The Clinical and Physiological Effect of Whole-Lung Lavage in Pulmonary Alveolm Proteinosis: A Ten-Year Experience Paul A. Selecky, M.D., Karlman Wasserman, M.D., Ph.D., John R. Benfield, M.D., and Maurice Lippmann, M.D. [12]. The clinical presentation of patients with PAP is generally marked by variable degrees of dyspnea associated with concomitant hypoxemia. The impaired oxygenation is often severe and is thought to be due to filling of the alveolar spaces by this material. The alveolar septae, however, are mysteriously spared. This unique characteristic of primarily alveolar involvement has prompted various investigators to use saline lavage of the lung to remove the proteinaceous material. Ramirez-R described the technique of wholelung lavage in 1965 [17], but there has been remarkable variation in the degree of success in applying it to patients with PAP. Controversy still exists concerning patient selection for lavage, when lavage should be done, and what technique brings the best results. Our experience with the treatment of PAP has spanned ten years. We have previously reported our experience with simultaneous bilateral lung lavage by means of partial cardiopulmonary bypass in 2 small children [24]. We have also described our technique of unilateral wholelung lavage in adults [lo]. Our procedure has Pulmonary alveolar proteinosis (PAP) was de- been modified as we have gained experience. scribed in 1958 by Rosen, Castleman, and This report summarizes our experience with Liebow 1211 as a disease process marked by fill- whole-lung lavage for PAP. ing of the alveolar spaces of the lung with an amorphous periodic acid-Schiff (PAS) positive Methods proteinaceous material. Since then other pa- All patients who had whole-lung lavages were tients with this disorder have been identified adults 45 years of age or younger, and all had progressive, severe exertional dyspnea. The diagnosis of PAP had been confirmed in each by From the Departments of Medicine, Surgery, and Anesopen-lung biopsy. If the biopsy was done at thesiology, UCLA School of Medicine, Los Angeles, and Harbor General Hospital Campus, Torrance, CA. another institution, the slides were reviewed by Supported in part by US Public Health Service Grant No. our pathologists and by us.
ABSTRACT We have utilized whole-lung lavage in
the successful treatment of 18 patients with pulmonary alveolar proteinosis. Our ten-year experience includes serial evaluationsof patients with disabling lung dysfunction who had a total of 49 whole-lung lavages under general anesthesia. Clinical and physiological responses were documented both before and after each lavage. There were no complications or deaths. All patients were radiographically, physiologically, and symptomatically improved within hours after the procedures. Five patients required from two to four repeat lavages one to three years later. The treatment of this disorder has included a wide variety of techniques. We attribute our results to the use of a lung lavage technique that includes: (1) unilateral whole-lung lavages at two to three day intervals; (2) isotonicsaline as the lavage solution; (3) use of a mechanical chest percussor during lavage; and (4) measuring the total thoracic compliance of each side in the immediate postlavage period as a guide for extubation. We conclude that whole-lung lavage is a safe, highly effective, repetitively applicable treatment for pulmonary alveolar proteinosis.
HL05916.
Address reprint requests to Dr. Selecky, Division of Respiratory Physiology and Medicine, Harbor General Hospital, 1000 W Carson St, Torrance, CA 90509. Presented at the Thirteenth Annual Meeting of The Society of Thoracic Surgeons, Jan24-26, 1977, San Francisco, CA.
451
Prelavage Evaluation Each patient was hospitalized several days prior to lavage. During this time a thorough history, physical examination, and routine laboratory
452 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
examination were conducted to rule out the from recordings of expiratory volume made presence of other pulmonary diseases. A careful with a Wright respirometer; inspiratory airway history of any occupational or other toxic expo- pressure is measured with an anaeroid masures was also obtained. Standard pulmonary nometer. function tests were performed, including vital After these measurements are recorded, the capacity (VC),forced expiratory volume in 1sec- lavage solution is allowed to run into the left ond (FEV,), total lung capacity (TLC) by the lung through one arm of a Y-tube while the right nitrogen-washout method, and single-breath lung is continuously ventilated with the highcarbon monoxide diffusing capacity ( D L ~ ~ )oxygen . mixture. The tubing on the other arm of Arterial blood gases were also measured. An the Y-tube is clamped, and its end is inserted incremental exercise test was performed on a into a collection bottle approximately 20 cm cycle ergometer in most of the adult patients. below the patient. Saline is allowed to run into the left lung as the oxygen is absorbed, requiring Lavage Protocol about 5 to 7 minutes until the lung is completely The procedure is performed in the operating degassed. Subsequent filling is much quicker. room under general anesthesia (halothane) and Mechanical chest percussion as previously demuscle paralysis (pancuronium) with standard scribed [lo], is performed during the filling and monitoring of heart rate, blood pressure, and draining of the lung. The left lung is then periodic arterial blood gases. The current tech- drained by clamping the inflow tube and unclamping the drainage tube. The cloudy gray nique of the lavage follows. effluent drains rapidly by gravity and siphon effect, being complete in 3 to 5 minutes. The 1. Perform general anesthesia using a tracheal divider with the patient in the supine posi- lung is then rapidly refilled with saline, percussed, and allowed to drain again; volumes tion. exchanged are recorded each time. Thik se2. Ventilate both lungs at F I 1.0. ~ ~ 3. Measure total thoracic compliance of each quence is repeated until the effluent is nearly clear. side. At the conclusion of the procedure, the lav4. Lavage one lung with isotonic saline at 37°C aged lung is ventilated with 10Oo/o oxygen and from container 30 cm above midchest. periodically suctioned with a stiff, slender cathe5. Do mechanical chest percussion. ter. Pressurelvolume measurements of the lav6. Perform gravity and siphon drainage. 7. Repeat lavage until effluent is almost clear. aged lung (+ chest wall = total thoracic compliance) are recorded repeatedly. When thoracic 8. Clear airways of saline by suction. 9. Measure total thoracic compliance of la- compliance has returned to a level equal to that of the ventilated lung, the paralysis and anesvaged lung. 10. Ventilate lavaged lung until compliance is thesia are reversed, and the patient is allowed to recover spontaneous ventilation and is subrestored to prelavage level. sequently extubated. Deep breathing and The patient is maintained in the supine position coughing are encouraged in the immediate postduring the entire procedure. A Carlens tracheal lavage period. The right lung is lavaged in a divider is inserted according to the method de- similar manner two to three days later. scribed by Lynch and Feraru [14]. The cuffs are inflated separately, and the tube is tested for Postlavage Evaluation leaks to ensure complete separation of both Repeat pulmonary function tests and chest lungs. A 3 liter container of sterile physiological roentgenograms were performed after each lung saline (no additives) warmed to 37°C is was lavaged. Incremental exercise tests were resupended 30 cm above the patient’s midchest. peated in most patients within several days of Both lungs are ventilated with 98.5% oxygen the conclusion of both lavages. Statistical comand 1.5% halothane. Before lavage, pressure/ parisons of pulmonary function tests and blood volume measurements are made on each lung gases before and after lavage were made using a
453
Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
paired t-test. Follow-up examinations of the patients were conducted at varying intervals by us and by the referring physicians. Repeat lavage was performed if symptoms recurred and pulmonary function deteriorated.
Results Our ten-year experience with PAP includes 19 patients and 49 whole-lung lavages. Biographical information reveals a wide range of ages (3 to 45 years) and a variety of occupations. Men predominate by greater than 5:l; the majority of patients are white. Two children have been described previously [241. One adult did not undergo lavage because of only mild disability at the time of referral. Sixteen patients were separated into 2 groups. Group 1(5 patients) were lavaged either at other institutions by one of us (Dr. Wasserman), acting as a visiting consultant, or by us earlier in our experience. Data from this group are incomplete. Group 2 (11patients), who make up the body of this report, were lavaged at Harbor General Hospital. Five patients in Group 2 were lavaged on more than one occasion because of recurrence of symptoms. Prelavage Evaluation
All patients complained of marked dyspnea on exertion, which had progressed slowly for 12 to 18 months. Cough occasionallyproduced a small amount of white sputum. Various forms of Fig 1 . Whole-lung lavage resulted in an increase in (left) vital capacity (p < 0.0005) and (right)total lung capacity (p < 0.005). Results are tabulated as percentage of lung volume predicted for each patient.
n w !-
2
Lavage Period All Group 2 adults were lavaged by the tech-
nique described, and all tolerated the procedure well. Each whole-lung lavage used a total of 15 to
Total Lung Capacity
Vital Capacity 100
P - - - - - - - - - -.
