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Progestins and Ventilatory Stimulation
24 Krawczyk WS. A pattern of epidermal cell migration during wound healing. J Cell Bioi 1971; 49:247-63 25 Giacometti L, Parakkal PF. Skin transplantation: orientation of epithelial cells by the basement membrane. Nature 1969; 223:514-15 26 Fujikawa LS, Foster CS, Gipson IK, Colvin RB. Basement membrane components in healing rabbit corneal epithelial wounds: immunofluorescence and ultrastructural studies. J Cell Bioi 1984; 98:128-38 27 Vracko R. Significance of basal lamina for regeneration of injured lung. Virchows Arch [A] 1972; 355:264-74 28 Volkmann R. Uber die regeneration des quergestreiften muskelgewebes beim menschen und saugethier. Beitr Path Anat 1893; 12:23. (cited by Vraeko") 29 Battersby S, Anderson TJ. Myofibroblast activity of radial scars. J Patho11985; 147:33-40 30 Rennard SL, Bitterman PB Crystal RG. Response of the lower respiratory tract to injury. Chest 1983; 84:735-39
Progestins and Ventilatory Stimulation lines of evidence indicate that synthetic Several progestins are relatively strong long-term ventilatory stimulants and, thus, may be useful in the correction of chronic CO 2 retention. First, medroxyprogesterone acetate (MPA) increased tidal volume and lowered Pco, despite the presence of potentially powerful inhibitory influences including peripheral blood and cerebrospinal fluid alkalosis in normal subjects' and severe mechanical impairment in patients with COPD.2,3Second, in selected patients with COPD, long-term MPA therapy was more consistent than chronic metabolic acidosis in correcting CO 2 retention." Therefore, progestins are unique ventilatory stimulants which cause hyperventilation in health and disease states independent of measurable changes in classic chemical stimuli. The mechanism of ventilatory stimulation by progestins is not mediated by the level of progestational activit)'. Some hormones with marked progestational activity such as anhydrohydroxyprogesterone or 19norethinyltestosterone show no stimulatory effect on ventilation." MPA has 15 times the progestational activity of progesterone and yet the ventilatory response in normal males treated with MPA is half that observed during pregnancy Chlormadinone acetate (CMA) has ten times the luteinizing action as MPA but produces the same amount of ventilatory stimulation." In this issue of Chest (p 1073), Tatsumi et al report that CMA was used at one tenth the dose previously reported and caused a similar degree of ventilatory stimulation. A role for estrogen-inducible progesterone receptors has been proposed as the reason for the variable ventilatory response in human studies and between species. Selection criteria are necessary to predict a ventilatory response in patients with chronic CO 2retention.
Patients with obesity-hypoventilation syndrome" and chronic mountain polycythemia" are good candidates for progesterone therapy Patients with COPD and severe mechanical limitation (FEV l<0.5 L) and those who are unable to lower PaC02greater than 5 mm Hg with voluntary hyperventilation are unlikely to respond to long-term ventilatory stimulation." Patients with acute ventilatory failure due to a deterioration of lung function are less likely to benefit because of the predominant contribution of mechanical and ventilation-perfusion impairment rather than an insufficient inspiratory effort. Patients with primary alveolar hypoventilation do not respond consistently. Patients with obstructive sleep apnea do not benefit from progesterone." However, the role of progesterone in patients with sleep apnea and daytime CO 2 retention is less well defined. A beneficial effect of synthetic progestins in the treatment of central sleep apnea is suggested by studies of periodic breathing at high altitude, since MPA caused a reduction in oscillations in oxygen saturation." These clinical observations indicate that progesterone is an effective ventilatory stimulant in patients who have an inadequate inspiratory effort relative to the degree of mechanical and ventilation-perfusion abnormality. Patients with COPD who correct their CO 2 retention report either no increase or a decrease in dyspnea. Noncorrectors with more severe mechanical impairment may experience an increase in dyspnea. Clinical improvement is occasionally dramatic, but is not well correlated with improvement in blood gas values. Decreased libido and impotence occur in about 20 percent of patients. The use of long-term progesterone therapy in patients with CO 2 retention is limited, especially in patients with COPD, because the long-term effect of ventilatory stimulation on oxygen delivery and pulmonary hypertension has not been well documented. In contrast, improvement in tissue oxygenation is suggested, in patients with obesity-hypoventilation syndrome and chronic mountain polycythemia, by a decrease in hematocrit following improvement in Pa02' Widespread use of synthetic progestins is further limited by the small number of patients whose CO 2 retention is due to an insufficient inspiratory effort rather than to a predominantly mechanical or neuromuscular abnormality James B. Skatrud, M.D. Madison Associate Professor of Medicine, University of Wisconsin. REFERENCES
