Pulmonary Hypertension a.nd Polymorphonuclear Leukocyte Elastase After Esophageal Cancer Operations Nobuhiro Sato, MD, Kouji Murakami, MD, KraoruIshida, MD, Kenichirou Ikeda, MD, and Kazuyoshi Saito, MD First Department of Surgery, Iwate Medical University, School of Medicine, Monoka, Japan
To evaluate the role of polymorphonuclear leukocyte (PMN)elastase in pulmonary impairment occurring after operation for esophageal cancer, 10 patients were randomized preoperatively into two equal groups. One group received a placebo infusion and the other, an infusion of the PMN elastase inhibitor ulinastatin. In the placebo group, the mean plasma PMN elastase level increased from 154 2 23 pg/L preoperatively to 449 2 56 pg/L at 6 hours postoperatively ( p < 0.01), whereas the mean plasma fibronectin concentration decreased from 490 -C 70 pg/mL preoperatively to 265 f 81 pg/mL on postoperative day 2 ( p < 0.01). The mean pulmonary
vascular resistance increased markedly from 151 2 24 dynes * s cm-5 * m-’ preoperatively to 284 -+ 76 dynes s * cm-5 m-’ at 6 hours postoperatively ( p < 0.01). In the group given ulinastatin, 150,000 units every 12 hours from the start of the operation, the mean PMN e1,astase value at 6 hours postoperatively was lower (275 :t 66 pg/L; p < 0.01) and the fibronectin level on postoperative days 1 and 2, higher ( p < 0.05). A lower pulmonary vascular resistance was noted into day 2 (p < 0.05). Our results suggest that PMN elastase may participate in the development of postoperative pulmonary impairment. (Ann Thorac Surg 1991;51:754-8)
P
formed consent was obtained from each patient before the start of our study.
ulmonary dysfunction that accompanies a severe injury has been theorized to be related to increased activation of the circulating blood cells, and the products of these cells, such as protease and free radicals, are thought to be involved in the direct mechanism of a pulmonary injury [l-31. In view of the great stress that occurs to the body during an operation for esophageal cancer, it is possible that interaction between the bioactive substances and postoperative hypoxemia occurs. This may create an environment for the onset of a pulmonary complication. This study was initiated to examine the postoperative changes in polymorphonuclear leukocyte (PMN) elastase and its role in the pulmonary circulation after radical lymph node dissection for thoracic esophageal cancer.
Material and Methods Ten patients, ranging in age from 52 to 68 years (mean age, 61 years), who had a thoracic esophageal cancer were treated by surgical intervention without prior immunochemotherapy or irradiation. Before operation, the following variables were assessed in each patient: lung volume, pulmonary mechanics, liver function, and nutritional state. All patients were confirmed to be free from any previous pulmonary disease or any other preoperative complication that might affect the results. Written inAccepted for publication Dec 28, 1990. Address reprint requests to Dr Sato, First Department of Surgery, Iwate Medical University, School of Medicine, 19-1 Uchimaru, Morioka, Japan 020.
0 1991 by The Society of Thoracic Surgeons
-
-
-
Operative Procedure The operative technique used, ie, our current technique [4, 51, is summarized here. The right pleural cavity was entered through a posterolateral incision in the fifth intercostal space. The radical procedure was commenced with a thorough dissection of the supradiaphragmatic nodes, the posterior mediastinal nodes, the paraesophageal nodes, the bilateral pulmonary hilar nodes, the right paratracheal nodes, some of the left paratracheal nodes along the recurrent nerve, and the thoracic esophagus. These intrathoracic procedures were performed under one-lung anesthesia using an endotracheal tube. After closure of the pleural cavity, the abdomen was entered through an upper midline incision, and the stomach was mobilized to create a gastric tube for the esophageal reconstruction. A proximal gastrectomy was performed with radical dissection of the lymph nodes along the common hepatic artery, the left gastric artery, the lesser curvature, and the cardia. A U-shaped incision was made in the neck, and then the cervical paraesophageal nodes, the right and left deep cervical nodes, and the supraclavicular nodes were radically dissected. For our reconstruction, the gastric tube was pulled up to the neck through the posterior mediastinum, and a gastroesophagotomy then followed.