-----
60
n W K
n
s
40
'"1
0'
PREPOSTLAVAGE LAVAGE
aerosol and expectorant therapy had been tried in most patients with little or no decrease in their dyspnea. Physical examination and routine laboratory studies were generally within normal limits. The lung examination was particularly benign, revealing no rales, rhonchi, or wheezes. ECGs were also unremarkable. Pulmonary function testing of patients in Group 2 revealed a decreased VC and TLC (< 80% predicted), characteristic of a restrictive defect in 6 patients (Fig 1);lung volumes were normal in the remaining 5. Diffusing capacity, however, was significantly reduced in all 11patients (Fig 2), with a mean D L of~48 ~? 10 ( OO/ predicted). Flow rates, characterized by FEV,/VC, were within normal limits. Arterial blood gases were obtained at rest and at the maximal level of exercise tolerated in 10 patients in Group 2 (Fig 3). The exercise was terminated at varying work rates in each patient because of progressive dyspnea. Resting Pao, was below normal in 9 patients (mean, 67 ? 9 mm Hg) and decreased further with exercise (mean, 52 k 11 mm Hg). Chest roentgenograms in all 19 patients were characterized by varying degrees of abnormality. Common findings included a diffuse ground-glass appearance, air bronchograms, and alveolar filling infiltrates, which spread diffusely over all lung fields but were more marked in the perihilar areas (Fig 4A).
I
PRELAVAGE
POSTLAVAGE
454 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
8ol
Im1
2ol "
CONTROL
POST-LAVAGE
Fig 2 . Diffusing capacity ( D L ~was ~ )severely reduced prior to lavage (control) and increased 50°/0 as a result of whole-lung lavage (p C 0.0005).
4
I
20
REST
EXERCISE
Fig 3. Pao, at rest was below normal (mean, 67 k 9 mm Hg) in almost all patients with pulmonary alveolar proteinosis before lavage and decreased further with exercise (mean, 52 k 11 mm Hg). Each patient exercised on a cycle ergometer to his highest tolerable work rate.
18 liters of saline in 1,000 to 1,800 ml aliquots, requiring 10 to 15 runs until the effluent was nearly clear. The lavages were then terminated. The average cumulative fluid retention at the conclusion of the lavage was 500 ml, most of which was subsequently removed by periodic suctioning. We interrupted the procedure prematurely in 1 patient in Group 2 because of a small amount of leakage into the ventilated side. This was readily detected by frequent auscultation; there was no untoward effect. It was also stopped prematurely because of hypoxemia, in 1 patient in Group 1. Nonetheless, both patients achieved noticeable physiological and clinical improvement from the lavages already completed. Pressurelvolume measurements of each lung were taken in all patients both before and after lavage. The compliance of the lavaged lung relative to the ventilated lung for 7 Group 2 patients is shown in Figure 5, which demonstrates a fall in compliance in the lavaged lung from prelavage levels and the gradual return to prelavage levels within 60 minutes.
Postlavage Evaluation Within several hours of the conclusion of each lavage, the patients generally stated that their lungs felt lighter, that they could breathe more easily, or that they could take a deeper breath. This was corroborated by repeat pulmonary function tests performed on the first or second day after each lung was lavaged. The results for Group 2 after both lungs were lavaged are given in Figure 1. They demonstrate a Significant increase in both VC (p < 0.0005) and TLC (p < 0.005). Diffusing capacity was increased greater than 50% in all patients as a result of the lavage (p < 0.0005) (see Fig 2). Arterial blood gases were obtained at rest and during exercise (90 watts) from one to three days after bilateral lavages in 6 Group 2 patients (Fig 6). These were compared to prelavage measurements and reveal a significant increase in both resting and exercise Paoz after lavage (p < 0.005). The hypocapnia noted before lavage had largely disappeared. Chest roentgenograms showed a marked and rapid decrease of the alveolar filling infiltrates after each lung was lavaged (see Fig 4B, C). Subsequently, the majority of the chest roentgeno-
455
Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
A
B
Fig4. Chest roeiitgeiiogranis of a patieiit ioitli pulmonary alveolar proteiiiosis. ( A )BEforc lovage patchy alveolar irifiltrates are seeii, sligh tl!y iuorsc ori the right. (€3) Orie d a y after lounge of tlrt k f t lung, clearirig ofirifiltrates is secii iri that lurig. ( C ) Orie day after h a g e of the right h i i g thcrc is dramatic clearing of the derise iiifiltrafe. (Tlic pleural scar 017 the right dinphragrii is secoiidary to opeti lung biopsy.)
C
grams continued to improve and commonly became normal. All patients were discharged within two to three days and returned to work within one to two weeks. There were no major postlavage complications; 1 patient was mildly febrile for one day postlavage with no other evidence of infection.
Follow-up Evaluations Long-term follow-up is available for 14 of the 18 lavaged patients. These are separated into 3 categories. (1)Clinical information on 7 patients (6 in Group 2 and 1 in Group 1)indicates sustained improvement for periods as long as two years after both lungs were lavaged. Data from pulmonary function tests and chest roentgeno-
grams are available for 5 patients in this category and show no deterioration over a period of 5 to 21 months. (2) A gradual return of dyspnea, infiltrates, and pulmonary disability occurred in 5 Group 2 patients within a variable time following each procedure. These patients required two to four repeat lavages at one- to three-year intervals to relieve their recurrent symptoms. This occurred despite a favorable response to the initial lavage; the repeat lavages were equally as effective as the first and produced a dramatic improvement in lung function. One of the patients required a total of four lavages over a period of five years, but she has been stable with no functional limitation for four years since her last lavage. Duration of follow-up in these 12 patients is shown in Figure 7, indicating the
456 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
LEFT LUNG LAVAGE
1.2.
RIGHT LUNG LAVAGE
I
I
I I
I I
I
I
I .o,
0.4
0.2 0 +/ PRE-
I
I
0
I
30
60
7 -
POST-LAVAGE TIME (Min)
PRE-
0
io
Fig 5. Measurement of total thoracic compliance of lavaged lung (CLav)compared to ventilated lung (CVent). Prelavage measurements show similar compliance characteristics between both lungs. Lavage results in fall in compliance of the lavaged lung secondary to loss of surface-active forces. Continued ventilation causes these to regenerate within 60 minutes, with compliance returning to near-baseline levels. The left and right lungs were lavaged two to three days apart.
90
-
00-
pa02 (torr)
7060
-
5040-
30
PRE-LAVAGE
POST-LIIVAGE
PRE-LAVAGEPOST-LAIAGE
REST
Fig 6 . Whole-lung lavage resulted in increases in Pao2(p < 0.005) in 6 patients measured both at rest and at the same level of exercise performed prelavage (90 watts).
$0
POST-LAVAGE TIME (Min
EXERCISE
457 Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
Lovage
I
0
(0
$0
3b
40
SO
TIME (months)
60
:
70
Fig 7 . Duration offollow-up of 12 patients after lavage ranges from five months to ten years. Most patients remain asymptomatic after one lavage. Five patients required repeat lavages at varying intervals because of return of symptoms. Recurrence was noted within one year in all 5.
individual variability in this disease. (3) The 2 children who were lavaged under partial cardiopulmonary bypass have been evaluated in greater detail as they have grown since our earlier report. After their lavage, they required only low-flow oxygen supplementation and were sent home. Over the past eight years their oxygen needs have increased. Our experience with them suggests that they had suffered permanent damage to the lung parenchyma during the year of hospitalization prior to their lavage, most likely secondary to the high-flow oxygen (as high as FIQ 0.8) that they required during that time.