1 Skatrud J, Dempsey J, Kaiser D. Ventilatory response to medroxyprogesterone acetate in normal subjects: time course and mechanism. J Appl Physiol1978; 44:939-44 2 Tyler JM. The effect of progesterone on the respiration of patients CHEST I 96 I 5 I NOVEMBER, 1989
989
with emphysema and hypercapnia. J Clin Invest 1960; 39:34-41 3 Skatrud J, Dempsey J. Relative effectiveness of acetazolamide versus medroxyprogesterone acetate in correction of chronic carbon dioxide retention. Am Rev Respir Dis 1983; 127:405-12 4 Morikawa T, Tanaka Y, Maruyama R, Nishibayashi Y, Honda Y. Comparison of two synthetic progesterones on ventilation in normal males: CMA vs MPA. J Appl Physioll987; 63:1610-15 5 Sutton FD Jr, Zwillich C~ Creagh CE, Pierson DJ, Wei! jv Progesterone for outpatient treatment of pickwickian syndrome. Ann Intern Med 1975; 83:476-79 6 Kryger M, Glas R, Jackson D. Impaired oxygenation during sleep in excessive polycythemia of high altitude: improvement with respiratory stimulation. Sleep 1978; 1:3-17 7 Rajagopal KR, Albrecht PH, Jabbari B. Effects of Medroxyprogesterone acetate in obstructive sleep apnea. Chest 1986; 90:81521 8 Wei! J~ Kryger MH, Scoggin CH. Sleep and breathing at high altitude. In: Guilleminault C, Dement ~ eds. Sleep apnea SYndromes. New York: Alan R Liss, 1978:119-36
Ten-year Survival after Esophagectomy for Carcinoma Surgical Triumph or Biologic Variation? Esophageal cancer in the United States has traditionally been viewed as a basically incurable disease for which palliation is essentially the primary goal of therapy There are nearly 10,000 new cases of esophageal cancer reported each year in the United States and 8,800 annual deaths from this tumor,' Between 80 and 90 percent of our patients with esophageal cancer succumb to their disease within two years of diagnosis regardless of the method of treatment, so the number of patients alive two years after esophageal resection has been equated with "long-term survival." Five-year survival in most Western series is 5 percent or less. 2-5 Among the available therapeutic modalities, esophageal resection and reconstruction provide the most efficient restoration of the ability to swallow comfortably for the patient's short remaining life. But despite advances in diagnostic imaging (CT and MRI scans), nutritional support, anesthetic and operative techniques, and postoperative care, the price of an esophagectomy remains high. Major thoracoabdominal operations in nutritionally depleted patients lead to significant postoperative respiratory complications. An intrathoracic esophagogastric anastomotic leak causes mediastinitis and sepsis, a complication that carries a 50 percent mortality in these patients. Thus, in many modern series of esophageal resection and reconstruction for carcinoma, operative mortality ranges from 15 to 40 percents" and averages 30 percent." When the operative mortality for resecting an esophageal cancer exceeds the expected two- to five-year survival, the wisdom of this approach must be questioned. 970
Against this backdrop of pessimism and discouraging results, which have caused many physicians to turn away from surgery for their patients with esophageal cancer, are a number of significant developments in this area. The report in this issue of Chest by Iizuka and coworkers (p 1005), is an extraordinary example of the results of national organization and efficiency mobilized to provide consistent reporting and data collection in these patients. Drawing on a national tumor registry that collected from 234 hospitals 10,113 cases of esophageal cancer from 1969 to 1980, this is a report of 5,506 patients who underwent esophageal resection. (Patients from 78 hospitals were excluded from this study because these institutions failed to achieve a five-year follow-up rate of at least 80 percent!) It has been argued for many years that the better survival of Japanese patients undergoing esophageal resection for carcinoma is a reflection not of better operative technique, but of a different biologic disease than is encountered in their Western counterparts. This report tends to reinforce this impression, for an extraordinary ten-year survival of 18.7 percent in patients undergoing esophagectomy for cancer has not, to my knowledge, been duplicated in any Western series. In fact, to my knowledge, there are only two other published ten-year survival reports following esophagectomy for carcinoma, both from the Orient (and both cited by Iizuka). Even though esophageal cancer may be a "different tumor in Japan," there are nonetheless some important "messages" in the Iizuka report. Esophageal resection clearly provides the only meaningful chance for longterm survival in these patients (fewer than 1 percent who did not undergo resection survived ten years). Radiation therapy given either preoperatively or postoperatively provides no improvement in survival. The revised TNM staging classification for esophageal carcinoma correlates well with survival in these patients. The rather arbitrary 5-cm tumor length used to define a stage 3 tumor in the older TNM classification correlates poorly with survival. The authors report the best survival with tumors less than 3 cm in length and no difference in survival with tumors between 3 and 10 cm. Ten-year survival with regional lymph node involvement falls to 14.1 percent from 32.4 percent without nodal spread, and with distant metastatic disease, ten-year survival is only 3 percent. Thus, patients with stage 1 disease limited to the mucosa have a 50 percent ten-year survival in Japan. Once the disease reaches the submucosa, the muscularis propria, or the adventitia of the esophagus, survival falls significantly, and the authors suggest that submucosal invasion may therefore be indicative of advanced disease. Ifthis is the case, since the majority of esophageal tumors encountered in the West clearly extend into the submucosa of the esophagus or deeper, Editorials