Postoperative Evaluation Lactated Ringer’s solution was administered to maintain a pulmonary artery wedge pressure of 5 to 10 mm Hg from 0003-4975/91/$3.50
SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
Ann Thorac Surg 1991;51:754-8
755
Table 1. Clinical Characteristics of the Patient Groups Ulinastatin Group (n = 5) Variable
Mean
Age (Y) Operative time (h) Fluid administered intraoperatively (mL . kg-' . h-') Estimated blood loss (mL) SD
=
61 7.8 9.3 704
SD 7 1.3 2.3 273
Placebo Group (n = 5)
Range
Mean
52-68 6.5-10 7.4-13.0
61 8.7 7.8
4204,110
738
Range
SD 3 1.0 1.4
57-61 7.5-10 5.4-8.8 55&1,030
201
standard deviation.
the start of the operation until 6 AM on the first postoperative day. For nutritional support intravenous administration of glucose and amino acids, 30 to 40 calories * kg-I 24 h-', was started beginning at 6 AM on postoperative day 1. No patient received any lipid infusion with the total parenteral nutrition during the study period. At the end of the operation, all patients were immediately given prophylactic mechanical ventilation with a positive end-expiratory pressure of 5 cm H,O in the intensive care unit. Fluid-filled catheters were used to measure the mean arterial pressure, the mean pulmonary artery pressure, and the pulmonary artery wedge pressure. Gas analysis of the arterial and the mixed venous blood was performed in the laboratories of the intensive care unit. The cardiac indices were measured by thermodilution with a thermistor-tipped pulmonary artery catheter. All measurements were obtained after each patient had been exposed to 100% oxygen at atmospheric pressure for 15 minutes. The values reported were derived from the hemodynamic data and the blood gas analysis by the following equations [6, 71:
-
-
Pulmonary vascular resistance (dynes * s cmP5 * m-') = 79.92 X (MAP - PAWP)/CI. Intrapulmonary shunt rate (shunt flowkotal flow) = (CcO, - CaO,)/(CcO, - CCO,) x 100%. In the first equation, MAP = mean arterial pressure, PAWP = pulmonary artery wedge pressure, and CI = cardiac index. In the second equation, CaO, and COO, = oxygen content in arterial and pulmonary arterial blood, respectively, and CcO, = oxygen content in the capillary blood, derived from the alveolar gas equation, assuming a respiratory quotient of 1. The PMN elastase that bound to the alpha,-protease inhibitor was measured by an enzyme-linked immunoassay [8], and the plasma fibronectin concentration was determined by a single radial immunodiffusion assay using a partigen-fibronectin plate (Hoeschst-Behring Institute) [9]. The 10 patients were randomly divided into two groups of 5 each. One group received an intravenous infusion of ulinastatin (Mochida Pharmaceutical Co, Ltd, Tokyo, Japan), a protease inhibitor of inactivated PMN elastase.
One unit of ulinastatin was defined as the amount inhibiting 2 pg of bovine pancreatic trypsin by 50%. The ulinastatin was given in a dose of 150,000 units every 12 hours from the start of the operation until the third postoperative day, with each dosage diluted in lactated Ringer's solution and infused for 3 hours. The other group of 5 patients received a placebo infusion in an identical manner. The measurements for each patient were obtained 2 hours before and 6 hours after operation, and all subsequent measurements were done daily until postoperative day 5.
Statistical Analysis
*
All data are presented as the mean the standard deviation. The data were subjected to paired and nonpaired t tests, and a p value of less than 0.05 was considered significant.