Comment Despite continued study of PAP since its description in 1958, the etiology remains obscure. In 1965, Larson 1121 suggested that a likely explanation for this proteinaceous substance found in the alveoli was an overabundance of the surface-active material (surfactant) produced by the type I1 alveolar lining cells. Subsequent research has demonstrated that this substance is largely a phospholipid with chemical and electron microscopical characteristics similar, although not identical, to normal surfactant [4,15, 16, 231. Clearance studies suggest that this ac-
/-
120
130
cumulation results from defective removal rather than increased production, although the cause of this defect is not understood [15, 161. Clinical studies have not revealed a common denominator to explain this abnormal clearance. PAP has been described in all age groups and races; likewise, there is no evidence of increased familial incidence or unique geographical distribution [121. Our experience reveals that the course in patients with PAP is quite varied. Some cases resolve spontaneously, others progress to hypoxemia and stop after one whole-lung lavage, whereas others require repeated lavages over several years. Microscopical findings similar to those of PAP have been described in association with silicosis, Pneumocystis carinii, and other diseases, suggesting to some authors a wide spectrum of causes [13]. We believe, however, that this similarity in microscopical description is nonspecific and suggest that the term pulmonary alveolar proteinosis be reserved for patients such as those described in this report and elsewhere; ie, patients who show no evidence of primary lung disease once the proteinaceous material has been removed, and who are otherwise healthy. This is in contrast to those patients with other primary diseases causing alveolar filling, but in whom fibrosis or evidence of parenchymal inflammation can also be found 16, 8, 271. It is a unique characteristic of PAP that the alveolar septae are largely spared any sequelae of the accumulation of proteinaceous material. Patchy fibrosis had been described occasionally
458 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
in early reports of PAP, but in retrospect this was likely the result of superinfection with various bacteria and fungi, notably nocardia. Larson [121 showed that the incidence of infection and subsequent mortality was higher in patients with PAP who were treated with corticosteroids. Our experience has been that the lung biopsies of untreated patients with PAP reveal only alveolar filling with minimal or no inflammatory changes in the interstitium. Thus there is no rationale for the use of corticosteroids in treating this disease.
Clinical Presentation The clinical presentation of patients with PAP is almost totally predictable when one considers the pathological picture. They generally complain of an insidious onset of dyspnea on exertion, occasionally associated with a mild cough. Their chest roentgenograms, not surprisingly, show the characteristics of alveolar filling disorders, ie, air bronchograms and diffuse homogeneous infiltrates. The disordered physiology is predicted by the altered anatomy: reduced diffusing capacity (Fig 2), arterial hypoxemia made worse with exercise (Fig 3), and, in more than half of the patients, a major restrictive defect (Fig 1).PAP is an excellent clinical example of the frequently cited but uncommon ”alveolar-capillary block syndrome” [ll. When the disease had progressed sufficiently to lower lung volumes in our patients, the D L was already severely reduced. Treatment The treatment of PAP was often unsuccessful in the early years after the disease was identified [121. Some patients had resolution of their disability under various forms of aerosol and expectorant therapy, although we have subsequently come to learn that such resolution can be spontaneous. As many as 30% of patients, however, progressed insidiously to severe dyspnea, hypoxemia, and death [12]. It wasn’t until Ramirez-R began experimenting with various forms of lung lavage that such a course was changed [18]. In 1965, he described the present method of lavaging an entire lung while simultaneously ventilating the contralateral lung with high inspired oxygen concentration [171. We
have gradually modified his approach, as described here, and we are now able to obtain dramatic improvement in the symptomatology and altered physiology in all patients with this disease. Controversy continues, however, over the clinical indications for whole-lung lavage [13]. Each center has also made changes in the technique [5, 7, 111. As a result, the outcome has been variable [2, 13, 17, 203. Some physicians reserve lavage for those patients who are severely disabled [131. Such thinking may be influenced by prior experiences that produced only fair results. We advocate lavage at a ti.me in the disease when the dyspnea has begun to affect the patient’s occupation or other daily activities; we do not wait until profound hypoxernia is present. This has produced a rapid and favorable response in all patients, allowing them to return to work and other pastimes that had previously been difficult because of dyspnea. We previously described a temporary worsening of hypoxemia during lavage when the lung being lavaged is drained [26]. This is the result of an increase in blood flow through the gasless lung when the alveolar pressure is reduced from a positive hydrostatic pressure during filling to subatmospheric pressure during draining. Since this is an unavoidable phenomenon during lavage, it is unwise to wait until the patient is severely hypoxemic before treating him, as the ~ risk ~ of lung lavage will be greater.
Lung Lavage Despite the fact that the lavage method seems straightforward, the published results vary. Some authors describe only mild improvernent, which is sometimes delayed for several days [2, 13, 17, 201. Lingering infiltrates have also been described, and most reports have documented only minor improvement in lung function. Our uniformly favorable results have therefore prompted us to examine our technique carefully. A successful whole-lung lavage requires a team approach, with several participants paying close attention to various parts of the procedure. We use sterile physiological saline as our lavage fluid. Our previous work indicates that additives such as heparin and acetylcysteine d o not increase the removal of sediment [lo]. We also
459 Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
position the saline reservoir 30 cm above the patient’s midchest to minimize the hypoxemia that occurs as the lavaged lung becomes degassed. Wasserman and colleagues [26], and later Smith and associates [25], showed that this decreases blood flow to the lavaged lung as it becomes gasless during filling. The hydrostatic pressure created by the column of saline suspended 30 cm above the patient generally exceeds mean pulmonary artery pressure and therefore decreases perfusion to the nonventilated lung, preventing severe hypoxemia [19]. For this same reason, we drain and refill the lung as rapidly as possible in order to lessen the period of hypoxemia while the degassed lung is drained of saline (and hydrostatic pressure is decreased). Periodic intraoperative arterial blood gas monitoring should be performed during lung filling to document that the Paoz is not critically low. Kylstra and co-workers [ll]have approached this problem by using “volume-controlled” lavage in which the lung is never completely drained of saline at the end of each run. A volume of saline comparable to the patient’s functional residual capacity is allowed to remain Fig 8 . Effect of repeated lavage for recurring pulmonary alveolar proteinosis in I patient. Decreases in lung volumes (VC, TLC) and diffusing capacity were restored to normal or near-normal with each lavage. There was no residual deterioration in lung function during45 months of follow-up.
‘0°1
in the lung after each filling, and smaller volumes (300-500 ml) are subsequently used to wash out the sediment. This technique is designed to prevent hydrostatic pressure from dropping to low levels in the hope of preventing hypoxemia. This is physiologically sound, but it results in a longer and less efficient lavage. Many authors have described a delay in improvement after lavage, whereas others have noted a temporary worsening of lung function [2, 13, 17, 201. They describe persistent hypoxemia and infiltrates for several days. Saline lavage of the lung is not benign. Huber and associates [9] have described changes in alveolar morphology and respiratory mechanics after lung lavage in dogs. This technique has also been shown to remove large quantities of surface-active material [15] as well as other proteins [22]. Thus it is not surprising that early extubation can result in a temporary worsening of lung function, largely secondary to atelectasis and associated with the loss of surfactant. We have seen a universally prompt and dramatic improvement in lung function and chest roentgenograms (see Fig 4) as each lung is lavaged. We attribute this to our practice of continuing to ventilate the lavaged lung so as to allow restoration of normal surface forces. This is evidenced by the return of thoracic compliance within one hour to the same level as in the contralateral lung (Fig 5). Whole-lung lavage for the treatment of PAP can be considered both curative and palliative.