Progestins and Ventilatory Stimulation lines of evidence indicate that synthetic Several progestins are relatively strong long-term ventilatory stimulants and, thus, may be useful in the correction of chronic CO 2 retention. First, medroxyprogesterone acetate (MPA) increased tidal volume and lowered Pco, despite the presence of potentially powerful inhibitory influences including peripheral blood and cerebrospinal fluid alkalosis in normal subjects' and severe mechanical impairment in patients with COPD.2,3Second, in selected patients with COPD, long-term MPA therapy was more consistent than chronic metabolic acidosis in correcting CO 2 retention." Therefore, progestins are unique ventilatory stimulants which cause hyperventilation in health and disease states independent of measurable changes in classic chemical stimuli. The mechanism of ventilatory stimulation by progestins is not mediated by the level of progestational activit)'. Some hormones with marked progestational activity such as anhydrohydroxyprogesterone or 19norethinyltestosterone show no stimulatory effect on ventilation." MPA has 15 times the progestational activity of progesterone and yet the ventilatory response in normal males treated with MPA is half that observed during pregnancy Chlormadinone acetate (CMA) has ten times the luteinizing action as MPA but produces the same amount of ventilatory stimulation." In this issue of Chest (p 1073), Tatsumi et al report that CMA was used at one tenth the dose previously reported and caused a similar degree of ventilatory stimulation. A role for estrogen-inducible progesterone receptors has been proposed as the reason for the variable ventilatory response in human studies and between species. Selection criteria are necessary to predict a ventilatory response in patients with chronic CO 2retention.
Patients with obesity-hypoventilation syndrome" and chronic mountain polycythemia" are good candidates for progesterone therapy Patients with COPD and severe mechanical limitation (FEV l<0.5 L) and those who are unable to lower PaC02greater than 5 mm Hg with voluntary hyperventilation are unlikely to respond to long-term ventilatory stimulation." Patients with acute ventilatory failure due to a deterioration of lung function are less likely to benefit because of the predominant contribution of mechanical and ventilation-perfusion impairment rather than an insufficient inspiratory effort. Patients with primary alveolar hypoventilation do not respond consistently. Patients with obstructive sleep apnea do not benefit from progesterone." However, the role of progesterone in patients with sleep apnea and daytime CO 2 retention is less well defined. A beneficial effect of synthetic progestins in the treatment of central sleep apnea is suggested by studies of periodic breathing at high altitude, since MPA caused a reduction in oscillations in oxygen saturation." These clinical observations indicate that progesterone is an effective ventilatory stimulant in patients who have an inadequate inspiratory effort relative to the degree of mechanical and ventilation-perfusion abnormality. Patients with COPD who correct their CO 2 retention report either no increase or a decrease in dyspnea. Noncorrectors with more severe mechanical impairment may experience an increase in dyspnea. Clinical improvement is occasionally dramatic, but is not well correlated with improvement in blood gas values. Decreased libido and impotence occur in about 20 percent of patients. The use of long-term progesterone therapy in patients with CO 2 retention is limited, especially in patients with COPD, because the long-term effect of ventilatory stimulation on oxygen delivery and pulmonary hypertension has not been well documented. In contrast, improvement in tissue oxygenation is suggested, in patients with obesity-hypoventilation syndrome and chronic mountain polycythemia, by a decrease in hematocrit following improvement in Pa02' Widespread use of synthetic progestins is further limited by the small number of patients whose CO 2 retention is due to an insufficient inspiratory effort rather than to a predominantly mechanical or neuromuscular abnormality James B. Skatrud, M.D. Madison Associate Professor of Medicine, University of Wisconsin. REFERENCES
1 Skatrud J, Dempsey J, Kaiser D. Ventilatory response to medroxyprogesterone acetate in normal subjects: time course and mechanism. J Appl Physiol1978; 44:939-44 2 Tyler JM. The effect of progesterone on the respiration of patients CHEST I 96 I 5 I NOVEMBER, 1989
989
