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Methylprednisolone
Methylprednisolone Pharmacologic doses in shock lung syndrome Patients with shock lung syndrome were identified as those who developed acute respiratory failure after a profound episode of hypotension secondary to hemorrhagic, gram-negative, or endotoxic shock. In this study, each of the 10 patients with shock lung syndrome received methylprednisolone sodium succinate, 30 mg. per kilogram, intravenously every 6 hours for 48 hours. In addition, all patients were supported with mechanical ventilation, with or without positive end-expiratory pressure (PEEP). Arterial oxygenation improved markedly, and pulmonary edema resolved in all patients. Nine were discharged from the hospital and one died subsequently of disseminated intravascular coagulation. This study demonstrated a significant improvement in mortality rate with repeated pharmacologic doses of methylprednisolone compared to previously reported mortality rates of 60 to 90 per cent in patients with shock lung syndrome treated without repeated pharmacologic doses of steroid therapy.
Arnold Sladen, M.D., Pittsburgh,
Pa.
A. he shock lung syndrome consists of a triad: gross intrapulmonary shunting with relative or absolute hypoxemia, a decreased pulmonary compliance, and chest x-ray findings consistent with diffuse bilateral pulmonary edema. The shock lung syndrome develops 18 to 36 hours following a profound hypotensive episode which occurs as the result of hemorrhagic, gram-negative, or endotoxic shock. The pulmonary edema in this syndrome is not a sequel to aspiration of gastric acid, inhalation of toxic gases, fluid overload, or left ventricular failure, nor are the radiographically observed pulmonary infiltrates associated with a diffuse infectious pneumonic process. 1 Mortality rates of 60 to 90 per cent have been reported, 2 ' 3 even with combinations of mechanical ventilation with or without positive end-expiratory pressure (PEEP), antibiotics, diuretics, cardiac glycosides, and a single pharmacologic dose of a corticosteroid. Death has been due to respiratory failure. From the Departments of Anesthesiology, The University of Texas Medical Schools at San Antonio and Houston. A preliminary report of this work was presented at the First World Congress of Intensive Care, London, June 24 to 27, 1974. Received for publication Nov. 17, 1975. Accepted for publication Dec. 18, 1975. Address for reprints: Dr. Arnold Sladen, Surgical Intensive Care Unit, Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, Pa. 15213. 800
This study was designed to demonstrate whether adjunctive therapy with repeated pharmacologic doses of methylprednisolone sodium succinate over a period of 48 hours would increase arterial oxygenation, resolve pulmonary edema, and reduce the mortality rate in patients with shock lung syndrome. Method Ten consecutive adult patients whose history, clinical examination, effective compliance, arterial oxygen tension, and chest x-ray evidence were compatible with a diagnosis of shock lung syndrome were admitted to the intensive care unit. Therapy included mechanical ventilation with or without PEEP and methylprednisolone sodium succinate, 30 mg. per kilogram intravenously every 6 hours, for a period of 48 hours. At the end of 48 hours, steroid therapy was terminated abruptly. Antibiotic therapy was included for patients with infectious processes. All 10 patients required mechanical ventilatory support. Volume-limited ventilators delivered a tidal volume of 10 to 15 ml. per kilogram. PEEP was added when, at an Fi 0 2 of 0.6, the Pao 2 was less than 60 torr. Once PEEP was initiated it was left unchanged during the entire 48 hours of study. Arterial carbon dioxide tensions were returned to normal and metabolic acidosis was corrected before and during the study. An Fi 0 2 of 1.0 was maintained for 20 minutes prior to specific arterial blood sampling. These samples were
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801
Methylprednisolone
Table I. Arterial oxygen tension (Pao2) studies at an Flo2 of 1.0 immediately before the start of methylprednisolone therapy and then 24 and 48 hours after therapy had been initiated Pa0l (ton) Patient No. 1 2 3* 4 5 6 7 8 9 10
Primary diagnosis Multiple trauma Multiple trauma Postoperative sepsis Postoperative sepsis Necrotizing fasciitis Postoperative sepsis Multiple trauma G.S.W. of kidney, duodenum Multiple trauma Postpartum hemorrhage
PEEP (cm. H2O)
Before therapy
After 24 hours
After 48 hours
0 0 0
88 81 208
297 183 400
395 339 427
0
89
265
440
0
104
209
356
12
67
175
245
15 12
118 67
372 157
433 177
15 15
103 51
553 248
552 357
Legend: PEEP, Positive end-expiratory pressure. G.S.W., Gunshot wound. *The patient died of disseminated intravascular coagulation on thefifthday.
Table II. The mean Pa0i's before and after methylprednisolone therapy in 5 patients without and 5 patients with PEEP; also mean Pao2s in the combined 10 patients
Table III. The mean changes in Pa02 after 48 hours of methylprednisolone therapy in 5 patients without PEEP and 5 patients with PEEP; also mean Pa02's in the combined 10 patients
Mean Pa0l (ton) No. of patients
Therapy
5 5 10
No PEEP PEEP Mixed
Before treatment
After 48 hours
114.0
391.4
81.2 97.6
372.1
*:
No. of patients
Therapy
Mean change in Pa0t (ton)
5 5 10
No PEEP PEEP Mixed
277.4 271.6 274.5
*„ T U „ -
p>t*l.lWllbl7 •
collected immediately before methylprednisolone therapy and then after each 24 hours. Additional arterial blood samples were drawn and evaluated at the lower Fioj's used for continuous mechanical ventilation. Arterial samples were collected and measured by standard techniques, and reported oxygen tensions included temperature corrections. In all 10 patients, the inspired oxygen concentration was reduced to 50 per cent or less as arterial oxygenation improved, so that oxygen toxicity would not develop. After appropriate blood, colloid, and fluid for primary resuscitation had been administered, fluid restriction was maintained to a maximum of 35 ml. per kilogram per day.4 Fluid intake, urinary output, and body weight were measured daily. Q S / Q T and pulmonary artery wedge pressures were measured in 2
M. 1 1 V
I11VUI1
V**U4*gV/U
1KX
M. * 4 ( J Q
VW-AVI W
UAIV*
U11V1
methylprednisolone therapy, without and with PEEP, were subjected to Student's t test and the probability was calculated. Results
There was a progressive increase in arterial oxygenation in all patients during the 48 hour period of study (Table I). In 5 patients, PEEP was initiated before steroid therapy was commenced. Table II shows the mean Pao2 in both groups before and after 48 hours of therapy. The mean Pao2's were 114 torr and 391.4 torr before and after methylprednisolone therapy in patients without PEEP and 81.2 torr and 352 torr in patients with PEEP. Table III shows that the mean changes in Pa 02 after 48 hours of therapy were 277.4 torr and 271.6 torr, respectively, in the non-PEEP and PEEP groups; t8 = 0.09 (p 0.01 = 3.355).