460 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
Follow-up of our patients has revealed a wide spectrum of results (Fig 7). It is fortunate that whole-lung lavage is effective and has limited morbidity, as it is sometimes necessary to lavage certain patients repeatedly every one to two years. Figure 8 illustrates the course of 1patient who required four lavages because of recurrent symptoms. Note that lung function returned to near-normal levels after each lavage. There have been no sequelae despite recurring PAP or repeated lung lavage in 5 patients whom we have followed. Recurrence of this disorder is not predictable. The clinical presentation, degree of impairment, or efficiency of lavage in these few patients were not different from the rest of the group. The initial return of symptoms occurred within one year in each, with variable progression of the disease thereafter. Some patients have remained asymptomatic for up to five years after one repeat lavage. Our experience therefore indicates that the disease has a variable course and that continued follow-up is necessary. References 1. Austrian R, McClement JH, Renzetti AD, et al: Clinical and physiologic features of some types of pulmonary disease with impairment of alveolar-capillary diffusion: the syndrome of “alveolar-capillary block.” Am J Med 11:667, 1951 2. Castleman B, McNeely BU: Case Records of the Massachusetts General Hospital. Case 34,1974. N Engl J Med 291:464, 1974 3. Cooper JD, Woolf CR, Brebner J: Improved method of pulmonary lavage for alveolar proteinosis. Surg Forum 26:298, 1975 4. Costello JF, Moriarty DC, Branthwaite MA, et al: Diagnosis and management of alveolar proteinosis: the role of electron microscopy. Thorax 30:121, 1975 5. Dupont FS, Sphire RD: Pulmonary lavage. Crit Care Med 2:161, 1974 6. Hamper1 H: Variants of Pneumocystis carinii. J Pathol Bacteriol 74:353, 1957 7. Harris JO, Castle JR, Swenson EW, et al: Lobar lavage: therapeutic benefit in pulmonary alveolar filling disorders. Chest 65:655, 1974 8. Heard BE, Cooke RA: Busulphan lung. Thorax 23:187, 1968 9. Huber GL, Edmunds LHM, Finley TN: Effect of experimental saline lavage on pulmonary mechanics and morphology. Am Rev Respir Dis 104:337, 1971 10. Kao D, Wasserman K, Costley D, et al: Advances
in the treatment of pulmonary alveolar proteinosis. Am Rev Respir Dis 111:361, 1975 11. Kylstra JA, Rausch DC, Hall KD, et al: Volumecontrolled lung lavage in the treatment of asthma, bronchiectasis, and mucoviscidosis. Am Rev Respir Dis 103:651, 1971 12. Larson RK, Gordinier R: Pulmonary alveolar proteinosis. Ann Intern Med 62:292, 1965 13. Lewiston NJ, Robin ED: Pulmonary alveolar proteinosis. West J Med 124:29, 1976 14. Lynch CG, Feraru F: Endobronchial anesthesia. Anesthesiology 18:138, 1957 15. McClenahan JB, Mussenden R: Pulmonary alveolar proteinosis. Arch Intern Med 133:284, 1974 16. Ramirez-R J, Harlan WR: Pulmonary alveolar proteinosis. Am J Med 45:520, 1968 17. Ramirez-R J, Kieffer RF, Ball WC: Bronchopulmonary lavage in man. Ann Intern Med 63:819, 1965 18. Ramirez-R J, Schultz RB, Dutton RE: Pulmonary alveolar proteinosis: a new technique and rationale for treatment. Arch Intern Med 11.2:173, 1963 19. Rogers RM, Szidon JP, Shelburne J, et al: Hemodynamic response of the pulmonary circulation to bronchopulmonary lavage in man. N Engl J Med 286:1230, 1972 20. Rogers RM, Tantum KR: Bronchopulmonary lavage. Med Clin North Am 54:755, 1970 21. Rosen SH, Castleman B, Liebow AA: I’ulmonary alveolar proteinosis. N Engl J Med 258:1123, 1958 22. Rupp GH, Wasserman K, Ogawa M, et al: Bronchopulmonary fluids in pulmonary alveolar proteinosis. J Allergy Clin Immunol !51:227, 1973 23, Sahu S, DiAugustine RP, Lynn WS: Lipids found in pulmonary lavage of patients with alveolar proteinosis and in rabbit lung lamellar organelles. Am Rev Respir Dis 114:177, 1976 24. Seard C, Wasserman K, Benfield JR, et al: Simultaneous bilateral lung lavage (alveolar washing) using partial cardiopulmonary bypass. Am Rev Respir Dis 101:877, 1970 25. Smith JD,Millen JE, Safar P, et al: Intrathoracic pressure, pulmonary vascular pressures and gas exchange during pulmonary lavage. Anest hesiology 33:401, 1970 26. Wasserman K, Blank N, Fletcher G: Lung lavage (alveolar washing) in alveolar proteinosis. Am J Med 44:611, 1968 27. Williams GEG, Medley DRK, Brown R: I’ulmonary alveolar proteinosis. Lancet 1:1385, 1960
Discussion
DR. JOEL COOPER (Toronto, Ont, Canada): Our experi-
ence is more modest than that presented. We recently performed our eighteenth lavage. I wholeheartedly support the conclusions of the authors, and I con-
461 Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
gratulate them on their present and past contribu- died two weeks later of bone marrow insufficiency and overwhelming sepsis. tions to this field. By way of emphasis, I would like to raise a few DR.J. P. GEIGER (San Francisco, CA): I have used an points. First, a matter of terminology: we like a less adjunctive or ancillary form of treatment, perhaps formal and perhaps more descriptive term to describe even an alternative form, in 4 instances of alveolar the procedure-we refer to it as a lung enema. We proteinosis. This form of therapy consists of inhalaagree that an organized team is very important in tion of alcohol in 25% or 20% solution, administered carrying out these procedures. A casual approach to by nebulization with a routine IPPB machine. I was lung lavage is courting disaster. When possible, we attracted to this approach by an article by J. B. prefer to use the Robertshaw rather than the Carlens McClenathan which stated that this lipid material is tube. It has a larger lumen size and we think it is a bit soluble in vitro in alcohol (Arch Intern Med 133284, safer. One to 2 liters of warm saline, without addi1974). Having treated many patients with pulmonary tives, is used for each cycle. Both lungs are ventilated edema by this method in the past, I thought it might with l0Oo/o oxygen. We then clamp the right lung and also be effective in alveolar proteinosis. The patients produce absorption atelectasis. We then fill the lung, agreed to the clinical trial. by gravity, with saline. A 40-year-old man had previously declined diagFor those who are about to do their first lavage, I nostic biopsy until his resting Po, fell to 33 torr on would warn that on the first cycle, when 1,500 ml of saline is run in and then drained, 400 or 500 ml will be room air. A pitfall in the diagnosis was experienced when our local pathologist found a negative PAS missing. It is left in the residual volume of the lung, and if one is not prepared for it, it can cause a bit of a stain, but the correct diagnosis was later made by Dr. A. Liebow. The initial roentgenogram was not very consternation. It certainly did to me during our first lavage. For a moment, I thought I had discovered the helpful, but his clinical condition and arterial gases were somewhat frightening. Volume and flow studies missing fluids in my pants. A couple of years ago, we started using chest showed an across-the-board drop of about 40%. After three and a half weeks of 25% alcohol inhalaphysiotherapy in the form of manual percussion. One tion with no other therapy, he had a marked degree of of our physiotherapists joined us in the operating improvement. The first sputum specimen he proroom. We have found this very effective and think it has added to the procedure. Chest physiotherapy duced looked like whipped egg white, which assured makes the lavage more rapid, improves the amount of me that there was efficacy in the treatment. The padebris removed, and gives better clearing on the post- tient remained well three years later, and his only operative chest roentgenogram. The amount of debris abnormal pulmonary function is a slight increase in in the effluent was quantitated with an optical den- residual volume. Three other patients have had somewhat less imsitometer in a patient who had chest physiotherapy pressive results, attributable to their lack of cooperaon certain cycles and not on others. It is clear that there tion in continuing the treatment. is less debris with physiotherapy. During each cycle of drainage, do a midstream catch DR.ALFRED JARETZKI (New York, NY): I would like to of the draining fluid, put it in a small bottle, and attest to the importance of chest percussion during the display it. This serves as a guide to tell us when we lavage maneuver. Several years ago we quantitated have done enough; we are able to see the progressive the sediment retrieved, alternating lavage alone and clearing that occurs. We also have an arterial line in lavage with percussion. We were able to retrieve five place, and we measure blood gases frequently. When times as much sediment when percussion was used. the lung is filled with saline, the pressure of the saline Previously some patients with PAP destops the pulmonary blood flow to that lung and the DR. SELECKY: Po, is quite satisfactory. Paradoxically, it is during the veloped progressive hypoxemia and died. Fortudraining phase when the lung is empty, allowing nately, the advent of whole-lung lavage has made it blood to flow to the nonventilated lung, that the Po, possible now to restore near-normal lung function in drops to about 60 mm Hg. At that phase, if the pa- all patients with this disorder. This dramatic response tient is turned with the ventilated lung down, the to treatment does not occur often in other disease Pop will rise sharply due to the gravitational redis- states. The unique success in treating PAP is largely tribution of blood flow. We normally don't use that the result of the pathology of this disease, in which the maneuver, but it is nice to know about just in case. alveoli are filled but the alveolar septae are spared. As Postoperatively, we ventilate for three or four a result, whole-lung lavage is very effective. Thus our hours. We have not done compliance measurements, experience would indicate that PAP is not a fatal disbut I see from the data presented by Dr. Selecky ease if treated properly. that this seems to get us over the dangerous period. The clinical response to alcohol aerosols is interWe have performed one procedure in a patient who esting. Many other forms of therapy have been tried in was on perfusion as well. This girl had leukemia and the past, each with an occasional therapeutic reproteinosis, and she was on a membrane oxygenator. sponse, but none have provided consistent improveWe lavaged the left lung on bypass and subsequently ment. I am not aware, however, of controlled studies lavaged the right lung. She was taken off bypass but performed with alcohol aerosols.