Results The postoperative course of each patient was satisfactory, and there were no hospital deaths. Further, there were no idiosyncratic reactions during the ulinastatin infusions. The clinical characteristics of each group are given in Table 1. There was no appreciable difference between the two groups in age, operative time, amount of fluid administered, and volume of blood transfused. Blood transfusions, which seemed to influence the measurement of elastase and fibronectin, were administered only during the operation. Also, no patient was treated with a colloid infusion during the study period. Postoperative changes in pulmonary artery wedge pressure and cardiac index did not differ significantly between the groups; consequently, it was thought that the two groups reflected similar systemic hemodynamics. In the placebo group, the operation resulted in an increase in PMN elastase from a preoperative level of 154 2 23 pg/L to 449 56 pg/L at 6 hours postoperatively ( p < 0.01). Although the level gradually decreased, a significant elevation ( p < 0.05) persisted up to postoperative day 5 (Fig 1). In contrast, the postoperative plasma fibronectin value decreased progressively from 490 t 70 pg/L before operation to 265 2 81 pg/mL on postoperative day 2 ( p < 0.01) (Fig 2). The pulmonary vascular resistance
*
756
Ann Thornc Surg
SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
1991;51:75&8
*
rose from a preoperative value of 151 24 dynes * s * cmP5 m-’ to 284 +- 76 dynes s cmP5 * m-’ at 6 hours postoperatively ( p < 0.01), and a significant increase ( p < 0.05) was demonstrated up to day 3 (Fig 3). The pulmonary artery wedge pressure was maintained at 5 to 10 mm Hg, and the cardiac index remained unchanged, keeping its preoperative value of 3.57 0.4 L * min-’ * m-’ during the study period. Finally, the intrapulmonary shunt rate increased significantly immediately postoperatively and remained elevated up to the end of day 5, reaching a maximum value of 23.5% 5.4% on day 2 ( p < 0.01) (Fig 4). In the ulinastatin group, PMN elastase also was elevated significantly, though the administration of ulinastatin kept the value lower (275 +- 66 pg/L at 6 hours postoperatively) than that in the placebo group ( p < 0.05) (see Fig 1). There was no significant decrease in the concentration of fibronectin, which had a higher value than that of the placebo group from postoperative day 1to postoperative day 2 ( p < 0.05) (see Fig 2). A small increase in the pulmonary vascular resistance was noted from 142 19 dynes s cm-5 m-’ preoperatively to 173 +- 65 dynes * s cmP5 m-’ at 6 hours postoperatively. The values measured up to postoperative day 2 were significantly lower than those in the placebo group ( p < 0.05)
-
- -
*
*
*
-
- -
-
pre. 0
1
3
2
4
5
DAYS Fig 2. Plasma fibronectin concentration decreased in the placebo group in contrast to the ulinastatin group. (op. = operation; SD = st,undard deviation; * = significant difference between placebo and ulinastatin groups.)
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(see Fig 3 ) . Finally, the marked increase in the intrapulmonary shunt rate was similar to that seen in the placebo group; it peaked at 21.8% +- 2.9% on postoperative day 2 (see Fig 4). There were no differences between the two groups in changes in the white blood cell count postoperatively.
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Fig 1 . Operation (op.) led to an increase in plasma polymorphonuclear leukocyte (PMN) elastase levels. The elevation was most prominent at 6 hours postoperatively, but significant increases were seen until day 5 . Administration of ulinastatin resulted in a lower P M N elastase value. (SD = standard deviation; * = significant dijference between placebo and ulinastatin groups.)
Polymorphonuclear leukocyte elastase is known to display numerous bioactivities, such as the capability to degrade fibronectin, collagen, the proteoglycans, the basement membranes, and the surfactant apoproteins; it also can activate the complements and the clotting systems [lo]. Further, elastase-induced damage to the ertdothelium and the basement membranes can alter the alveolar-capillary membrane permeability. In this regard, a previous study [ll]has indicated that a trypsin inhibitor in a human urine preparation, ulinastatin, suppresses the activity of trypsin, PMN elastase, cathepsin G, and hLyaluronidase, all of which participate in decomposing the extracellular and intracellular matrix. In Japan, this protective effect of ulinastatin on tissue degradation has been used for the treatment of acute pancreatic inflammation and shock [12]. More recently, ulinastatin has been spec-
SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
Ann Thorac Surg
1991;51:754-8
I
pre. 0
1
2
3
4
5
DAYS
Fig 3 . Operation (op.) led to an increase in pulmonary vascular resistance in the placebo group. This increase was blunted by administration of ulinastatin. (SD = standard deviation; * = signijicant dif ference between placebo and ulinastatin groups.)