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The Journal of Thoracic and Cardiovascular Surgery
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Fig. 1. Case 5. Chest x-ray film prior to therapy showed diffuse bilateral pulmonary edema. Pa02 = 104 torr.
Fig. 3. Case 5. Progressive clearing of pulmonary edema after 48 hours of therapy. PaQ2 = 356 torr. No withdrawal effects were seen following the sudden stoppage after 48 hours of therapy with pharmacologic doses of methylprednisolone. The following 2 cases correlate history, arterial oxygenation, and chest x-ray changes. Case reports
Fig. 2. Case 5. Clearing of pulmonary edema after 24 hours of therapy. Pao2 = 209 torr. There was no significant difference in the mean change in arterial oxygenation after 48 hours of therapy with methylprednisolone in the group treated without PEEP compared to the group treated with PEEP. The improvement in arterial oxygenation was greater than the radiologic improvement. In Case 5 Q S / Q T decreased from 27 per cent before treatment to 14 per cent after treatment, and in Case 7, Q S / Q T decreased from 24 per cent before to 10 per cent after treatment. The pulmonary wedge pressure in these 2 patients did not exceed 10 mm. Hg during the 48 hour period of study.
CASE 5. A 52-year-old woman was admitted with necrotizing fasciitis of the anterior abdominal wall. The blood pressure fell from 130/70 to 70/40 mm. Hg, and she remained hypotensive for 4 hours. Gram-positive and gram-negative organisms were isolated from the blood and infected tissue. Therapy consisted of appropriate fluid replacement, antibiotic drugs to which the organisms were sensitive, and debridement. Forty-eight hours after the hypotensive episode, she developed acute respiratory failure. Mechanical ventilation (without PEEP) was commenced and, in addition, methylprednisolone was given in a dosage of 2 Gm. every 6 hours for 48 hours. Arterial oxygen studies. At an Fi„2 of 1.0, the Pa02 was 104 torr immediately prior to methylprednisolone therapy, 209 torr after 24 hours, and 356 torr after 48 hours. The chest x-ray film prior to therapy (Fig. 1) showed diffuse bilateral edema with progressive clearing during the next 48 hours (Figs. 2 and 3). The patient was subsequently weaned from the ventilator and made an uneventful recovery. CASE 10. A 27-year-old woman was admitted in hemorrhagic shock, 9 hours after the forceps delivery of a term fetus. No blood pressure could be recorded (a Doppler was not used), and the heart rate was 140 beats per minute. During the next 12 hours, she had two operative procedures—ligation of the hypogastric and ovarian vessels
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Methylprednisolone
803
Fig. 4. Case 10. Chest x-ray film prior to therapy showed gross diffuse bilateral pulmonary edema. Pa02 = 51 ton. and then total abdominal hysterectomy and bilateral salpingo-oophorectomy. She received over 30 units of blood and blood products. Postoperatively, the patient developed acute respiratory failure. Treatment consisted of mechanical ventilation with PEEP and methylprednisolone, 2 Gm. every 6 hours. Arterial oxygen studies. At an Fi02 of 1.0, mechanical ventilation with an Engstrom ventilator without PEEP resulted in a Pa02 of 38 torr; with a PEEP of 15 cm. H 2 0, the Pao2 increased to 51 torr. The chest x-rayfilmprior to therapy (Fig. 4) showed gross bilateral pulmonary edema, with some clearing during the next 48 hours (Figs. 5 and 6). The patient was subsequently weaned from the ventilator and made a successful recovery.
Fig. 5. Case 10. Clearing of pulmonary edema after 24 hours of therapy. Pao2 = 248 torr.
Discussion This study demonstrated that, in the 10 patients with shock lung syndrome treated with methylprednisolone sodium succinate 30 mg. per kilogram every 6 hours for 48 hours, there was a progressive increase in oxygenation and a resolution of the pulmonary edema. No patient died during the 48 hours of therapy. One death from disseminated intravascular coagulopathy occurred 3 days after steroid therapy was discontinued. The other 9 patients were subsequently discharged from the intensive care unit after the initiating factors causing the shock lung syndrome had been appropriately treated. There was no significant difference in the mean change in arterial oxygenation after 48 hours of methylprednisolone therapy between the group treated without PEEP and the group treated with PEEP.
Fig. 6. Case 10. Progressive clearing of pulmonary edema after 48 hours of therapy. Pao2 = 357 torr.