ABSTRACT We have utilized whole-lung lavage in
the successful treatment of 18 patients with pulmonary alveolar proteinosis. Our ten-year experience includes serial evaluationsof patients with disabling lung dysfunction who had a total of 49 whole-lung lavages under general anesthesia. Clinical and physiological responses were documented both before and after each lavage. There were no complications or deaths. All patients were radiographically, physiologically, and symptomatically improved within hours after the procedures. Five patients required from two to four repeat lavages one to three years later. The treatment of this disorder has included a wide variety of techniques. We attribute our results to the use of a lung lavage technique that includes: (1) unilateral whole-lung lavages at two to three day intervals; (2) isotonicsaline as the lavage solution; (3) use of a mechanical chest percussor during lavage; and (4) measuring the total thoracic compliance of each side in the immediate postlavage period as a guide for extubation. We conclude that whole-lung lavage is a safe, highly effective, repetitively applicable treatment for pulmonary alveolar proteinosis.
HL05916.
Address reprint requests to Dr. Selecky, Division of Respiratory Physiology and Medicine, Harbor General Hospital, 1000 W Carson St, Torrance, CA 90509. Presented at the Thirteenth Annual Meeting of The Society of Thoracic Surgeons, Jan24-26, 1977, San Francisco, CA.
451
Prelavage Evaluation Each patient was hospitalized several days prior to lavage. During this time a thorough history, physical examination, and routine laboratory
452 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
examination were conducted to rule out the from recordings of expiratory volume made presence of other pulmonary diseases. A careful with a Wright respirometer; inspiratory airway history of any occupational or other toxic expo- pressure is measured with an anaeroid masures was also obtained. Standard pulmonary nometer. function tests were performed, including vital After these measurements are recorded, the capacity (VC),forced expiratory volume in 1sec- lavage solution is allowed to run into the left ond (FEV,), total lung capacity (TLC) by the lung through one arm of a Y-tube while the right nitrogen-washout method, and single-breath lung is continuously ventilated with the highcarbon monoxide diffusing capacity ( D L ~ ~ )oxygen . mixture. The tubing on the other arm of Arterial blood gases were also measured. An the Y-tube is clamped, and its end is inserted incremental exercise test was performed on a into a collection bottle approximately 20 cm cycle ergometer in most of the adult patients. below the patient. Saline is allowed to run into the left lung as the oxygen is absorbed, requiring Lavage Protocol about 5 to 7 minutes until the lung is completely The procedure is performed in the operating degassed. Subsequent filling is much quicker. room under general anesthesia (halothane) and Mechanical chest percussion as previously demuscle paralysis (pancuronium) with standard scribed [lo], is performed during the filling and monitoring of heart rate, blood pressure, and draining of the lung. The left lung is then periodic arterial blood gases. The current tech- drained by clamping the inflow tube and unclamping the drainage tube. The cloudy gray nique of the lavage follows. effluent drains rapidly by gravity and siphon effect, being complete in 3 to 5 minutes. The 1. Perform general anesthesia using a tracheal divider with the patient in the supine posi- lung is then rapidly refilled with saline, percussed, and allowed to drain again; volumes tion. exchanged are recorded each time. Thik se2. Ventilate both lungs at F I 1.0. ~ ~ 3. Measure total thoracic compliance of each quence is repeated until the effluent is nearly clear. side. At the conclusion of the procedure, the lav4. Lavage one lung with isotonic saline at 37°C aged lung is ventilated with 10Oo/o oxygen and from container 30 cm above midchest. periodically suctioned with a stiff, slender cathe5. Do mechanical chest percussion. ter. Pressurelvolume measurements of the lav6. Perform gravity and siphon drainage. 7. Repeat lavage until effluent is almost clear. aged lung (+ chest wall = total thoracic compliance) are recorded repeatedly. When thoracic 8. Clear airways of saline by suction. 9. Measure total thoracic compliance of la- compliance has returned to a level equal to that of the ventilated lung, the paralysis and anesvaged lung. 10. Ventilate lavaged lung until compliance is thesia are reversed, and the patient is allowed to recover spontaneous ventilation and is subrestored to prelavage level. sequently extubated. Deep breathing and The patient is maintained in the supine position coughing are encouraged in the immediate postduring the entire procedure. A Carlens tracheal lavage period. The right lung is lavaged in a divider is inserted according to the method de- similar manner two to three days later. scribed by Lynch and Feraru [14]. The cuffs are inflated separately, and the tube is tested for Postlavage Evaluation leaks to ensure complete separation of both Repeat pulmonary function tests and chest lungs. A 3 liter container of sterile physiological roentgenograms were performed after each lung saline (no additives) warmed to 37°C is was lavaged. Incremental exercise tests were resupended 30 cm above the patient’s midchest. peated in most patients within several days of Both lungs are ventilated with 98.5% oxygen the conclusion of both lavages. Statistical comand 1.5% halothane. Before lavage, pressure/ parisons of pulmonary function tests and blood volume measurements are made on each lung gases before and after lavage were made using a
453
Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
paired t-test. Follow-up examinations of the patients were conducted at varying intervals by us and by the referring physicians. Repeat lavage was performed if symptoms recurred and pulmonary function deteriorated.
Results Our ten-year experience with PAP includes 19 patients and 49 whole-lung lavages. Biographical information reveals a wide range of ages (3 to 45 years) and a variety of occupations. Men predominate by greater than 5:l; the majority of patients are white. Two children have been described previously [241. One adult did not undergo lavage because of only mild disability at the time of referral. Sixteen patients were separated into 2 groups. Group 1(5 patients) were lavaged either at other institutions by one of us (Dr. Wasserman), acting as a visiting consultant, or by us earlier in our experience. Data from this group are incomplete. Group 2 (11patients), who make up the body of this report, were lavaged at Harbor General Hospital. Five patients in Group 2 were lavaged on more than one occasion because of recurrence of symptoms. Prelavage Evaluation
All patients complained of marked dyspnea on exertion, which had progressed slowly for 12 to 18 months. Cough occasionallyproduced a small amount of white sputum. Various forms of Fig 1 . Whole-lung lavage resulted in an increase in (left) vital capacity (p < 0.0005) and (right)total lung capacity (p < 0.005). Results are tabulated as percentage of lung volume predicted for each patient.
n w !-
2
Lavage Period All Group 2 adults were lavaged by the tech-
nique described, and all tolerated the procedure well. Each whole-lung lavage used a total of 15 to
Total Lung Capacity
Vital Capacity 100
P - - - - - - - - - -.
-----
60
n W K
n
s
40
'"1
0'
PREPOSTLAVAGE LAVAGE
aerosol and expectorant therapy had been tried in most patients with little or no decrease in their dyspnea. Physical examination and routine laboratory studies were generally within normal limits. The lung examination was particularly benign, revealing no rales, rhonchi, or wheezes. ECGs were also unremarkable. Pulmonary function testing of patients in Group 2 revealed a decreased VC and TLC (< 80% predicted), characteristic of a restrictive defect in 6 patients (Fig 1);lung volumes were normal in the remaining 5. Diffusing capacity, however, was significantly reduced in all 11patients (Fig 2), with a mean D L of~48 ~? 10 ( OO/ predicted). Flow rates, characterized by FEV,/VC, were within normal limits. Arterial blood gases were obtained at rest and at the maximal level of exercise tolerated in 10 patients in Group 2 (Fig 3). The exercise was terminated at varying work rates in each patient because of progressive dyspnea. Resting Pao, was below normal in 9 patients (mean, 67 ? 9 mm Hg) and decreased further with exercise (mean, 52 k 11 mm Hg). Chest roentgenograms in all 19 patients were characterized by varying degrees of abnormality. Common findings included a diffuse ground-glass appearance, air bronchograms, and alveolar filling infiltrates, which spread diffusely over all lung fields but were more marked in the perihilar areas (Fig 4A).