ulated to possess potential benefits for treating acute pulmonary impairment. After our total thoracic esophagectomy, which includes radical dissection of the lymph nodes, the plasma PMN elastase levels showed the most prominent increase at 6 hours postoperatively. Associated with the increase in PMN elastase were an increase in the pulmonary vascular resistance and a decrease in the concentration of plasma fibronectin, which cleared slowly over the next 2 days. That the inhibition of PMN elastase significantly limited pulmonary hypertension and the degradation of fibronectin suggests that PMN elastase somehow participates in the body's response to a pulmonary microvascular injury. The precise mechanism of how this is accomplished in this setting is unknown, though these results seem to indicate that PMN elastase directly influences the endothelial cell gap junctions by affecting the fibronectin content, opening the interendothelial junctions, and increasing the microvascular permeability. Although pulmonary hypertension and degradation of fibronectin may be important in the development of pulmonary dysfunction, no significant difference was seen in the intrapulmonary shunt rate between the placebo and ulinastatin groups. The precise pathophysiology of an alveolar-capillary membrane injury is not yet clear. One hypothesis is the activation of the complements, the arachidonate metabolites, the cytokines, and the oxygen
757
free radicals (13-151, though it remains questionable whether any of these mechanisms is more predominant. We cannot rule out such participation in the pathogenesis of a pulmonary injury. What can be proven, however, is that the pulmonary injury would have worsened. Under certain conditions, PMN elastase plays a major role in a pulmonary injury. This can occur when a great amount of elastase develops, caused by a massive blood transfusion; or when the alpha,-protease inhibitor is restrained by the development of a free radical, caused by tissue anoxia resulting from hypovolemia; or at the time of reexpansion because of improper inducement of one-lung anesthesia. Other factors also must be considered. A broad spectrum of pulmonary impairments can occur after operation for esophageal cancer [16], and it is impossible to elucidate the status of postoperative hypoxemia only by noting the increase in PMN elastase levels and the decrease in fibronectin concentrations. Thorough dissection of the upper mediastinal lymph nodes constitutes a direct invasive assault on the respiratory system, thus causing injurious effects on the vagus nerve and the lymphatic vessels. These effects can lead to an increased microvascular permeability, and the excess fluids that accumulate may exceed the pumping ability of the lymphatic vessels [ 171. Such conditions can be considered a preliminary stage of adult respiratory distress syndrome and should be viewed with concern, as even a slight incident can lead to a fatal complication. Thus, postoperative management should include preventive treatment for all possible
l1
*-a Placebo mean +SD
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3 4 5 DAYS Fig 4 . Operation (op.) caused an increase in intrapulmonay shunt in both groups of patients. (SD = standard deviation.) pre. 0
1
2
758
SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
pathological situations, and it is important to create as beneficial a milieu as possible for repair. Careful attention must be paid to various aberrant reactions that may be caused by bioactive substances. In general, we did not observe any differences in clinical changes between the two groups even when PMN elastase was inhibited. Our results suggest that under certain conditions, PMN elastase somehow participates in the postoperative mechanisms of a pulmonary injury within the pulmonary vasculature and causes a worsening of the condition, whereas other co-mediators and inhibitors may potentiate or neutralize each other. These mechanisms of intervention, acting at different stages in the pathogenesis of an injury, should be studied further in patients undergoing radical dissection of the upper mediastinal lymph nodes for thoracic esophageal cancer.
References 1. Malech HL, Gallin JI. Neutrophils in human diseases. N Engl J Med 1987;317687-94. 2. Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome: clinical and pathophysiologic significance. Am Rev Respir Dis 1986;133:218-25. 3. Idell S, Kucich U, Fein A, et al. Neutrophil elastase-releasing factors in bronchoalveolar lavage from patients with adult respiratory distress syndrome. Am Rev Respir Dis 1985;132: 1098-105. 4. Ishida K, Mori S, Okamoto K, et al. Results of extended dissection of lymph nodes in operation for thoracic esophageal cancer. In: Siewart IR, Holscher AH, eds. Diseases of the esophagus. Berlin: Springer-Verlag, 1987690-2. 5. Akiyama H. Cardinals in the regional lymph node dissection in surgery of thoracic esophageal cancer. In: Siewart IR,