with emphysema and hypercapnia. J Clin Invest 1960; 39:34-41 3 Skatrud J, Dempsey J. Relative effectiveness of acetazolamide versus medroxyprogesterone acetate in correction of chronic carbon dioxide retention. Am Rev Respir Dis 1983; 127:405-12 4 Morikawa T, Tanaka Y, Maruyama R, Nishibayashi Y, Honda Y. Comparison of two synthetic progesterones on ventilation in normal males: CMA vs MPA. J Appl Physioll987; 63:1610-15 5 Sutton FD Jr, Zwillich C~ Creagh CE, Pierson DJ, Wei! jv Progesterone for outpatient treatment of pickwickian syndrome. Ann Intern Med 1975; 83:476-79 6 Kryger M, Glas R, Jackson D. Impaired oxygenation during sleep in excessive polycythemia of high altitude: improvement with respiratory stimulation. Sleep 1978; 1:3-17 7 Rajagopal KR, Albrecht PH, Jabbari B. Effects of Medroxyprogesterone acetate in obstructive sleep apnea. Chest 1986; 90:81521 8 Wei! J~ Kryger MH, Scoggin CH. Sleep and breathing at high altitude. In: Guilleminault C, Dement ~ eds. Sleep apnea SYndromes. New York: Alan R Liss, 1978:119-36
Ten-year Survival after Esophagectomy for Carcinoma Surgical Triumph or Biologic Variation? Esophageal cancer in the United States has traditionally been viewed as a basically incurable disease for which palliation is essentially the primary goal of therapy There are nearly 10,000 new cases of esophageal cancer reported each year in the United States and 8,800 annual deaths from this tumor,' Between 80 and 90 percent of our patients with esophageal cancer succumb to their disease within two years of diagnosis regardless of the method of treatment, so the number of patients alive two years after esophageal resection has been equated with "long-term survival." Five-year survival in most Western series is 5 percent or less. 2-5 Among the available therapeutic modalities, esophageal resection and reconstruction provide the most efficient restoration of the ability to swallow comfortably for the patient's short remaining life. But despite advances in diagnostic imaging (CT and MRI scans), nutritional support, anesthetic and operative techniques, and postoperative care, the price of an esophagectomy remains high. Major thoracoabdominal operations in nutritionally depleted patients lead to significant postoperative respiratory complications. An intrathoracic esophagogastric anastomotic leak causes mediastinitis and sepsis, a complication that carries a 50 percent mortality in these patients. Thus, in many modern series of esophageal resection and reconstruction for carcinoma, operative mortality ranges from 15 to 40 percents" and averages 30 percent." When the operative mortality for resecting an esophageal cancer exceeds the expected two- to five-year survival, the wisdom of this approach must be questioned. 970
Against this backdrop of pessimism and discouraging results, which have caused many physicians to turn away from surgery for their patients with esophageal cancer, are a number of significant developments in this area. The report in this issue of Chest by Iizuka and coworkers (p 1005), is an extraordinary example of the results of national organization and efficiency mobilized to provide consistent reporting and data collection in these patients. Drawing on a national tumor registry that collected from 234 hospitals 10,113 cases of esophageal cancer from 1969 to 1980, this is a report of 5,506 patients who underwent esophageal resection. (Patients from 78 hospitals were excluded from this study because these institutions failed to achieve a five-year follow-up rate of at least 80 percent!) It has been argued for many years that the better survival of Japanese patients undergoing esophageal resection for carcinoma is a reflection not of better operative technique, but of a different biologic disease than is encountered in their Western counterparts. This report tends to reinforce this impression, for an extraordinary ten-year survival of 18.7 percent in patients undergoing esophagectomy for cancer has not, to my knowledge, been duplicated in any Western series. In fact, to my knowledge, there are only two other published ten-year survival reports following esophagectomy for carcinoma, both from the Orient (and both cited by Iizuka). Even though esophageal cancer may be a "different tumor in Japan," there are nonetheless some important "messages" in the Iizuka report. Esophageal resection clearly provides the only meaningful chance for longterm survival in these patients (fewer than 1 percent who did not undergo resection survived ten years). Radiation therapy given either preoperatively or postoperatively provides no improvement in survival. The revised TNM staging classification for esophageal carcinoma correlates well with survival in these patients. The rather arbitrary 5-cm tumor length used to define a stage 3 tumor in the older TNM classification correlates poorly with survival. The authors report the best survival with tumors less than 3 cm in length and no difference in survival with tumors between 3 and 10 cm. Ten-year survival with regional lymph node involvement falls to 14.1 percent from 32.4 percent without nodal spread, and with distant metastatic disease, ten-year survival is only 3 percent. Thus, patients with stage 1 disease limited to the mucosa have a 50 percent ten-year survival in Japan. Once the disease reaches the submucosa, the muscularis propria, or the adventitia of the esophagus, survival falls significantly, and the authors suggest that submucosal invasion may therefore be indicative of advanced disease. Ifthis is the case, since the majority of esophageal tumors encountered in the West clearly extend into the submucosa of the esophagus or deeper, Editorials