I
PRELAVAGE
POSTLAVAGE
454 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
8ol
Im1
2ol "
CONTROL
POST-LAVAGE
Fig 2 . Diffusing capacity ( D L ~was ~ )severely reduced prior to lavage (control) and increased 50°/0 as a result of whole-lung lavage (p C 0.0005).
4
I
20
REST
EXERCISE
Fig 3. Pao, at rest was below normal (mean, 67 k 9 mm Hg) in almost all patients with pulmonary alveolar proteinosis before lavage and decreased further with exercise (mean, 52 k 11 mm Hg). Each patient exercised on a cycle ergometer to his highest tolerable work rate.
18 liters of saline in 1,000 to 1,800 ml aliquots, requiring 10 to 15 runs until the effluent was nearly clear. The lavages were then terminated. The average cumulative fluid retention at the conclusion of the lavage was 500 ml, most of which was subsequently removed by periodic suctioning. We interrupted the procedure prematurely in 1 patient in Group 2 because of a small amount of leakage into the ventilated side. This was readily detected by frequent auscultation; there was no untoward effect. It was also stopped prematurely because of hypoxemia, in 1 patient in Group 1. Nonetheless, both patients achieved noticeable physiological and clinical improvement from the lavages already completed. Pressurelvolume measurements of each lung were taken in all patients both before and after lavage. The compliance of the lavaged lung relative to the ventilated lung for 7 Group 2 patients is shown in Figure 5, which demonstrates a fall in compliance in the lavaged lung from prelavage levels and the gradual return to prelavage levels within 60 minutes.
Postlavage Evaluation Within several hours of the conclusion of each lavage, the patients generally stated that their lungs felt lighter, that they could breathe more easily, or that they could take a deeper breath. This was corroborated by repeat pulmonary function tests performed on the first or second day after each lung was lavaged. The results for Group 2 after both lungs were lavaged are given in Figure 1. They demonstrate a Significant increase in both VC (p < 0.0005) and TLC (p < 0.005). Diffusing capacity was increased greater than 50% in all patients as a result of the lavage (p < 0.0005) (see Fig 2). Arterial blood gases were obtained at rest and during exercise (90 watts) from one to three days after bilateral lavages in 6 Group 2 patients (Fig 6). These were compared to prelavage measurements and reveal a significant increase in both resting and exercise Paoz after lavage (p < 0.005). The hypocapnia noted before lavage had largely disappeared. Chest roentgenograms showed a marked and rapid decrease of the alveolar filling infiltrates after each lung was lavaged (see Fig 4B, C). Subsequently, the majority of the chest roentgeno-
455
Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
A
B
Fig4. Chest roeiitgeiiogranis of a patieiit ioitli pulmonary alveolar proteiiiosis. ( A )BEforc lovage patchy alveolar irifiltrates are seeii, sligh tl!y iuorsc ori the right. (€3) Orie d a y after lounge of tlrt k f t lung, clearirig ofirifiltrates is secii iri that lurig. ( C ) Orie day after h a g e of the right h i i g thcrc is dramatic clearing of the derise iiifiltrafe. (Tlic pleural scar 017 the right dinphragrii is secoiidary to opeti lung biopsy.)
C
grams continued to improve and commonly became normal. All patients were discharged within two to three days and returned to work within one to two weeks. There were no major postlavage complications; 1 patient was mildly febrile for one day postlavage with no other evidence of infection.
Follow-up Evaluations Long-term follow-up is available for 14 of the 18 lavaged patients. These are separated into 3 categories. (1)Clinical information on 7 patients (6 in Group 2 and 1 in Group 1)indicates sustained improvement for periods as long as two years after both lungs were lavaged. Data from pulmonary function tests and chest roentgeno-
grams are available for 5 patients in this category and show no deterioration over a period of 5 to 21 months. (2) A gradual return of dyspnea, infiltrates, and pulmonary disability occurred in 5 Group 2 patients within a variable time following each procedure. These patients required two to four repeat lavages at one- to three-year intervals to relieve their recurrent symptoms. This occurred despite a favorable response to the initial lavage; the repeat lavages were equally as effective as the first and produced a dramatic improvement in lung function. One of the patients required a total of four lavages over a period of five years, but she has been stable with no functional limitation for four years since her last lavage. Duration of follow-up in these 12 patients is shown in Figure 7, indicating the
456 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
LEFT LUNG LAVAGE
1.2.
RIGHT LUNG LAVAGE
I
I
I I
I I
I
I
I .o,
0.4
0.2 0 +/ PRE-
I
I
0
I
30
60
7 -
POST-LAVAGE TIME (Min)
PRE-
0
io
Fig 5. Measurement of total thoracic compliance of lavaged lung (CLav)compared to ventilated lung (CVent). Prelavage measurements show similar compliance characteristics between both lungs. Lavage results in fall in compliance of the lavaged lung secondary to loss of surface-active forces. Continued ventilation causes these to regenerate within 60 minutes, with compliance returning to near-baseline levels. The left and right lungs were lavaged two to three days apart.
90
-
00-
pa02 (torr)
7060
-
5040-
30
PRE-LAVAGE
POST-LIIVAGE
PRE-LAVAGEPOST-LAIAGE
REST
Fig 6 . Whole-lung lavage resulted in increases in Pao2(p < 0.005) in 6 patients measured both at rest and at the same level of exercise performed prelavage (90 watts).
$0
POST-LAVAGE TIME (Min
EXERCISE
457 Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
Lovage
I
0
(0
$0
3b
40
SO
TIME (months)
60
:
70
Fig 7 . Duration offollow-up of 12 patients after lavage ranges from five months to ten years. Most patients remain asymptomatic after one lavage. Five patients required repeat lavages at varying intervals because of return of symptoms. Recurrence was noted within one year in all 5.
individual variability in this disease. (3) The 2 children who were lavaged under partial cardiopulmonary bypass have been evaluated in greater detail as they have grown since our earlier report. After their lavage, they required only low-flow oxygen supplementation and were sent home. Over the past eight years their oxygen needs have increased. Our experience with them suggests that they had suffered permanent damage to the lung parenchyma during the year of hospitalization prior to their lavage, most likely secondary to the high-flow oxygen (as high as FIQ 0.8) that they required during that time.
Comment Despite continued study of PAP since its description in 1958, the etiology remains obscure. In 1965, Larson 1121 suggested that a likely explanation for this proteinaceous substance found in the alveoli was an overabundance of the surface-active material (surfactant) produced by the type I1 alveolar lining cells. Subsequent research has demonstrated that this substance is largely a phospholipid with chemical and electron microscopical characteristics similar, although not identical, to normal surfactant [4,15, 16, 231. Clearance studies suggest that this ac-
/-
120
130
cumulation results from defective removal rather than increased production, although the cause of this defect is not understood [15, 161. Clinical studies have not revealed a common denominator to explain this abnormal clearance. PAP has been described in all age groups and races; likewise, there is no evidence of increased familial incidence or unique geographical distribution [121. Our experience reveals that the course in patients with PAP is quite varied. Some cases resolve spontaneously, others progress to hypoxemia and stop after one whole-lung lavage, whereas others require repeated lavages over several years. Microscopical findings similar to those of PAP have been described in association with silicosis, Pneumocystis carinii, and other diseases, suggesting to some authors a wide spectrum of causes [13]. We believe, however, that this similarity in microscopical description is nonspecific and suggest that the term pulmonary alveolar proteinosis be reserved for patients such as those described in this report and elsewhere; ie, patients who show no evidence of primary lung disease once the proteinaceous material has been removed, and who are otherwise healthy. This is in contrast to those patients with other primary diseases causing alveolar filling, but in whom fibrosis or evidence of parenchymal inflammation can also be found 16, 8, 271. It is a unique characteristic of PAP that the alveolar septae are largely spared any sequelae of the accumulation of proteinaceous material. Patchy fibrosis had been described occasionally
458 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
in early reports of PAP, but in retrospect this was likely the result of superinfection with various bacteria and fungi, notably nocardia. Larson [121 showed that the incidence of infection and subsequent mortality was higher in patients with PAP who were treated with corticosteroids. Our experience has been that the lung biopsies of untreated patients with PAP reveal only alveolar filling with minimal or no inflammatory changes in the interstitium. Thus there is no rationale for the use of corticosteroids in treating this disease.