804
Sladen
This fact clearly demonstrated that the addition of PEEP was not the etiologic factor in the improvement of oxygenation 48 hours after the start of therapy. The shock lung syndrome must be differentiated from adult respiratory distress syndrome (ARDS). ARDS 5-7 consists of a heterogeneous group of clinical entities resulting in acute respiratory insufficiency. This group includes thermal pulmonary injuries, aspiration of noxious gases, gastric fluid, fresh and salt water drowning, pulmonary fat emboli, acute pancreatitis, oxygen toxicity, fluid overload, and viral lung infections. The diseases classified under the term ARDS present with intrapulmonary shunting, decreased pulmonary compliance, and a chest radiogram consistent with pulmonary edema—hence the similarity between ARDS and shock lung syndrome. However, shock lung syndrome, as defined here, is preceded by hemorrhagic or gram-negative shock, whereas ARDS is not. In addition, therapy directed to shock lung syndrome may not prove beneficial in all the clinical entities included in the all-encompassing ARDS. During World War II, surgeons became aware of acute respiratory failure in casualties without direct chest trauma and coined the term "wet lung," which remained in vogue for some time. Respiratory failure following severe nonthoracic battle injuries was seen again in the Korean and Vietnamese conflicts. In civilian practice, identical physiological and anatomic derangements have been observed in patients after severe hemorrhage and resuscitation and after gramnegative or endotoxic shock. Dissatisfied with the term "wet lung," various other authors have subsequently used such terms as "shock lung," "noninfective congestive atelectasis," "the adult equivalent of the respiratory syndrome of the newborn," "the pulmonary equivalent of acute tubular necrosis," "progressive pulmonary consolidation," and "post-traumatic lung." The variations in terminology have added to the confusion and to the lack of understanding of the causes for acute respiratory failure in this group of patients. The increased incidence of this syndrome results not from poor management, but rather from the present capability of salvaging severely traumatized patients in hemorrhagic shock or patients in endotoxic shock who, a decade ago, would have died within a short time following "shock." Modern methods of resuscitation allow the acute episode to be managed, but death often follows 24 to 48 hours later. Brewer,8 in 1946, reviewed surgical casualties in the North African campaign. He coined the term "wet
The Journal of Thoracic and Cardiovascular Surgery
lung" and stated that he had found no prior reference in the literature. Brewer noted that casualties with dry lungs did not constitute a problem but that those with wet lungs were difficult to resuscitate, were poor risks for emergency operations, and frequently developed progressive respiratory complications. The clinical picture of a wet lung was observed in casualties with combinations of mild or severe injury and considerable blood loss. Symptoms and signs were a wet cough which persisted even though sputum was continuously raised, dyspnea, and high-pitched wheezes and diffuse rales which could be ausculated over both lung fields. Chest radiographic findings varied from minimal atelectasis to gross pulmonary edema. Mallory's9 manuscript published in 1950 and his10 subsequent Surgery in World War II: Physiologic Effects of Wounds, in 1952, commented on the organ changes which could be considered sequel to the shock in patients who died some time after the shock. Casualties who died within 12 hours had normal lung tissue, whereas those who were resuscitated and died 18 to 36 hours after the initial shock episode had gross pathological changes in the lung. The autopsies of casualties who had died 18 to 36 hours after shock showed evidence of pulmonary congestion in 100 per cent, edema in 85 per cent, atelectasis in 70 per cent, and intra-alveolar hemorrhage in 55 per cent. Pulmonary edema was more common in those who had been resuscitated and subsequently died than in those who had died shortly after the shock episode. During the Vietnamese conflict, Simmons11 and Martin12 reported pulmonary edema in 80 and 89 per cent, respectively, of casualties who had died 48 hours after multisystem (nonthoracic) injuries and shock. In addition, atelectasis and intra-alveolar and interstitial hemorrhage were documented. The lung appears to be a target organ of the shock state. The initial response of the lung to shock is pulmonary arteriolar vasoconstriction.13 This phase is followed by vascular endothelial damage, a change in permeability of the pulmonary microcirculation, and a leakage of proteinaceous fluid into the interstitial space and alveoli. The intra-alveolar edema is facilitated by degeneration of alveolar cells, allowing migration of fluid from the interstitial space into the alveoli. Degeneration of alveolar type II cells results in a reduction of surfactant production14 and the development of atelectasis. These processes may be augmented by the release of serotonin from platelet microemboli degeneration in the lung and by lysosomal enzymes released by fragmenting polymorphonuclear leukocytes.15' 16 Wil-
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son17' 18 has reported on the loss of activity of the pseudopodia of the leukocyte and the subsequent degeneration of the leukocyte in the shock state. After the infusion of methylprednisolone, the fragmentation of the leukocyte ceased,17 lysosomal enzymes were no longer released, and pseudopodial activity returned to normal. Platelet destruction and serotonin release were also reduced. Kusajima19 constructed a transparent window in the thoracic wall of an experimental animal, and, with the aid of microphotography, observed the pulmonary circulation. Marked sludging of the red cells was seen following the development of hemorrhagic shock. After an intravenous infusion of methylprednisolone, there was a marked improvement in pulmonary blood flow. Sladen20 reported the results of methylprednisolone in the treatment of pulmonary edema in subjects almost drowning in fresh water. This pulmonary edema was due to an increase in permeability in the pulmonary vascular bed, secondary to endothelial damage produced by the hypotonic solution. Proteinaceous fluid leaked into the interstitial