Ann Thorac Surg 1991;51:7544
Holscher AH, eds. Diseases of the esophagus. Berlin: Springer-Verlag, 1987:41&20. 6. Shoemaker WC. A new approach to physiology, monitoring, and therapy of shock states. World J Surg 1987;11:133-46. 7. Berggren SM. The oxygen deficit of arterial blood caused by non-ventilating parts of the lung. Acta Physiol Scand [Suppl] 1942;11:1-92. 8. Neumann S, Hennrich N, Gunzer G, Lang H. Enzymelinked immunoassay for human granulocyte elastase in complex with alpha,-proteinase inhibitor. In: Horl WH, Heidland A, eds. Protease. New York: Plenum, 1987379. 9. Chadwick SJD, Mowbray JF, Dudby HAF. Plasma fibronectin and complement in surgical patients. Br J Surg 1984;71: 71~~20. 10. Havemann K, Gramse M. Physiology and pathophysiology of neutral proteinase of human granulocytes. In: Horl WH, Heidland A, eds. Protease. New York: Plenum, 19871. 11. Shibutani Y, Kunihiro Y. Preventative effects of ulinastatin on tissue degradation. Jpn Pharmacol Ther 1986;14:17-32. 12. Ohnishi H, Kosuzume H, Ashida Y, Kato K, Honjo I. Effect of urinary trypsin inhibitor on pancreatic enzymes and experimental acute pancreatitis. Dig Dis Sci 1984;29:26-32. 13. Kubo K, Kobayashi T. Effects of OK-046, a selective thromboxane-induced lung injury, in unanesthetized sheep. Am Rev Respir Dis 1985;13249&9. 14. Bevilacqua MP, Pober JS, Wheeler ME, Cortran RS, Gimbrone MA. Interleukin-1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest 1985;762003-11. 15. Ratych RE, Chuknyiska RS, Bulkey GB. The primary localization of free radical generation after anoxia/reoxygenation in isolated endothelial cells. Surgery 1987;102:122-31. 16. Nakayama K, Kakegawa T. Latest management of pulmonary complications following esophageal cancer surgery in Japan. Int Adv Surg Oncol 1981;4111-25. 17. Shimada I. The preserving effects of bronchial arteries and pulmonary nerves at radical esophagectomy on cardiorespiratory functions in the dog. Nippon Kyobu Geka Ciakkai Zasshi 1989;37:2305-17.
To evaluate the role of polymorphonuclear leukocyte (PMN)elastase in pulmonary impairment occurring after operation for esophageal cancer, 10 patients were randomized preoperatively into two equal groups. One group received a placebo infusion and the other, an infusion of the PMN elastase inhibitor ulinastatin. In the placebo group, the mean plasma PMN elastase level increased from 154 2 23 pg/L preoperatively to 449 2 56 pg/L at 6 hours postoperatively ( p < 0.01), whereas the mean plasma fibronectin concentration decreased from 490 -C 70 pg/mL preoperatively to 265 f 81 pg/mL on postoperative day 2 ( p < 0.01). The mean pulmonary
vascular resistance increased markedly from 151 2 24 dynes * s cm-5 * m-’ preoperatively to 284 -+ 76 dynes s * cm-5 m-’ at 6 hours postoperatively ( p < 0.01). In the group given ulinastatin, 150,000 units every 12 hours from the start of the operation, the mean PMN e1,astase value at 6 hours postoperatively was lower (275 :t 66 pg/L; p < 0.01) and the fibronectin level on postoperative days 1 and 2, higher ( p < 0.05). A lower pulmonary vascular resistance was noted into day 2 (p < 0.05). Our results suggest that PMN elastase may participate in the development of postoperative pulmonary impairment. (Ann Thorac Surg 1991;51:754-8)
P
formed consent was obtained from each patient before the start of our study.
ulmonary dysfunction that accompanies a severe injury has been theorized to be related to increased activation of the circulating blood cells, and the products of these cells, such as protease and free radicals, are thought to be involved in the direct mechanism of a pulmonary injury [l-31. In view of the great stress that occurs to the body during an operation for esophageal cancer, it is possible that interaction between the bioactive substances and postoperative hypoxemia occurs. This may create an environment for the onset of a pulmonary complication. This study was initiated to examine the postoperative changes in polymorphonuclear leukocyte (PMN) elastase and its role in the pulmonary circulation after radical lymph node dissection for thoracic esophageal cancer.
Material and Methods Ten patients, ranging in age from 52 to 68 years (mean age, 61 years), who had a thoracic esophageal cancer were treated by surgical intervention without prior immunochemotherapy or irradiation. Before operation, the following variables were assessed in each patient: lung volume, pulmonary mechanics, liver function, and nutritional state. All patients were confirmed to be free from any previous pulmonary disease or any other preoperative complication that might affect the results. Written inAccepted for publication Dec 28, 1990. Address reprint requests to Dr Sato, First Department of Surgery, Iwate Medical University, School of Medicine, 19-1 Uchimaru, Morioka, Japan 020.
