Corticosteroids and Prevention of Pulmonary Damage Following Cardiopulmonary Bypass in Puppies

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1 Corticosteroids and Prevention of Pulmonary Damage Following Cardiopulmonary Bypass in Puppies David G. Hill, M.D., Mary Jane Aguilar, Jon C. Kosek, M.D., and J. Donald Hill, M.D., M.D. ABSTRACT A technique of inducing hypothermia using surface cooling and rewarming with a pump oxygenator has been applied clinically in infants with satisfactory results. Respiratory problems postoperatively, however, are reported to be among the complications contributing most to mortality and morbidity. Prednisolone sodium succinate (Solumedrol) has helped to obviate pulmonary damage in hemorrhagic and endotoxic shock and therefore may be effective in preventing pulmonary damage following hypothermia. This hypothesis was investigated in 12 mongrel puppies, 6 that had hypothermic cardiopulmonary bypass and circulatory arrest but were not given Solumedrol, and 6 that were treated preoperatively with Solumedrol. In lung biopsies taken immediately after bypass the pathological changes in both the group treated with steroids and the control group were similar. At six hours, however, lung biopsies from the control group showed further signs of progressive damage, while in the steroid-treated group there was a striking improvement with some lung biopsies showing a normal appearance. Thus, Solumedrol did not prevent initial lung damage, but the progressive and probably permanent changes were reduced. The bloodless field and quiet heart achieved when hypothermia and circulatory arrest are used in cardiovascular surgery make these attractive methods for open-heart procedures in infants. A technique of inducing hypothermia by surface cooling and rewarming using a pump From the Heart Research Institute, Institutes of Medical Sciences, the Department of Pathology, and Presbyterian Hospital, Pacific Medical Center, San Francisco, and Stanford University Medical Center, Palo Alto, CA. Aided in part by National Institutes of Health General Research Grant no RR , the Upjohn Pharmaceutical Co, and Pioneer Filter Corp. Accepted for publication Nov 6, Address reprint requests to Dr. Aguilar, Department of Pathology, Pacific Medical Center, PO Box 7999, San Francisco, CA oxygenator has been applied clinically in infants with satisfactory results [l, 2, 4, 11, 123. Respiratory problems occur postoperatively, however, and are reported to be among the complications contributing most to mortality and morbidity [lll. Lung damage has been shown to follow the use of hypothermia in animals [3, 51. The pathological changes encountered resemble those produced by hemorrhagic and endotoxic shock [31. Prednisolone sodium succinate (Solumedrol), given in pharmacological doses, has been shown to be effective in preventing pulmonary damage in hemorrhagic and endotoxic shock and therefore may help to avoid pulmonary damage following hypothermia [14]. This hypothesis was investigated in two groups of mongrel puppies. Materials and Methods Twelve puppies weighing between 4 and 6 kg were anesthetized with sodium pentobarbital, intubated, and ventilated with a volume respirator using room air. The femoral artery and vein were cannulated. Six puppies chosen at random were given Solumedrol, 30 mg per kilogram of body weight, intravenously before operation. Surface cooling using ice packs was begun. Temperature was measured by a probe placed in the esophagus, and blood samples were taken at every 3 C temperature drop for blood gas and ph studies. At 30 C the chest was opened and the right atrium and aorta were cannulated for bypass. A left atrial vent cannula was inserted. A Bentley infant oxygenator primed with 300 ml of blood and 200 ml of lactated Ringer s solution was used for core-cooling the puppies down to 20 C. A Swank blood filter was placed in the arterial line. The oxygenator was ventilated with oxygen at 2.3 liters per minute. Pco2 was kept above 30 mm Hg. 36