space and alveoli of the lung. Methylprednisolone therapy for 48 hours reduced the inflammatory process, stabilized the capillary wall, stopped the leak of proteinaceous fluid, and resulted in a decrease in pulmonary edema and a marked improvement in arterial oxygenation. Many of the factors initiating and extending the pulmonary edema in shock lung are known. The sequela to the precipitating factors is an acute inflammatory response, edema, in the target organ, the lung. Methylprednisolone is a potent anti-inflammatory agent and, therefore, should be an effective therapeutic agent in the treatment of shock lung syndrome. Lillehei21 and Motsay22 have advocated the use of methylprednisolone, 30 mg. per kilogram, as a single or once-repeated dose in the management of gramnegative or endotoxic shock. Methylprednisolone has been used in the treatment of shock lung syndrome, but only in a single pharmacologic dose or, at best, one repeated dose after 2 to 4 hours. The experience gained in the study of pulmonary edema in fresh water near drowning promoted the hypothesis that the shock lung syndrome might be reversed if the same therapeutic principles were adopted—repeated doses of methylprednisolone over a 48 hour period. If methylprednisolone is to exert its therapeutic activity to improve pulmonary blood flow, stabilize the endothelial wall of the pulmonary microcirculation, and reduce and stop the leak of proteinaceous fluid, it is essential that adequate tissue levels be maintained long enough to arrest and reverse the pathological progress. These
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tissue levels are probably achieved with the same dosage that Lillehei21 had indicated to be beneficial in the treatment of the pure shock state. Based on these principles of dosage and time, methylprednisolone, 30 mg. per kilogram every 6 hours for 48 hours, proved to be beneficial in improving arterial oxygenation and in resolving the pulmonary edema in patients with shock lung syndrome. Methylprednisolone should not be used alone but rather as an adjunct to other therapeutic modalities. The primary etiologic factor producing the shock lung syndrome must be treated, because the steroid therapy is directed not at the disease but at the lung, the target organ of the disease. REFERENCES 1 Joffe, N.: Roentgenologic Findings in Post-shock and Postoperative Pulmonary Insufficiency, Radiology 94: 369, 1970. 2 Sugerman, H. J., Olofsson, K. B., Pollock, T. W., Agnew, R. F., Rogers, R. M., and Miller, L. D.: Continuous Positive End-Expiratory Pressure Ventilation (PEEP) for the Treatment of Diffuse Interstitial Pulmonary Edema, J. Trauma 12: 263, 1972. 3 Wilson, R. F., Kafi, A., Asuncion, Z., and Walt, A. J.: Clinical Respiratory Failure After Shock or Trauma: Prognosis and Methods of Diagnosis, Arch. Surg. 98: 539, 1969. 4 Sladen, A., Laver, M. B., and Pontoppidan, H.: Pulmonary Complications and Water Retention in Prolonged Mechanical Ventilation, N. Engl. J. Med. 279: 448, 1968. 5 Blaisdell, F. W., and Schlobohm, R. M.: The Respiratory Distress Syndrome: A Review, Surgery 74: 251, 1973. 6 Wardle, E. N.: Post-traumatic Respiratory Insufficiency: What Is "Shock Lung?" J. R. Coll. Physicians Lond. 8: 251, 1974. 7 Joffe, N.: The Adult Respiratory Distress Syndrome, Am. J. Roentgenol. Radium Ther. Nucl. Med. 122: 719, 1974. 8 Brewer, L. A., Ill, Burbank, B., Samson, P. C , et. al.: The "Wet Lung" in War Casualties, Ann. Surg. 123: 343, 1946. 9 Mallory, T. B., Sullivan, E. R., Burnett, C. H., et. al.: Acute Pulmonary Edema in Battle Casualties, J. Trauma 9: 760, 1969. 10 Surgery in World War II: Physiologic Effects of Wounds, Washington, D. C , 1952, Office of the Surgeon General, Department of the Army. 11 Simmons, R. L., Heisterkamp, C. A., Ill, Collins, J. A., et. al.: Acute Pulmonary Edema in Battle Casualties, J. Trauma 9: 760, 1969. 12 Martin, A. M., Simmons, R. L., and Heisterkamp, C. A.: Respiratory Insufficiency in Combat Casualties. I.
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15
16
17
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Pathologic Changes in the Lungs of Patients Dying of Wounds, Ann. Surg. 170: 30, 1969. Veith, F. J., Hagstrom, J. W. C , Panossian, A., et. al.: Pulmonary Microcirculatory Response to Shock, Transfusion, and Pump-Oxygenator Procedures: A Unified Mechanism Underlying Pulmonary Damage, Surgery 64: 95, 1968. Moss, G. S., Newson, B., and Das Gupta, T. K.: The Normal Electron Histochemistry and the Effect of Hemorrhagic Shock on the Pulmonary Surfactant System, Surg. Gynecol. Obstet. 140: 53, 1975. Weissman, G., and Thomas, L.: Studies on Lysosomes. I. The Effects of Endotoxin, Endotoxin Tolerance, and Cortisone on the Release of Acid Hydrolases From a Granular Fraction of Rabbit Liver, J. Exp. Med. 116: 433, 1962. Janoff, A., Weissman, G., Zweifach, B. W., and Thomas, L.: Pathogenesis of Experimental Shock. IV. Studies on Lysosomes in Normal and Tolerant Animals Subjected to Lethal Trauma and Endotoxemia, J. Exp. Med. 116: 451, 1962. Wilson, J. W., Ratliff, N. B., Young, W. G., Hackel, D. B., and Mikat, E.: Changes in the Morphology of Leukocytes Trapped in Pulmonary Circulation During
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19 20 21
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Hemorrhagic Shock, Microcirculatory Approaches to Current Therapeutic Problems. Symposia. Sixth European Conference on Microcirculation, Aalborg, 1970, Basel, 1971, S. Karger, AG, pp. 41-48. Wilson, J. W., Ratliff, N. B., Mikat, E., Hackel, D. B., Young, W. G., and Graham, T. C : Leukocyte Changes in the Pulmonary Circulation: A Mechanism of Acute Pulmonary Injury by Various Stimuli, Chest 59: 36, 1971. Kusajima, K., Wax, S. D., and Webb, W. R.: Effects of Methylprednisolone on Pulmonary Microcirculation, Surg. Gynecol. Obstet. 139: I, 1974. Sladen, A., and Zauder, H. L.: Methylprednisolone Therapy for Pulmonary Edema Following Near Drowning, J. A. M. A. 215: 1793, 1971. Lillehei, R. C , Dietzman, R. H., Motsay, G. J., Beckman, C. B., Rombero, L. H., and Shatney, C. H.: Growth of the Concept of Shock and Review of Present Knowledge, in Steroids and Shock, Baltimore, University Park Press, 1974, pp. 377-409. Motsay, G. J., Alho, A., Jaeger, T., Dietzman, R. H., and Lillehei, R. C : Effects of Corticosteroids on the Circulation in Shock: Experimental and Clinical Results, Fed. Proc. 29: 1861, 1970.
