alveolar-arterial oxygen tension difference. The diffusing capacity measurement (single breath, carbon monoxide) also increased. In view of this gratifying response as measured by functional and roentgenographic studies the entire procedure was then performed on the right side on June 16, 1966. The right lung underwent thirteen lavages at a single session, with the same type of effluent return as had been obtained from the lavage of the left lung. The first three lavages consisted of saline solution alone. We could not visually detect any reduction in the effect of the lavages with the omission of the acetylcysteine and heparin. Addition of these agents to the fourth and subsequent lavages did not result in thicker effluents. A chest film made at 8 A.M. on the following morning, approximately twenty hours following completion of the procedure, showed remarkable reduction of the infiltrate in the right lung (Fig. 5). Before discharge, four days following lavage of the right lung, there was further improvement. Repeat respiratory function tests on June 20, 1966 (Table I), showed considerable further improvement in blood gases and diffusing capacity. The patient was discharged on June 20, 1966 feeling greatly improved but with some persistent physiologic impairment. AMERICAN
JOURNAL
OF
MEDICINE
Lung Lavage-
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Wasserman Pt al.
TABLE II CHANGES
IN
ARTERIAL OXYGEN
TENSION
RESULTING
RIGHT LUNG P (mm%,)
pl 1
~______ 7.59 7.56 7.62 7.55 7.60 7.56 7.57 7.53 7.57 7.54 7.48
425 225 445 185 560 64 515 51 475 51 315
OF INTRAPULMONARY
CHANGES
ON VENOUS
DURING
LUNG
FROM FILLING FLUID
pcoz (mm. Hg)
Venous Admixture (% of cardiac output)
26 26 22 27 24 25 25 29 24 30 32
14 27 13 30 6 43 9 52 12 52 21
The patient was seen at a clinic visit two and a half months later. At that time respiratory function studies were within normal limits (Table I). Chest films showed a striking sustained reduction in the amount of pulmonary infiltrate, so much so that the smaller ramifications of the pulmonary vascular tree could be identified easily (Fig. 6). Thus complete removal of the physiological abnormalities as well as remarkable roentgenographic clearing of the disease process was apparent two and a half months following the lung lavages. The patient was without symptoms at that time. EFFECT
WITH
PRESSURE
ADMIXTURE
LAVAGE
The arterial oxygen tension during 100 per cent oxygen breathing should be reduced in proportion to the admixture of venous and pulmonary capillary blood. If venous admixture is not present, the systemic arterial blood oxygen tension should equal the alveolar tension since there is apparent diffusion equilibrium across the normal alveolar-capillary membrane [7,8]. The
Sodium (mEq./L.) Potassium (mEq./L.) Carbon dioxide capacity (mM/L.) Chloride (mEq./L.) Blood urea nitrogen (mg.%) Packed cell volume (70)
Hemoglobin
(pm. ‘%)
139 4.1 24 103 9
54.5 17.7
* Four hours after left lung lavage (16 L.). 1 Four hours after right lung lavage (20 L.). VOL.
44,
APRIL
1968
When
Oh
Measured
Before lung degassing After lung degassing 1st wash, lung full 1st wash, lung empty 3rd wash, lung full 3rd wash, lung empty 7th wash, lung full 7th wash, lung empty 11 th wash, lung full 11 th wash, lung empty 20 minutes after regassing
FOLLOWING
6113
6/13*
(P.M.)
6/14
138 4.3 22.5 104
144 4.1 19 109
48’.;
136 4.0 21.5 106 4
‘47
(A.M.)
EMPTYING
oxygen and carbon dioxide tensions in the radial artery blood were monitored during filling and draining of the lungs, and the venous admixture was calculated assuming a systemic arterialvenous oxygen difference of 4.5 volumes per cent. The results of these measurements during the lavage of the right lung are given in Table II. When the right lung was filled with solution to a pressure of 25 cm. of water, the blood shunted away from this lung. Calculations of venous admixture indicate that only 6 to 13 per cent of the cardiac output could be perfusing this lung at the time of maximal filling with lavage fluid (Table II). However, when the alveolar pressure of the lavaged lung was decreased to -20 cm. of water during the emptying phase, the venous admixture increased to 30 to 52 per cent of the cardiac output. The amount of venous admixture during the emptying phase increased as the lavages progressed. In fact, the large amount of venous admixture during the eleventh lavage on the left side limited continuation of the procedure.
TABLE III HEMODILUTION AND ELECTROLYTE CHANGES
6/l
AND
L”NG
LAVAGE
6/16 (A.M.)
6/16t (P.M.)