Clinical Presentation The clinical presentation of patients with PAP is almost totally predictable when one considers the pathological picture. They generally complain of an insidious onset of dyspnea on exertion, occasionally associated with a mild cough. Their chest roentgenograms, not surprisingly, show the characteristics of alveolar filling disorders, ie, air bronchograms and diffuse homogeneous infiltrates. The disordered physiology is predicted by the altered anatomy: reduced diffusing capacity (Fig 2), arterial hypoxemia made worse with exercise (Fig 3), and, in more than half of the patients, a major restrictive defect (Fig 1).PAP is an excellent clinical example of the frequently cited but uncommon ”alveolar-capillary block syndrome” [ll. When the disease had progressed sufficiently to lower lung volumes in our patients, the D L was already severely reduced. Treatment The treatment of PAP was often unsuccessful in the early years after the disease was identified [121. Some patients had resolution of their disability under various forms of aerosol and expectorant therapy, although we have subsequently come to learn that such resolution can be spontaneous. As many as 30% of patients, however, progressed insidiously to severe dyspnea, hypoxemia, and death [12]. It wasn’t until Ramirez-R began experimenting with various forms of lung lavage that such a course was changed [18]. In 1965, he described the present method of lavaging an entire lung while simultaneously ventilating the contralateral lung with high inspired oxygen concentration [171. We
have gradually modified his approach, as described here, and we are now able to obtain dramatic improvement in the symptomatology and altered physiology in all patients with this disease. Controversy continues, however, over the clinical indications for whole-lung lavage [13]. Each center has also made changes in the technique [5, 7, 111. As a result, the outcome has been variable [2, 13, 17, 203. Some physicians reserve lavage for those patients who are severely disabled [131. Such thinking may be influenced by prior experiences that produced only fair results. We advocate lavage at a ti.me in the disease when the dyspnea has begun to affect the patient’s occupation or other daily activities; we do not wait until profound hypoxernia is present. This has produced a rapid and favorable response in all patients, allowing them to return to work and other pastimes that had previously been difficult because of dyspnea. We previously described a temporary worsening of hypoxemia during lavage when the lung being lavaged is drained [26]. This is the result of an increase in blood flow through the gasless lung when the alveolar pressure is reduced from a positive hydrostatic pressure during filling to subatmospheric pressure during draining. Since this is an unavoidable phenomenon during lavage, it is unwise to wait until the patient is severely hypoxemic before treating him, as the ~ risk ~ of lung lavage will be greater.
Lung Lavage Despite the fact that the lavage method seems straightforward, the published results vary. Some authors describe only mild improvernent, which is sometimes delayed for several days [2, 13, 17, 201. Lingering infiltrates have also been described, and most reports have documented only minor improvement in lung function. Our uniformly favorable results have therefore prompted us to examine our technique carefully. A successful whole-lung lavage requires a team approach, with several participants paying close attention to various parts of the procedure. We use sterile physiological saline as our lavage fluid. Our previous work indicates that additives such as heparin and acetylcysteine d o not increase the removal of sediment [lo]. We also
459 Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
position the saline reservoir 30 cm above the patient’s midchest to minimize the hypoxemia that occurs as the lavaged lung becomes degassed. Wasserman and colleagues [26], and later Smith and associates [25], showed that this decreases blood flow to the lavaged lung as it becomes gasless during filling. The hydrostatic pressure created by the column of saline suspended 30 cm above the patient generally exceeds mean pulmonary artery pressure and therefore decreases perfusion to the nonventilated lung, preventing severe hypoxemia [19]. For this same reason, we drain and refill the lung as rapidly as possible in order to lessen the period of hypoxemia while the degassed lung is drained of saline (and hydrostatic pressure is decreased). Periodic intraoperative arterial blood gas monitoring should be performed during lung filling to document that the Paoz is not critically low. Kylstra and co-workers [ll]have approached this problem by using “volume-controlled” lavage in which the lung is never completely drained of saline at the end of each run. A volume of saline comparable to the patient’s functional residual capacity is allowed to remain Fig 8 . Effect of repeated lavage for recurring pulmonary alveolar proteinosis in I patient. Decreases in lung volumes (VC, TLC) and diffusing capacity were restored to normal or near-normal with each lavage. There was no residual deterioration in lung function during45 months of follow-up.
‘0°1
in the lung after each filling, and smaller volumes (300-500 ml) are subsequently used to wash out the sediment. This technique is designed to prevent hydrostatic pressure from dropping to low levels in the hope of preventing hypoxemia. This is physiologically sound, but it results in a longer and less efficient lavage. Many authors have described a delay in improvement after lavage, whereas others have noted a temporary worsening of lung function [2, 13, 17, 201. They describe persistent hypoxemia and infiltrates for several days. Saline lavage of the lung is not benign. Huber and associates [9] have described changes in alveolar morphology and respiratory mechanics after lung lavage in dogs. This technique has also been shown to remove large quantities of surface-active material [15] as well as other proteins [22]. Thus it is not surprising that early extubation can result in a temporary worsening of lung function, largely secondary to atelectasis and associated with the loss of surfactant. We have seen a universally prompt and dramatic improvement in lung function and chest roentgenograms (see Fig 4) as each lung is lavaged. We attribute this to our practice of continuing to ventilate the lavaged lung so as to allow restoration of normal surface forces. This is evidenced by the return of thoracic compliance within one hour to the same level as in the contralateral lung (Fig 5). Whole-lung lavage for the treatment of PAP can be considered both curative and palliative.