0 1991 by The Society of Thoracic Surgeons
-
-
-
Operative Procedure The operative technique used, ie, our current technique [4, 51, is summarized here. The right pleural cavity was entered through a posterolateral incision in the fifth intercostal space. The radical procedure was commenced with a thorough dissection of the supradiaphragmatic nodes, the posterior mediastinal nodes, the paraesophageal nodes, the bilateral pulmonary hilar nodes, the right paratracheal nodes, some of the left paratracheal nodes along the recurrent nerve, and the thoracic esophagus. These intrathoracic procedures were performed under one-lung anesthesia using an endotracheal tube. After closure of the pleural cavity, the abdomen was entered through an upper midline incision, and the stomach was mobilized to create a gastric tube for the esophageal reconstruction. A proximal gastrectomy was performed with radical dissection of the lymph nodes along the common hepatic artery, the left gastric artery, the lesser curvature, and the cardia. A U-shaped incision was made in the neck, and then the cervical paraesophageal nodes, the right and left deep cervical nodes, and the supraclavicular nodes were radically dissected. For our reconstruction, the gastric tube was pulled up to the neck through the posterior mediastinum, and a gastroesophagotomy then followed.
Postoperative Evaluation Lactated Ringer’s solution was administered to maintain a pulmonary artery wedge pressure of 5 to 10 mm Hg from 0003-4975/91/$3.50
SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
Ann Thorac Surg 1991;51:754-8
755
Table 1. Clinical Characteristics of the Patient Groups Ulinastatin Group (n = 5) Variable
Mean
Age (Y) Operative time (h) Fluid administered intraoperatively (mL . kg-' . h-') Estimated blood loss (mL) SD
=
61 7.8 9.3 704
SD 7 1.3 2.3 273
Placebo Group (n = 5)
Range
Mean
52-68 6.5-10 7.4-13.0
61 8.7 7.8
4204,110
738
Range
SD 3 1.0 1.4
57-61 7.5-10 5.4-8.8 55&1,030
201
standard deviation.
the start of the operation until 6 AM on the first postoperative day. For nutritional support intravenous administration of glucose and amino acids, 30 to 40 calories * kg-I 24 h-', was started beginning at 6 AM on postoperative day 1. No patient received any lipid infusion with the total parenteral nutrition during the study period. At the end of the operation, all patients were immediately given prophylactic mechanical ventilation with a positive end-expiratory pressure of 5 cm H,O in the intensive care unit. Fluid-filled catheters were used to measure the mean arterial pressure, the mean pulmonary artery pressure, and the pulmonary artery wedge pressure. Gas analysis of the arterial and the mixed venous blood was performed in the laboratories of the intensive care unit. The cardiac indices were measured by thermodilution with a thermistor-tipped pulmonary artery catheter. All measurements were obtained after each patient had been exposed to 100% oxygen at atmospheric pressure for 15 minutes. The values reported were derived from the hemodynamic data and the blood gas analysis by the following equations [6, 71:
-
-
Pulmonary vascular resistance (dynes * s cmP5 * m-') = 79.92 X (MAP - PAWP)/CI. Intrapulmonary shunt rate (shunt flowkotal flow) = (CcO, - CaO,)/(CcO, - CCO,) x 100%. In the first equation, MAP = mean arterial pressure, PAWP = pulmonary artery wedge pressure, and CI = cardiac index. In the second equation, CaO, and COO, = oxygen content in arterial and pulmonary arterial blood, respectively, and CcO, = oxygen content in the capillary blood, derived from the alveolar gas equation, assuming a respiratory quotient of 1. The PMN elastase that bound to the alpha,-protease inhibitor was measured by an enzyme-linked immunoassay [8], and the plasma fibronectin concentration was determined by a single radial immunodiffusion assay using a partigen-fibronectin plate (Hoeschst-Behring Institute) [9]. The 10 patients were randomly divided into two groups of 5 each. One group received an intravenous infusion of ulinastatin (Mochida Pharmaceutical Co, Ltd, Tokyo, Japan), a protease inhibitor of inactivated PMN elastase.