140 4.9 24 106
148 4.0 17.5 114
46 15.3
.41
14.2
6117 138 4.5 24 105 5
39.5 13.4
Lung Lavage-
FIG. 7. Histiocyte acid-Schiff-positive placed nucleus. ELECTROLYTE
from lavage fluid showing periodic staining cytoplasm and eccentrically
CHANGES
FOLLOWING
AND HEMODILUTION
LUNG
LAVAGE
Because of the large volumes of the lavage fluid, we assumed that there would be a certain amount of solute redistribution between body fluids and lavage fluid as well as hemodilution. Therefore, the hematocrit and electrolytes were measured just before the lavage and approximately four hours following the completion of the lavage (Table III). In addition, the blood urea nitrogen was measured at intervals. Sodium and chloride increased following the lavages, whereas potassium and the carbon dioxide capacity decreased. However, these measurements returned to their original values by the next day. The blood urea nitrogen was reduced and hemodilution occurred following both lavage procedures. However, the hemodilution occurred to a relatively small degree on the left. The right side lavage might have been associated with more hemodilution than the left because of the longer procedure associated with the larger volume used. COMMENTS
As yet, no specific agent has been found to be effective in the management of patients with
Wasserman et al. pulmonary alveolar proteinosis. Indeed, it is difficult to evaluate therapy in this disorder because of the factor of spontaneous improvement. According to Summers [2], most patients with pulmonary alveolar proteinosis who are still alive have had no special therapy. It is feared that the use of steroids is dangerous because of the threat of fungus infections. Nevertheless, patients have been treated with steroids apparently with little consistent improvement. Saturated solutions of potassium iodide have been used in several cases as well as oral and parenteral forms of trypsin and chymoptrysin. A variety of preparations have been used for administration by intermittent positive pressure nebulization. Among these have been solutions containing streptokinase, streptodornase, trypsin and varidase. The results in all forms of treatment have been variable [3 3. Ramirez-R and collaborators [9] first utilized repeated washings of segments of the lungs by means of an indwelling catheter passed into the trachea via a subglottic approach. Subsequently, however, it was concluded that this method was relatively inefficient since only small amounts of alveolar material were removed with each treatment and the severely hypoxic patients were unable to tolerate the marked coughing caused by the infusions. Consequently, a technic was described by Ramirez-R et al. [6] for lavaging one whole lung at a time. They employed this form of treatment in four patients with alveolar proteinosis [6] but used no more than 3.0 L. of lavage fluid at any session. The technic used for the patient described in this report differed from the latter studies only in that a much larger total volume of lavage solution was used for each treatment. The results demonstrated significant early improvement. Smears made from the sediment of the lavage effluent revealed a great deal of pink granular material which stained with periodic acid-S&8 stain. Other than large histiocytes filled with periodic acid-Schiff positive material (Fig. 7), no inflammatory cells were present. It would appear that the major benefit from this form of treatment lies in the mechanical removal of inspissated material from the finer ramifications of the tracheobronchial tree. It is unlikely that there is any basic alteration of the underlying disease process. Nevertheless, it is anticipated that this technic, employed judiciously, might provide relief for the patients with severe hypoxemia due to a variety of diseases in which filling
Lung of the alveoli tracheobronchial factor.
and small tree is
Lavage-
ramifications of the a major pathologic
Acknowledgment: We wish to thank Dr. George Gordon of San Jo&, California for referring the patient to the Stanford Medical Service.
FVu.sxerman pt al. 4.
5.
6.
REFERENCES
S. H., CASTLEMAN, B. and LIEBOW, A. ,4. Pulmonary alveolar proteinosis. New England J. Med., 258: 1123, 1958. 2. SUMMERS, J. E. Pulmonary alveolar proteinosis. Review of the literature with follow-up studies and report of two cases. Calif. Med., 104: 428, 1966. 3. BALA, R. M. and SNIDAL, D. P. Pulmonary alveolar proteinosis. A case report and review of the literature. Dir. Chest, 49: 643, 1966. 1.
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APRIL
1968
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K. K. and GORDINIER. K. Pulmonq alvrolar proteinosis, report of six cases, review of the literature and formulation of d Ned theory. ilnn. Int. Med., 62: 292, 1965. FURST, \‘V. E., BELL, B. M. and IRONS, G. V., .JR. .%ymptomatic pulmonary al\-rolar protcinosis. Am. J. Med., 28: 453, 1960. RAMIRE%-R, J., KIEFPER, R. F., JR. and BALL. [V. C. Bronchopulmonary lavagr in man. :lrrn. In/. &fed., 63: 813, 1965. COMROE, J. H. Physiology of Respiration, p. 140. Chicago, 1965. Yearbook Medical Publishers, Inc. HOLMGREN,:\. and MCILROY, M. B. Effect of temperature on arterial blood gas tensions and pH during exercise. J. Ap,bl. P/p&l., 19: 243, 1964.. RAMIREZ-R, J., NYKA, W. and MCLAUGHLIN, J. Pulmonary alveolar proteinosis. New England J. Med., 268: 453, 1960.
IARSON,