American Board of Thoracic Surgery Examination The 1977 annual certifying examination of the American Board of Thoracic Surgery (written and oral) will be held on March 17 to 19, 1977. Final date for filing application is August 1, 1976. Please address all communications to the American Board of Thoracic Surgery, 14624 East Seven Mile Road, Detroit, Michigan 48205.
Arnold Sladen, M.D., Pittsburgh,
Pa.
A. he shock lung syndrome consists of a triad: gross intrapulmonary shunting with relative or absolute hypoxemia, a decreased pulmonary compliance, and chest x-ray findings consistent with diffuse bilateral pulmonary edema. The shock lung syndrome develops 18 to 36 hours following a profound hypotensive episode which occurs as the result of hemorrhagic, gram-negative, or endotoxic shock. The pulmonary edema in this syndrome is not a sequel to aspiration of gastric acid, inhalation of toxic gases, fluid overload, or left ventricular failure, nor are the radiographically observed pulmonary infiltrates associated with a diffuse infectious pneumonic process. 1 Mortality rates of 60 to 90 per cent have been reported, 2 ' 3 even with combinations of mechanical ventilation with or without positive end-expiratory pressure (PEEP), antibiotics, diuretics, cardiac glycosides, and a single pharmacologic dose of a corticosteroid. Death has been due to respiratory failure. From the Departments of Anesthesiology, The University of Texas Medical Schools at San Antonio and Houston. A preliminary report of this work was presented at the First World Congress of Intensive Care, London, June 24 to 27, 1974. Received for publication Nov. 17, 1975. Accepted for publication Dec. 18, 1975. Address for reprints: Dr. Arnold Sladen, Surgical Intensive Care Unit, Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, Pa. 15213. 800
This study was designed to demonstrate whether adjunctive therapy with repeated pharmacologic doses of methylprednisolone sodium succinate over a period of 48 hours would increase arterial oxygenation, resolve pulmonary edema, and reduce the mortality rate in patients with shock lung syndrome. Method Ten consecutive adult patients whose history, clinical examination, effective compliance, arterial oxygen tension, and chest x-ray evidence were compatible with a diagnosis of shock lung syndrome were admitted to the intensive care unit. Therapy included mechanical ventilation with or without PEEP and methylprednisolone sodium succinate, 30 mg. per kilogram intravenously every 6 hours, for a period of 48 hours. At the end of 48 hours, steroid therapy was terminated abruptly. Antibiotic therapy was included for patients with infectious processes. All 10 patients required mechanical ventilatory support. Volume-limited ventilators delivered a tidal volume of 10 to 15 ml. per kilogram. PEEP was added when, at an Fi 0 2 of 0.6, the Pao 2 was less than 60 torr. Once PEEP was initiated it was left unchanged during the entire 48 hours of study. Arterial carbon dioxide tensions were returned to normal and metabolic acidosis was corrected before and during the study. An Fi 0 2 of 1.0 was maintained for 20 minutes prior to specific arterial blood sampling. These samples were
Volume 71 Number 5 May, 1976
801
Methylprednisolone
Table I. Arterial oxygen tension (Pao2) studies at an Flo2 of 1.0 immediately before the start of methylprednisolone therapy and then 24 and 48 hours after therapy had been initiated Pa0l (ton) Patient No. 1 2 3* 4 5 6 7 8 9 10
Primary diagnosis Multiple trauma Multiple trauma Postoperative sepsis Postoperative sepsis Necrotizing fasciitis Postoperative sepsis Multiple trauma G.S.W. of kidney, duodenum Multiple trauma Postpartum hemorrhage
PEEP (cm. H2O)
Before therapy
After 24 hours
After 48 hours
0 0 0
88 81 208
297 183 400
395 339 427
0
89
265
440
0
104
209
356
12
67
175
245
15 12
118 67
372 157
433 177
15 15
103 51
553 248
552 357
Legend: PEEP, Positive end-expiratory pressure. G.S.W., Gunshot wound. *The patient died of disseminated intravascular coagulation on thefifthday.
Table II. The mean Pa0i's before and after methylprednisolone therapy in 5 patients without and 5 patients with PEEP; also mean Pao2s in the combined 10 patients
Table III. The mean changes in Pa02 after 48 hours of methylprednisolone therapy in 5 patients without PEEP and 5 patients with PEEP; also mean Pa02's in the combined 10 patients
Mean Pa0l (ton) No. of patients
Therapy
5 5 10
No PEEP PEEP Mixed
Before treatment
After 48 hours
114.0
391.4
81.2 97.6
372.1
*:
No. of patients
Therapy
Mean change in Pa0t (ton)
5 5 10
No PEEP PEEP Mixed
277.4 271.6 274.5
*„ T U „ -
p>t*l.lWllbl7 •
collected immediately before methylprednisolone therapy and then after each 24 hours. Additional arterial blood samples were drawn and evaluated at the lower Fioj's used for continuous mechanical ventilation. Arterial samples were collected and measured by standard techniques, and reported oxygen tensions included temperature corrections. In all 10 patients, the inspired oxygen concentration was reduced to 50 per cent or less as arterial oxygenation improved, so that oxygen toxicity would not develop. After appropriate blood, colloid, and fluid for primary resuscitation had been administered, fluid restriction was maintained to a maximum of 35 ml. per kilogram per day.4 Fluid intake, urinary output, and body weight were measured daily. Q S / Q T and pulmonary artery wedge pressures were measured in 2
M. 1 1 V
I11VUI1
V**U4*gV/U
1KX
M. * 4 ( J Q
VW-AVI W
UAIV*
U11V1
methylprednisolone therapy, without and with PEEP, were subjected to Student's t test and the probability was calculated. Results
There was a progressive increase in arterial oxygenation in all patients during the 48 hour period of study (Table I). In 5 patients, PEEP was initiated before steroid therapy was commenced. Table II shows the mean Pao2 in both groups before and after 48 hours of therapy. The mean Pao2's were 114 torr and 391.4 torr before and after methylprednisolone therapy in patients without PEEP and 81.2 torr and 352 torr in patients with PEEP. Table III shows that the mean changes in Pa 02 after 48 hours of therapy were 277.4 torr and 271.6 torr, respectively, in the non-PEEP and PEEP groups; t8 = 0.09 (p 0.01 = 3.355).