2 37 Hill et al: Corticosteroids following Bypass in Puppies At 20 C the puppies underwent 30 minutes of circulatory arrest. The lungs were inflated and the respirator was shut off. The puppies were then rewarmed by pump to 35 C and decannulated. The perfusion time was kept constant at 50 minutes. At the end of bypass a biopsy was taken from the right lung for light and electron microscopy. After the chest was closed the puppies were maintained on a heating blanket until they could be taken off the ventilator. All survived operation. After six hours the chest was reopened and a second lung biopsy was taken from the right lung. The puppies were then killed. The following physiological studies were made in all puppies before bypass and again at six hours after bypass: cardiac output by contrast medium dilution, left atrial and pulmonary artery pressures, maximum inspiratory pressure (in cm H,O), and tidal volume. From these measurements pulmonary vascular resistance and lung compliance were derived. Results Lung Pathology Pathological evidence of lung damage was seen in all puppies and involved vessels, interstitial tissues, and alveoli. The pathological changes were graded according to the following findings: 1. Vascular a. Endothelial swelling and leukocyte margination b. Fibrin-platelet aggregates 2. Interstitial a. Interstitial hemorrhage b. Sequestration of leukocytes 3. Alveolar a. Intraalveolar hemorrhage b. Proteinaceous exudation and edema Lung biopsies taken immediately after bypass were similar in both groups (Table). Early evidence of damage included endothelial swelling, leukocyte margination, interstitial hemorrhage, sequestration of leukocytes, and alveolar hemorrhage (Figs 1, 2). Lung biopsies taken six hours after bypass showed a consistent difference between the two groups (see the Table). In the control group, early damage had progressed. The notable findings were fibrin-platelet aggregation, further sequestration of leukocytes, proteinaceous exudation, and aggravation of intraalveolar and interstitial hemorrhage (Figs 3, 4A). In the puppies treated with steroids the initial endothelial swelling was less severe, and leukocyte margination and extravasation were substantially less after six hours. Alveolar hemorrhage, edema, and proteinaceous exudation, as seen by light microscopy, were also less frequent (Fig 4B). Pulmonary Function Pulmonary function in both groups had deteriorated six hours after bypass. Pulmonary vascular resistance in the control group increased from a mean of 4.79 before bypass to 9.88 six hours after bypass, while in the group treated with steroids the increase was from a mean of PathologicaI Findings in the Lungs of 12 Puppies Immediately after Bypass and Six Hours Later Immediately after Bypass SIX Hours after Bypass Without Steroids- Steroids- Without Steroids- Steroids- Puppy No.: Puppy No: Puppy No.. Puppy No., Finding 1 3 s 9 in 2.I s 9 i n 2 J 7 R 1112 Endothelial o o n n n n n o n swelling Fibrin-platelet ( U U U aggregates Interstitial n o + n hemorrhage Leukocyte o n n n n n seques tra tion Alveolar n n o n o o hemorrhage Proteinaceous n u exudate

3 38 The Annals of Thoracic Surgery Vol 22 No 1 July 1976 Fig 1. Electron micrograph of alveolar septum immediately following bypass, showing adherence of polymorphonuclear leukocyte to endothelial cell of distended capillary. (Original magnification X.5000.) 4.29 to The numbers were too small to be of statistical significance. The mean compliance decreased in control animals from before bypass to 8.35 six hours after bypass; in the steroid group the decrease was from to Comment The pulmonary damage that has been shown to follow hypothermic cardiopulmonary bypass in animals includes edema, peribronchial hemorrhage, and atelectasis [5]. Miller and Kuenzig [3], using hypothermic perfusion at 10 C for one hour in dogs, found that these changes chiefly affect the dependent portions of the lungs. In this study, lung damage occurred in all puppies following standard hypothermic cardiopulmonary bypass and circulatory arrest. Pulmonary function tests showed consistent deterioration six hours after bypass. Pathological Fig 2. lntraalveolar and interstitial hemorrhage and leukocytesequestration in lung biopsy taken immediately after bypass. The two groups of puppies showed strikingly similar changes (see the Table). (Hb E; original magnification X120.) findings from lung biopsies taken immediately and six hours after bypass involved blood vessels, interstitial tissues, and alveoli. The pulmonary vessels showed endothelial swelling and margination of leukocytes at an early stage. On electron microscopy leukocytes were seen as a ring clinging to the swollen vessel wall (see Fig 1); later, with more severe damage, fibrinplatelet aggregates were found occluding small blood vessels. Edema and peribronchial hemorrhage were the early signs of interstitial damage. More severe destruction was evidenced by infiltration of leukocytes. Alveolar hemorrhage, which was found in many lung biopsies taken at the end of bypass, had little influence on the outcome after six hours. In the more severely damaged lungs, hemorrhage, edema, and proteinaceous exudates were seen in the alveoli after six hours. The mechanism of these changes has not been