One unit of ulinastatin was defined as the amount inhibiting 2 pg of bovine pancreatic trypsin by 50%. The ulinastatin was given in a dose of 150,000 units every 12 hours from the start of the operation until the third postoperative day, with each dosage diluted in lactated Ringer's solution and infused for 3 hours. The other group of 5 patients received a placebo infusion in an identical manner. The measurements for each patient were obtained 2 hours before and 6 hours after operation, and all subsequent measurements were done daily until postoperative day 5.
Statistical Analysis
*
All data are presented as the mean the standard deviation. The data were subjected to paired and nonpaired t tests, and a p value of less than 0.05 was considered significant.
Results The postoperative course of each patient was satisfactory, and there were no hospital deaths. Further, there were no idiosyncratic reactions during the ulinastatin infusions. The clinical characteristics of each group are given in Table 1. There was no appreciable difference between the two groups in age, operative time, amount of fluid administered, and volume of blood transfused. Blood transfusions, which seemed to influence the measurement of elastase and fibronectin, were administered only during the operation. Also, no patient was treated with a colloid infusion during the study period. Postoperative changes in pulmonary artery wedge pressure and cardiac index did not differ significantly between the groups; consequently, it was thought that the two groups reflected similar systemic hemodynamics. In the placebo group, the operation resulted in an increase in PMN elastase from a preoperative level of 154 2 23 pg/L to 449 56 pg/L at 6 hours postoperatively ( p < 0.01). Although the level gradually decreased, a significant elevation ( p < 0.05) persisted up to postoperative day 5 (Fig 1). In contrast, the postoperative plasma fibronectin value decreased progressively from 490 t 70 pg/L before operation to 265 2 81 pg/mL on postoperative day 2 ( p < 0.01) (Fig 2). The pulmonary vascular resistance
*
756
Ann Thornc Surg
SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
1991;51:75&8
*
rose from a preoperative value of 151 24 dynes * s * cmP5 m-’ to 284 +- 76 dynes s cmP5 * m-’ at 6 hours postoperatively ( p < 0.01), and a significant increase ( p < 0.05) was demonstrated up to day 3 (Fig 3). The pulmonary artery wedge pressure was maintained at 5 to 10 mm Hg, and the cardiac index remained unchanged, keeping its preoperative value of 3.57 0.4 L * min-’ * m-’ during the study period. Finally, the intrapulmonary shunt rate increased significantly immediately postoperatively and remained elevated up to the end of day 5, reaching a maximum value of 23.5% 5.4% on day 2 ( p < 0.01) (Fig 4). In the ulinastatin group, PMN elastase also was elevated significantly, though the administration of ulinastatin kept the value lower (275 +- 66 pg/L at 6 hours postoperatively) than that in the placebo group ( p < 0.05) (see Fig 1). There was no significant decrease in the concentration of fibronectin, which had a higher value than that of the placebo group from postoperative day 1to postoperative day 2 ( p < 0.05) (see Fig 2). A small increase in the pulmonary vascular resistance was noted from 142 19 dynes s cm-5 m-’ preoperatively to 173 +- 65 dynes * s cmP5 m-’ at 6 hours postoperatively. The values measured up to postoperative day 2 were significantly lower than those in the placebo group ( p < 0.05)
-
- -
*
*
*
-
- -
-
pre. 0
1
3
2
4
5
DAYS Fig 2. Plasma fibronectin concentration decreased in the placebo group in contrast to the ulinastatin group. (op. = operation; SD = st,undard deviation; * = significant difference between placebo and ulinastatin groups.)
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(see Fig 3 ) . Finally, the marked increase in the intrapulmonary shunt rate was similar to that seen in the placebo group; it peaked at 21.8% +- 2.9% on postoperative day 2 (see Fig 4). There were no differences between the two groups in changes in the white blood cell count postoperatively.
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,
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L
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3
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4
5
DAYS
Fig 1 . Operation (op.) led to an increase in plasma polymorphonuclear leukocyte (PMN) elastase levels. The elevation was most prominent at 6 hours postoperatively, but significant increases were seen until day 5 . Administration of ulinastatin resulted in a lower P M N elastase value. (SD = standard deviation; * = significant dijference between placebo and ulinastatin groups.)