802
The Journal of Thoracic and Cardiovascular Surgery
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Fig. 1. Case 5. Chest x-ray film prior to therapy showed diffuse bilateral pulmonary edema. Pa02 = 104 torr.
Fig. 3. Case 5. Progressive clearing of pulmonary edema after 48 hours of therapy. PaQ2 = 356 torr. No withdrawal effects were seen following the sudden stoppage after 48 hours of therapy with pharmacologic doses of methylprednisolone. The following 2 cases correlate history, arterial oxygenation, and chest x-ray changes. Case reports
Fig. 2. Case 5. Clearing of pulmonary edema after 24 hours of therapy. Pao2 = 209 torr. There was no significant difference in the mean change in arterial oxygenation after 48 hours of therapy with methylprednisolone in the group treated without PEEP compared to the group treated with PEEP. The improvement in arterial oxygenation was greater than the radiologic improvement. In Case 5 Q S / Q T decreased from 27 per cent before treatment to 14 per cent after treatment, and in Case 7, Q S / Q T decreased from 24 per cent before to 10 per cent after treatment. The pulmonary wedge pressure in these 2 patients did not exceed 10 mm. Hg during the 48 hour period of study.
CASE 5. A 52-year-old woman was admitted with necrotizing fasciitis of the anterior abdominal wall. The blood pressure fell from 130/70 to 70/40 mm. Hg, and she remained hypotensive for 4 hours. Gram-positive and gram-negative organisms were isolated from the blood and infected tissue. Therapy consisted of appropriate fluid replacement, antibiotic drugs to which the organisms were sensitive, and debridement. Forty-eight hours after the hypotensive episode, she developed acute respiratory failure. Mechanical ventilation (without PEEP) was commenced and, in addition, methylprednisolone was given in a dosage of 2 Gm. every 6 hours for 48 hours. Arterial oxygen studies. At an Fi„2 of 1.0, the Pa02 was 104 torr immediately prior to methylprednisolone therapy, 209 torr after 24 hours, and 356 torr after 48 hours. The chest x-ray film prior to therapy (Fig. 1) showed diffuse bilateral edema with progressive clearing during the next 48 hours (Figs. 2 and 3). The patient was subsequently weaned from the ventilator and made an uneventful recovery. CASE 10. A 27-year-old woman was admitted in hemorrhagic shock, 9 hours after the forceps delivery of a term fetus. No blood pressure could be recorded (a Doppler was not used), and the heart rate was 140 beats per minute. During the next 12 hours, she had two operative procedures—ligation of the hypogastric and ovarian vessels
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803
Fig. 4. Case 10. Chest x-ray film prior to therapy showed gross diffuse bilateral pulmonary edema. Pa02 = 51 ton. and then total abdominal hysterectomy and bilateral salpingo-oophorectomy. She received over 30 units of blood and blood products. Postoperatively, the patient developed acute respiratory failure. Treatment consisted of mechanical ventilation with PEEP and methylprednisolone, 2 Gm. every 6 hours. Arterial oxygen studies. At an Fi02 of 1.0, mechanical ventilation with an Engstrom ventilator without PEEP resulted in a Pa02 of 38 torr; with a PEEP of 15 cm. H 2 0, the Pao2 increased to 51 torr. The chest x-rayfilmprior to therapy (Fig. 4) showed gross bilateral pulmonary edema, with some clearing during the next 48 hours (Figs. 5 and 6). The patient was subsequently weaned from the ventilator and made a successful recovery.
Fig. 5. Case 10. Clearing of pulmonary edema after 24 hours of therapy. Pao2 = 248 torr.
Discussion This study demonstrated that, in the 10 patients with shock lung syndrome treated with methylprednisolone sodium succinate 30 mg. per kilogram every 6 hours for 48 hours, there was a progressive increase in oxygenation and a resolution of the pulmonary edema. No patient died during the 48 hours of therapy. One death from disseminated intravascular coagulopathy occurred 3 days after steroid therapy was discontinued. The other 9 patients were subsequently discharged from the intensive care unit after the initiating factors causing the shock lung syndrome had been appropriately treated. There was no significant difference in the mean change in arterial oxygenation after 48 hours of methylprednisolone therapy between the group treated without PEEP and the group treated with PEEP.
Fig. 6. Case 10. Progressive clearing of pulmonary edema after 48 hours of therapy. Pao2 = 357 torr.