460 The Annals of Thoracic Surgery Vol 24 No 5 November 1977
Follow-up of our patients has revealed a wide spectrum of results (Fig 7). It is fortunate that whole-lung lavage is effective and has limited morbidity, as it is sometimes necessary to lavage certain patients repeatedly every one to two years. Figure 8 illustrates the course of 1patient who required four lavages because of recurrent symptoms. Note that lung function returned to near-normal levels after each lavage. There have been no sequelae despite recurring PAP or repeated lung lavage in 5 patients whom we have followed. Recurrence of this disorder is not predictable. The clinical presentation, degree of impairment, or efficiency of lavage in these few patients were not different from the rest of the group. The initial return of symptoms occurred within one year in each, with variable progression of the disease thereafter. Some patients have remained asymptomatic for up to five years after one repeat lavage. Our experience therefore indicates that the disease has a variable course and that continued follow-up is necessary. References 1. Austrian R, McClement JH, Renzetti AD, et al: Clinical and physiologic features of some types of pulmonary disease with impairment of alveolar-capillary diffusion: the syndrome of “alveolar-capillary block.” Am J Med 11:667, 1951 2. Castleman B, McNeely BU: Case Records of the Massachusetts General Hospital. Case 34,1974. N Engl J Med 291:464, 1974 3. Cooper JD, Woolf CR, Brebner J: Improved method of pulmonary lavage for alveolar proteinosis. Surg Forum 26:298, 1975 4. Costello JF, Moriarty DC, Branthwaite MA, et al: Diagnosis and management of alveolar proteinosis: the role of electron microscopy. Thorax 30:121, 1975 5. Dupont FS, Sphire RD: Pulmonary lavage. Crit Care Med 2:161, 1974 6. Hamper1 H: Variants of Pneumocystis carinii. J Pathol Bacteriol 74:353, 1957 7. Harris JO, Castle JR, Swenson EW, et al: Lobar lavage: therapeutic benefit in pulmonary alveolar filling disorders. Chest 65:655, 1974 8. Heard BE, Cooke RA: Busulphan lung. Thorax 23:187, 1968 9. Huber GL, Edmunds LHM, Finley TN: Effect of experimental saline lavage on pulmonary mechanics and morphology. Am Rev Respir Dis 104:337, 1971 10. Kao D, Wasserman K, Costley D, et al: Advances
in the treatment of pulmonary alveolar proteinosis. Am Rev Respir Dis 111:361, 1975 11. Kylstra JA, Rausch DC, Hall KD, et al: Volumecontrolled lung lavage in the treatment of asthma, bronchiectasis, and mucoviscidosis. Am Rev Respir Dis 103:651, 1971 12. Larson RK, Gordinier R: Pulmonary alveolar proteinosis. Ann Intern Med 62:292, 1965 13. Lewiston NJ, Robin ED: Pulmonary alveolar proteinosis. West J Med 124:29, 1976 14. Lynch CG, Feraru F: Endobronchial anesthesia. Anesthesiology 18:138, 1957 15. McClenahan JB, Mussenden R: Pulmonary alveolar proteinosis. Arch Intern Med 133:284, 1974 16. Ramirez-R J, Harlan WR: Pulmonary alveolar proteinosis. Am J Med 45:520, 1968 17. Ramirez-R J, Kieffer RF, Ball WC: Bronchopulmonary lavage in man. Ann Intern Med 63:819, 1965 18. Ramirez-R J, Schultz RB, Dutton RE: Pulmonary alveolar proteinosis: a new technique and rationale for treatment. Arch Intern Med 11.2:173, 1963 19. Rogers RM, Szidon JP, Shelburne J, et al: Hemodynamic response of the pulmonary circulation to bronchopulmonary lavage in man. N Engl J Med 286:1230, 1972 20. Rogers RM, Tantum KR: Bronchopulmonary lavage. Med Clin North Am 54:755, 1970 21. Rosen SH, Castleman B, Liebow AA: I’ulmonary alveolar proteinosis. N Engl J Med 258:1123, 1958 22. Rupp GH, Wasserman K, Ogawa M, et al: Bronchopulmonary fluids in pulmonary alveolar proteinosis. J Allergy Clin Immunol !51:227, 1973 23, Sahu S, DiAugustine RP, Lynn WS: Lipids found in pulmonary lavage of patients with alveolar proteinosis and in rabbit lung lamellar organelles. Am Rev Respir Dis 114:177, 1976 24. Seard C, Wasserman K, Benfield JR, et al: Simultaneous bilateral lung lavage (alveolar washing) using partial cardiopulmonary bypass. Am Rev Respir Dis 101:877, 1970 25. Smith JD,Millen JE, Safar P, et al: Intrathoracic pressure, pulmonary vascular pressures and gas exchange during pulmonary lavage. Anest hesiology 33:401, 1970 26. Wasserman K, Blank N, Fletcher G: Lung lavage (alveolar washing) in alveolar proteinosis. Am J Med 44:611, 1968 27. Williams GEG, Medley DRK, Brown R: I’ulmonary alveolar proteinosis. Lancet 1:1385, 1960
Discussion
DR. JOEL COOPER (Toronto, Ont, Canada): Our experi-
ence is more modest than that presented. We recently performed our eighteenth lavage. I wholeheartedly support the conclusions of the authors, and I con-
461 Selecky et al: Whole-Lung Lavage in Pulmonary Alveolar Proteinosis
gratulate them on their present and past contribu- died two weeks later of bone marrow insufficiency and overwhelming sepsis. tions to this field. By way of emphasis, I would like to raise a few DR.J. P. GEIGER (San Francisco, CA): I have used an points. First, a matter of terminology: we like a less adjunctive or ancillary form of treatment, perhaps formal and perhaps more descriptive term to describe even an alternative form, in 4 instances of alveolar the procedure-we refer to it as a lung enema. We proteinosis. This form of therapy consists of inhalaagree that an organized team is very important in tion of alcohol in 25% or 20% solution, administered carrying out these procedures. A casual approach to by nebulization with a routine IPPB machine. I was lung lavage is courting disaster. When possible, we attracted to this approach by an article by J. B. prefer to use the Robertshaw rather than the Carlens McClenathan which stated that this lipid material is tube. It has a larger lumen size and we think it is a bit soluble in vitro in alcohol (Arch Intern Med 133284, safer. One to 2 liters of warm saline, without addi1974). Having treated many patients with pulmonary tives, is used for each cycle. Both lungs are ventilated edema by this method in the past, I thought it might with l0Oo/o oxygen. We then clamp the right lung and also be effective in alveolar proteinosis. The patients produce absorption atelectasis. We then fill the lung, agreed to the clinical trial. by gravity, with saline. A 40-year-old man had previously declined diagFor those who are about to do their first lavage, I nostic biopsy until his resting Po, fell to 33 torr on would warn that on the first cycle, when 1,500 ml of saline is run in and then drained, 400 or 500 ml will be room air. A pitfall in the diagnosis was experienced when our local pathologist found a negative PAS missing. It is left in the residual volume of the lung, and if one is not prepared for it, it can cause a bit of a stain, but the correct diagnosis was later made by Dr. A. Liebow. The initial roentgenogram was not very consternation. It certainly did to me during our first lavage. For a moment, I thought I had discovered the helpful, but his clinical condition and arterial gases were somewhat frightening. Volume and flow studies missing fluids in my pants. A couple of years ago, we started using chest showed an across-the-board drop of about 40%. After three and a half weeks of 25% alcohol inhalaphysiotherapy in the form of manual percussion. One tion with no other therapy, he had a marked degree of of our physiotherapists joined us in the operating improvement. The first sputum specimen he proroom. We have found this very effective and think it has added to the procedure. Chest physiotherapy duced looked like whipped egg white, which assured makes the lavage more rapid, improves the amount of me that there was efficacy in the treatment. The padebris removed, and gives better clearing on the post- tient remained well three years later, and his only operative chest roentgenogram. The amount of debris abnormal pulmonary function is a slight increase in in the effluent was quantitated with an optical den- residual volume. Three other patients have had somewhat less imsitometer in a patient who had chest physiotherapy pressive results, attributable to their lack of cooperaon certain cycles and not on others. It is clear that there tion in continuing the treatment. is less debris with physiotherapy. During each cycle of drainage, do a midstream catch DR.ALFRED JARETZKI (New York, NY): I would like to of the draining fluid, put it in a small bottle, and attest to the importance of chest percussion during the display it. This serves as a guide to tell us when we lavage maneuver. Several years ago we quantitated have done enough; we are able to see the progressive the sediment retrieved, alternating lavage alone and clearing that occurs. We also have an arterial line in lavage with percussion. We were able to retrieve five place, and we measure blood gases frequently. When times as much sediment when percussion was used. the lung is filled with saline, the pressure of the saline Previously some patients with PAP destops the pulmonary blood flow to that lung and the DR. SELECKY: Po, is quite satisfactory. Paradoxically, it is during the veloped progressive hypoxemia and died. Fortudraining phase when the lung is empty, allowing nately, the advent of whole-lung lavage has made it blood to flow to the nonventilated lung, that the Po, possible now to restore near-normal lung function in drops to about 60 mm Hg. At that phase, if the pa- all patients with this disorder. This dramatic response tient is turned with the ventilated lung down, the to treatment does not occur often in other disease Pop will rise sharply due to the gravitational redis- states. The unique success in treating PAP is largely tribution of blood flow. We normally don't use that the result of the pathology of this disease, in which the maneuver, but it is nice to know about just in case. alveoli are filled but the alveolar septae are spared. As Postoperatively, we ventilate for three or four a result, whole-lung lavage is very effective. Thus our hours. We have not done compliance measurements, experience would indicate that PAP is not a fatal disbut I see from the data presented by Dr. Selecky ease if treated properly. that this seems to get us over the dangerous period. The clinical response to alcohol aerosols is interWe have performed one procedure in a patient who esting. Many other forms of therapy have been tried in was on perfusion as well. This girl had leukemia and the past, each with an occasional therapeutic reproteinosis, and she was on a membrane oxygenator. sponse, but none have provided consistent improveWe lavaged the left lung on bypass and subsequently ment. I am not aware, however, of controlled studies lavaged the right lung. She was taken off bypass but performed with alcohol aerosols.