4 39 Hill et al: Corticosteroids following Bypass in Puppies A Fig3. Electron micrograph ofalveolar septum six hours after bypass, w i t h extrauasated red blood cells andpolyrnorphonuclear leukocytes in contact with collagen fibrils. (Original magnification X3000.) clearly elucidated [lo, 121. The passage and subsequent breakdown of leukocytes in interstitial tissues is of major importance, as these cells contain hydrolytic and proteolytic enzymes capable of destroying lung tissue if released. It has been suggested that platelet aggregation and the release of serotonin may be the initial events in vessel wall damage. In this study, however, fibrin-platelet aggregates were seen only in the biopsies taken six hours after bypass. Solumedrol was given preoperatively at random to half the puppies in this study. In lung biopsies taken immediately after bypass the pathological changes in both the steroid-treated Fig4. Lung biopsiessix hours after bypass, showing ( A )progression of pulmonary damage in untreated puppies in contrast to (B)markedimprovement in the treated puppies. ( H & E ; original magnification X120.) B

5 40 The Annals of Thoracic Surgery Vol 22 No 1 July 1976 group and the control group were similar. At six hours, however, lung biopsies from the control group showed further signs of progressive damage, while in the steroid group there was improvement, with some lung biopsies having a normal appearance. Solumedrol, then, did not prevent initial lung damage, but the progressive and probably permanent changes were reduced. The mechanism of action of Solumedrol is unclear [81. Its principal action appears to be on leukocytes. Wilson [14] has shown that when Solumedrol is given prophylactically in various forms of shock, the leukocytes sequestered in the lungs, although altered internally, retain their ability to produce pseudopods and to migrate. Alteration of platelets or direct action on the vessel wall have been suggested as other possible mechanisms of steroid influence, but in this study initial vessel wall damage was similar in both the treated and untreated groups, and platelet thrombi were seen only at a late stage. A direct inference cannot be made between these experimental findings and those that occur in clinical practice. However, respiratory problems are prevalent after hypothermic cardiopulmonary bypass and circulatory arrest in infants, and it has been shown that the lungs of different animals respond in a similar and limited way to insult [7, 131. Solumedrol therefore may be useful in preventing pulmonary damage following this type of operation in infants. References Barratt-Boyes BG, Simpson M, Neutze JM: Intracardiac surgery in neonates and infants using deep hypothermia with surface cooling and limited cardiopulmonary bypass. Circulation 43,44:Suppl:25, 1971 Hikasa Y, Shirotani H, Satomura K, et al: Open heart surgery in infants with an aid of hypothermic anesthesia (11). Arch Jap Chirurg 37:399, Miller DR, Kuenzig MC: Pulmonary changes following normothermic and profound hypothermic perfusion in dogs. J Thorac Cardiovasc Surg 56:717, Mori A, Muraoka R, Yokota Y, et al: Deep hypothermia combined with cardiopulmonary bypass for cardiac surgery in neonates and infants. J Thorac Cardiovasc Surg 64:422, Neville WE, Kameya S, Oz M, et al: Profound hypothermia and complete circulation interruption. Arch Surg 82:128, Pacific0 AD, Bargeron LM Jr, Kirklin JW: Primary total correction of tetralogy of Fallot in children less than four years of age. Circulation 48:1085, Ratliff NB, Wilson JW, Hackel DB, et al: The lung in hemorrhagic shock: II. Observations on alveolar and vascular ultrastructure. Am J Pathol 58:353, Replogle RL, Gazzaniga AB, Gross RE: Use of corticosteroids during cardiopulmonary bypass: possible lysosome stabilization. Circulation 33:Suppl 136, Shoemaker WC: Pattern of pulmonary hemodynamic and functional changes in shock. Crit Care Med 2:200, Subramanian S: Complications after deep hypothermia procedure in infancy, Open Heart Surgery in Infancy: Proceedings of the International Symposium Held in Marseille. Edited by Parenzan L, Carcassonne M. 1972, p Subramanian S, Wagner H: Correction of transposition of the great arteries in infants under surface-induced deep hypothermia. Ann Thorac Surg 16:391, Subramanian S, Wagner H, Wad P, et al: Surface induced deep hypothermia in cardiac surgery. J Pediatr Surg 6:612, Teplitz C: The ultrastructural basis for pulmonary pathophysiology following trauma. Trauma 8:700, Wilson JW: Treatment or prevention of pulmonary cellular damage with pharmacologic doses of corticosteroid. Surg Gynecol Obstet 134:675, Wilson JW: Pulmonary microcirculation: cellular pathophysiology in acute respiratory failure. Crit Care Med 2:186, 1974