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This fact clearly demonstrated that the addition of PEEP was not the etiologic factor in the improvement of oxygenation 48 hours after the start of therapy. The shock lung syndrome must be differentiated from adult respiratory distress syndrome (ARDS). ARDS 5-7 consists of a heterogeneous group of clinical entities resulting in acute respiratory insufficiency. This group includes thermal pulmonary injuries, aspiration of noxious gases, gastric fluid, fresh and salt water drowning, pulmonary fat emboli, acute pancreatitis, oxygen toxicity, fluid overload, and viral lung infections. The diseases classified under the term ARDS present with intrapulmonary shunting, decreased pulmonary compliance, and a chest radiogram consistent with pulmonary edema—hence the similarity between ARDS and shock lung syndrome. However, shock lung syndrome, as defined here, is preceded by hemorrhagic or gram-negative shock, whereas ARDS is not. In addition, therapy directed to shock lung syndrome may not prove beneficial in all the clinical entities included in the all-encompassing ARDS. During World War II, surgeons became aware of acute respiratory failure in casualties without direct chest trauma and coined the term "wet lung," which remained in vogue for some time. Respiratory failure following severe nonthoracic battle injuries was seen again in the Korean and Vietnamese conflicts. In civilian practice, identical physiological and anatomic derangements have been observed in patients after severe hemorrhage and resuscitation and after gramnegative or endotoxic shock. Dissatisfied with the term "wet lung," various other authors have subsequently used such terms as "shock lung," "noninfective congestive atelectasis," "the adult equivalent of the respiratory syndrome of the newborn," "the pulmonary equivalent of acute tubular necrosis," "progressive pulmonary consolidation," and "post-traumatic lung." The variations in terminology have added to the confusion and to the lack of understanding of the causes for acute respiratory failure in this group of patients. The increased incidence of this syndrome results not from poor management, but rather from the present capability of salvaging severely traumatized patients in hemorrhagic shock or patients in endotoxic shock who, a decade ago, would have died within a short time following "shock." Modern methods of resuscitation allow the acute episode to be managed, but death often follows 24 to 48 hours later. Brewer,8 in 1946, reviewed surgical casualties in the North African campaign. He coined the term "wet
The Journal of Thoracic and Cardiovascular Surgery
lung" and stated that he had found no prior reference in the literature. Brewer noted that casualties with dry lungs did not constitute a problem but that those with wet lungs were difficult to resuscitate, were poor risks for emergency operations, and frequently developed progressive respiratory complications. The clinical picture of a wet lung was observed in casualties with combinations of mild or severe injury and considerable blood loss. Symptoms and signs were a wet cough which persisted even though sputum was continuously raised, dyspnea, and high-pitched wheezes and diffuse rales which could be ausculated over both lung fields. Chest radiographic findings varied from minimal atelectasis to gross pulmonary edema. Mallory's9 manuscript published in 1950 and his10 subsequent Surgery in World War II: Physiologic Effects of Wounds, in 1952, commented on the organ changes which could be considered sequel to the shock in patients who died some time after the shock. Casualties who died within 12 hours had normal lung tissue, whereas those who were resuscitated and died 18 to 36 hours after the initial shock episode had gross pathological changes in the lung. The autopsies of casualties who had died 18 to 36 hours after shock showed evidence of pulmonary congestion in 100 per cent, edema in 85 per cent, atelectasis in 70 per cent, and intra-alveolar hemorrhage in 55 per cent. Pulmonary edema was more common in those who had been resuscitated and subsequently died than in those who had died shortly after the shock episode. During the Vietnamese conflict, Simmons11 and Martin12 reported pulmonary edema in 80 and 89 per cent, respectively, of casualties who had died 48 hours after multisystem (nonthoracic) injuries and shock. In addition, atelectasis and intra-alveolar and interstitial hemorrhage were documented. The lung appears to be a target organ of the shock state. The initial response of the lung to shock is pulmonary arteriolar vasoconstriction.13 This phase is followed by vascular endothelial damage, a change in permeability of the pulmonary microcirculation, and a leakage of proteinaceous fluid into the interstitial space and alveoli. The intra-alveolar edema is facilitated by degeneration of alveolar cells, allowing migration of fluid from the interstitial space into the alveoli. Degeneration of alveolar type II cells results in a reduction of surfactant production14 and the development of atelectasis. These processes may be augmented by the release of serotonin from platelet microemboli degeneration in the lung and by lysosomal enzymes released by fragmenting polymorphonuclear leukocytes.15' 16 Wil-
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son17' 18 has reported on the loss of activity of the pseudopodia of the leukocyte and the subsequent degeneration of the leukocyte in the shock state. After the infusion of methylprednisolone, the fragmentation of the leukocyte ceased,17 lysosomal enzymes were no longer released, and pseudopodial activity returned to normal. Platelet destruction and serotonin release were also reduced. Kusajima19 constructed a transparent window in the thoracic wall of an experimental animal, and, with the aid of microphotography, observed the pulmonary circulation. Marked sludging of the red cells was seen following the development of hemorrhagic shock. After an intravenous infusion of methylprednisolone, there was a marked improvement in pulmonary blood flow. Sladen20 reported the results of methylprednisolone in the treatment of pulmonary edema in subjects almost drowning in fresh water. This pulmonary edema was due to an increase in permeability in the pulmonary vascular bed, secondary to endothelial damage produced by the hypotonic solution. Proteinaceous fluid leaked into the interstitial space and alveoli of the lung. Methylprednisolone therapy for 48 hours reduced the inflammatory