Polymorphonuclear leukocyte elastase is known to display numerous bioactivities, such as the capability to degrade fibronectin, collagen, the proteoglycans, the basement membranes, and the surfactant apoproteins; it also can activate the complements and the clotting systems [lo]. Further, elastase-induced damage to the ertdothelium and the basement membranes can alter the alveolar-capillary membrane permeability. In this regard, a previous study [ll]has indicated that a trypsin inhibitor in a human urine preparation, ulinastatin, suppresses the activity of trypsin, PMN elastase, cathepsin G, and hLyaluronidase, all of which participate in decomposing the extracellular and intracellular matrix. In Japan, this protective effect of ulinastatin on tissue degradation has been used for the treatment of acute pancreatic inflammation and shock [12]. More recently, ulinastatin has been spec-
SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
Ann Thorac Surg
1991;51:754-8
I
pre. 0
1
2
3
4
5
DAYS
Fig 3 . Operation (op.) led to an increase in pulmonary vascular resistance in the placebo group. This increase was blunted by administration of ulinastatin. (SD = standard deviation; * = signijicant dif ference between placebo and ulinastatin groups.)
ulated to possess potential benefits for treating acute pulmonary impairment. After our total thoracic esophagectomy, which includes radical dissection of the lymph nodes, the plasma PMN elastase levels showed the most prominent increase at 6 hours postoperatively. Associated with the increase in PMN elastase were an increase in the pulmonary vascular resistance and a decrease in the concentration of plasma fibronectin, which cleared slowly over the next 2 days. That the inhibition of PMN elastase significantly limited pulmonary hypertension and the degradation of fibronectin suggests that PMN elastase somehow participates in the body's response to a pulmonary microvascular injury. The precise mechanism of how this is accomplished in this setting is unknown, though these results seem to indicate that PMN elastase directly influences the endothelial cell gap junctions by affecting the fibronectin content, opening the interendothelial junctions, and increasing the microvascular permeability. Although pulmonary hypertension and degradation of fibronectin may be important in the development of pulmonary dysfunction, no significant difference was seen in the intrapulmonary shunt rate between the placebo and ulinastatin groups. The precise pathophysiology of an alveolar-capillary membrane injury is not yet clear. One hypothesis is the activation of the complements, the arachidonate metabolites, the cytokines, and the oxygen
757
free radicals (13-151, though it remains questionable whether any of these mechanisms is more predominant. We cannot rule out such participation in the pathogenesis of a pulmonary injury. What can be proven, however, is that the pulmonary injury would have worsened. Under certain conditions, PMN elastase plays a major role in a pulmonary injury. This can occur when a great amount of elastase develops, caused by a massive blood transfusion; or when the alpha,-protease inhibitor is restrained by the development of a free radical, caused by tissue anoxia resulting from hypovolemia; or at the time of reexpansion because of improper inducement of one-lung anesthesia. Other factors also must be considered. A broad spectrum of pulmonary impairments can occur after operation for esophageal cancer [16], and it is impossible to elucidate the status of postoperative hypoxemia only by noting the increase in PMN elastase levels and the decrease in fibronectin concentrations. Thorough dissection of the upper mediastinal lymph nodes constitutes a direct invasive assault on the respiratory system, thus causing injurious effects on the vagus nerve and the lymphatic vessels. These effects can lead to an increased microvascular permeability, and the excess fluids that accumulate may exceed the pumping ability of the lymphatic vessels [ 171. Such conditions can be considered a preliminary stage of adult respiratory distress syndrome and should be viewed with concern, as even a slight incident can lead to a fatal complication. Thus, postoperative management should include preventive treatment for all possible
l1
*-a Placebo mean +SD
5T
L
,
-
3 4 5 DAYS Fig 4 . Operation (op.) caused an increase in intrapulmonay shunt in both groups of patients. (SD = standard deviation.) pre. 0
1
2
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SATOETAL ELASTASE AND ESOPHAGEAL CANCER OPERATIONS
pathological situations, and it is important to create as beneficial a milieu as possible for repair. Careful attention must be paid to various aberrant reactions that may be caused by bioactive substances. In general, we did not observe any differences in clinical changes between the two groups even when PMN elastase was inhibited. Our results suggest that under certain conditions, PMN elastase somehow participates in the postoperative mechanisms of a pulmonary injury within the pulmonary vasculature and causes a worsening of the condition, whereas other co-mediators and inhibitors may potentiate or neutralize each other. These mechanisms of intervention, acting at different stages in the pathogenesis of an injury, should be studied further in patients undergoing radical dissection of the upper mediastinal lymph nodes for thoracic esophageal cancer.
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