process, stabilized the capillary wall, stopped the leak of proteinaceous fluid, and resulted in a decrease in pulmonary edema and a marked improvement in arterial oxygenation. Many of the factors initiating and extending the pulmonary edema in shock lung are known. The sequela to the precipitating factors is an acute inflammatory response, edema, in the target organ, the lung. Methylprednisolone is a potent anti-inflammatory agent and, therefore, should be an effective therapeutic agent in the treatment of shock lung syndrome. Lillehei21 and Motsay22 have advocated the use of methylprednisolone, 30 mg. per kilogram, as a single or once-repeated dose in the management of gramnegative or endotoxic shock. Methylprednisolone has been used in the treatment of shock lung syndrome, but only in a single pharmacologic dose or, at best, one repeated dose after 2 to 4 hours. The experience gained in the study of pulmonary edema in fresh water near drowning promoted the hypothesis that the shock lung syndrome might be reversed if the same therapeutic principles were adopted—repeated doses of methylprednisolone over a 48 hour period. If methylprednisolone is to exert its therapeutic activity to improve pulmonary blood flow, stabilize the endothelial wall of the pulmonary microcirculation, and reduce and stop the leak of proteinaceous fluid, it is essential that adequate tissue levels be maintained long enough to arrest and reverse the pathological progress. These
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tissue levels are probably achieved with the same dosage that Lillehei21 had indicated to be beneficial in the treatment of the pure shock state. Based on these principles of dosage and time, methylprednisolone, 30 mg. per kilogram every 6 hours for 48 hours, proved to be beneficial in improving arterial oxygenation and in resolving the pulmonary edema in patients with shock lung syndrome. Methylprednisolone should not be used alone but rather as an adjunct to other therapeutic modalities. The primary etiologic factor producing the shock lung syndrome must be treated, because the steroid therapy is directed not at the disease but at the lung, the target organ of the disease. REFERENCES 1 Joffe, N.: Roentgenologic Findings in Post-shock and Postoperative Pulmonary Insufficiency, Radiology 94: 369, 1970. 2 Sugerman, H. J., Olofsson, K. B., Pollock, T. W., Agnew, R. F., Rogers, R. M., and Miller, L. D.: Continuous Positive End-Expiratory Pressure Ventilation (PEEP) for the Treatment of Diffuse Interstitial Pulmonary Edema, J. Trauma 12: 263, 1972. 3 Wilson, R. F., Kafi, A., Asuncion, Z., and Walt, A. J.: Clinical Respiratory Failure After Shock or Trauma: Prognosis and Methods of Diagnosis, Arch. Surg. 98: 539, 1969. 4 Sladen, A., Laver, M. B., and Pontoppidan, H.: Pulmonary Complications and Water Retention in Prolonged Mechanical Ventilation, N. Engl. J. Med. 279: 448, 1968. 5 Blaisdell, F. W., and Schlobohm, R. M.: The Respiratory Distress Syndrome: A Review, Surgery 74: 251, 1973. 6 Wardle, E. N.: Post-traumatic Respiratory Insufficiency: What Is "Shock Lung?" J. R. Coll. Physicians Lond. 8: 251, 1974. 7 Joffe, N.: The Adult Respiratory Distress Syndrome, Am. J. Roentgenol. Radium Ther. Nucl. Med. 122: 719, 1974. 8 Brewer, L. A., Ill, Burbank, B., Samson, P. C , et. al.: The "Wet Lung" in War Casualties, Ann. Surg. 123: 343, 1946. 9 Mallory, T. B., Sullivan, E. R., Burnett, C. H., et. al.: Acute Pulmonary Edema in Battle Casualties, J. Trauma 9: 760, 1969. 10 Surgery in World War II: Physiologic Effects of Wounds, Washington, D. C , 1952, Office of the Surgeon General, Department of the Army. 11 Simmons, R. L., Heisterkamp, C. A., Ill, Collins, J. A., et. al.: Acute Pulmonary Edema in Battle Casualties, J. Trauma 9: 760, 1969. 12 Martin, A. M., Simmons, R. L., and Heisterkamp, C. A.: Respiratory Insufficiency in Combat Casualties. I.
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Pathologic Changes in the Lungs of Patients Dying of Wounds, Ann. Surg. 170: 30, 1969. Veith, F. J., Hagstrom, J. W. C , Panossian, A., et. al.: Pulmonary Microcirculatory Response to Shock, Transfusion, and Pump-Oxygenator Procedures: A Unified Mechanism Underlying Pulmonary Damage, Surgery 64: 95, 1968. Moss, G. S., Newson, B., and Das Gupta, T. K.: The Normal Electron Histochemistry and the Effect of Hemorrhagic Shock on the Pulmonary Surfactant System, Surg. Gynecol. Obstet. 140: 53, 1975. Weissman, G., and Thomas, L.: Studies on Lysosomes. I. The Effects of Endotoxin, Endotoxin Tolerance, and Cortisone on the Release of Acid Hydrolases From a Granular Fraction of Rabbit Liver, J. Exp. Med. 116: 433, 1962. Janoff, A., Weissman, G., Zweifach, B. W., and Thomas, L.: Pathogenesis of Experimental Shock. IV. Studies on Lysosomes in Normal and Tolerant Animals Subjected to Lethal Trauma and Endotoxemia, J. Exp. Med. 116: 451, 1962. Wilson, J. W., Ratliff, N. B., Young, W. G., Hackel, D. B., and Mikat, E.: Changes in the Morphology of Leukocytes Trapped in Pulmonary Circulation During
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Hemorrhagic Shock, Microcirculatory Approaches to Current Therapeutic Problems. Symposia. Sixth European Conference on Microcirculation, Aalborg, 1970, Basel, 1971, S. Karger, AG, pp. 41-48. Wilson, J. W., Ratliff, N. B., Mikat, E., Hackel, D. B., Young, W. G., and Graham, T. C : Leukocyte Changes in the Pulmonary Circulation: A Mechanism of Acute Pulmonary Injury by Various Stimuli, Chest 59: 36, 1971. Kusajima, K., Wax, S. D., and Webb, W. R.: Effects of Methylprednisolone on Pulmonary Microcirculation, Surg. Gynecol. Obstet. 139: I, 1974. Sladen, A., and Zauder, H. L.: Methylprednisolone Therapy for Pulmonary Edema Following Near Drowning, J. A. M. A. 215: 1793, 1971. Lillehei, R. C , Dietzman, R. H., Motsay, G. J., Beckman, C. B., Rombero, L. H., and Shatney, C. H.: Growth of the Concept of Shock and Review of Present Knowledge, in Steroids and Shock, Baltimore, University Park Press, 1974, pp. 377-409. Motsay, G. J., Alho, A., Jaeger, T., Dietzman, R. H., and Lillehei, R. C : Effects of Corticosteroids on the Circulation in Shock: Experimental and Clinical Results, Fed. Proc. 29: 1861, 1970.
American Board of Thoracic Surgery Examination The 1977 annual certifying examination of the American Board of Thoracic Surgery (written and oral) will be held on March 17 to 19, 1977. Final date for filing application is August 1, 1976. Please address all communications to the American Board of Thoracic Surgery, 14624 East Seven Mile Road, Detroit, Michigan 48205.