1540 CORRESPONDENCE
GASTROENTEROLOGY
is because they only studied four patients with secondary peritonitis compared with our 15 patients. In summary, it seems that this algorithm is valid in differentiating patients with SBP from those with secondary peritonitis in more than one patient population on more than one continent. Perhaps it should be used for this purpose everywhere. B.A. RUNYON. M.D.
University of Southern California Liver Unit Downey, California 1. Akriviadis EA, Runyon BA. The utility of an algorithm in differentiating spontaneous from secondary peritonitis. Gastroenterology 1990;98:127-133.
Hemodynamic Infusion
Status During Famotidine
Dear Sir: We read with great interest the article by Kirch et al. (1) on the possible interaction of famotidine and nifedipine in noninvasive parameters of cardiac performance. While impedance cardiography, electrocardiog raphy, and phonocardiography may be used for the noninvasive measurement of cardiac performance, they each have large inherent problems of inaccuracy and error. We performed an invasive, double-blind, placebo-controlled study of eleven critically ill but hemodynamically stable intensive care patients who were receiving famotidine. Measurements were performed via a Swan-Ganz catheter and an intraarterial line after a 2-minute bolus injection of either famotidine or placebo at l-. 3-. 5-, and lo-minute intervals. Parameters measured included cardiac output, cardiac index, left and right ventricular stroke work indexes, mean arterial pressure, heart rate, pulmonary capillary wedge pressure, right atria1 pressure, and pulmonary arterial pressure. Using analysis of variance (P < 0.05), no clinical or statistically significant change was noted in any of the invasively measured or calculated parameters of cardiac performance (submitted for publication). In addition, Omote et al. (2) compared hemodynamic parameters of intensive care patients receiving cimetidine. ranitidine. and famotidine and found no significant change in hemodynamics with the use of famotidine. Ohnishi et al. (3) studied hepatic hemodynamits in 20 patients with peptic ulcers and chronic liver disease. These invasive studies showed no changes in portal or hepatic blood flow, cardiac output, or gradient between wedged hepatic vein pressure and free hepatic vein pressure. In conclusion, famotidine seems to show no significant changes in hemodynamics measured by invasive techniques of cardiac performance. This lack of change was confirmed in critically ill patients who would have had the most risk of hemodynamic instability. DARELL E. HEISELMAN. D.O. MARK MALIK. M.D. LYNN J. WHITE, MS.
Department of Critical Care Medicine Akron General Medical Center 400 Wabash Avenue Akron, Ohio 44307 1. Kirch W, Halabi A, Linde M, Santos SR. Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 1989:96: 1388-1392. 2. Omote K, Namiki A, Sumita S, Takahashi T, Ujike Y, Hagiwara T. Comparative studies on hemodynamic effects of intravenous cimetidine, ranitidine and famotidine in intensive care unit patients. Masui 1987;36:940-947.
Vol. 99, No. 5
3. Ohnishi K, Saito M, Normura F. Okuda K, Suzuki N, Ohtsuki T, Goto N, Takashi M. Effect of famotidine on hepatic hemodynamits and peptic ulcer. Am ] Gastroenterol1987;82:415-418. Reply. It is questionable to determine hemodynamic effects of famotidine in patients in an intensive care unit because these critically ill subjects are mostly under concurrent treatment with various drugs, e.g., positive inotropic substances such as dopamine or dobutamine (1). This was the case in the studies of Omote et al. and Matsukawa et al. (2,3), who invasively investigated hemodynamic parameters following IV administration of famotidine in these patients. The study presented by Heiselmann et al. lacks any information on concurrent treatment of the critically ill patients to whom famotidine was administered. Furthermore, because of the circumstances of an intensive care unit, patients are under maximum sympathomimetic stimulation. This additionally leads to alteration of the results of hemodynamic measurements. Both invasive and noninvasive techniques for the measurement of cardiac performance have disadvantages with inherent problems of inaccuracy and errors. These largely depend on the investigator’s experience and on the conditions under which the subjects are studied. Thus, in our opinion, hemodynamic data found with famotidine are not dependent on the measurement of invasive or noninvasive methods but rather on the study design used. Thus, in conclusion, most probably the circumstances under which patients were investigated are responsible (critically ill patients of an intensive care unit) for the results found by Heiselman et al. and the Japanese groups (2,3). Finally, one should be aware that HZ-antagonists have been shown to exert negative inotropic effects also in vitro (4). whereas famotidine at higher concentrations causes an unsurmountable HZ-receptor antagonism 151. W. KIRCH A. HALABI H. HINRICHSEN
Christian-Albrechts-Universitiit Schittenhelmstrasse 12 D-2300 Kiel, Federal Republic of Germany 1. Kirch W, Halabi A, Linde M, Santos SR, Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 1989;96: 1388-1392.
2. Omote K, Namiki A, Sumita S, Takahashi T, Ujike Y, Hagiwara T. Comparative studies on hemodynamic effects of intravenous cimetidine, ranitidine, and famotidine in intensive care unit patients. Masui 1987;36:940-947. 3. Matsukawa S, Hoshi K. Kaise A, Sasaki I, Hashimoto Y, Amaha K. The cardiovascular effect of famotidine in intensive care patients. J Intensive Care Med 1986;10:763-767. 4. Bertaccini G. Coruzzi G, Poli E, Adami M. Pharmacology of the novel HZ-antagonist famotidine: in vitro studies. Agents Actions 1986:19:180-187, 5. Pendleton RG, Torchiama ML, Chung C. Cook P, Wiese S, Clineschmidt BV. Studies on MK-208 (YM-11170) a new slowly dissociable HZ-receptor antagonist. Arch Int Pharmacodyn Ther 1983;266:4-16.
Geopathology
of Early Gastric Cancer
Dear Sir: Eckardt et al. (1) report their experience with early gastric cancer (EGC] in Germany. They showed a 21.2% incidence of EGC and an 83.4% crude 5-year survival rate. This survival rate was comparable to a group of patients with benign gastric ulcers. They point out that
November
CORRESPONDENCE
1990
EGC may be underestimated in Western countries and that 5-year survival rates do not reach those reported for Japanese patients. We have, however, reported a series of patients with EGC treated at Columbia Presbyterian Medical Center in New York [2) in whom we showed a >97% 5-year survival rate (age-adjusted). Thisgroup of patients in fact have a survival rate comparable to the U.S. population (1980 census]. This survival rate is comparable to the age-adjusted 5-year survival rate of Japanese patients with EGC (3). This is the survival rate in our patients despite the presence of lymph node involvement in 28%. We have also noted an increasing incidence with an annual incidence approaching 30% of resections for gastric cancer. Early gastric cancer in the U.S. resembles that found in Japan in every way (morphology, clinical presentation, and curability]. The maJor difference lies in the fact that the concept of early gastric cancer is not widely appreciated by endoscopists or surgeons in this country. PETER H. R. GREEN, M.D. K. M. O’TOOLE,M.D. D. SLONIM Departments of Medicine and Pathology Columbia Presbyterian Medical Center New York, New York 10032 Eckardt V, GieBler W, Kanzler G, Remmele W, Bernhard G. Clinical and morphological characteristics of early gastric cancer. A case-control study. Gastroenterology 1990;98:708-714. Green PHR, O’Toole KM, Slonim D, Wang T, Weg A. Increasing incidence and excellent survival of patients with early gastric cancer: experience in a United States medical center. Am J Med 1988;85:658-661. Kidoro T. Frequency of resection, metastases and five year survival rate of early gastric cancer in a surgical clinic. Jpn J Cancer Res 1971;11:45-49. Reply.
Although we have cited the work of Dr. Green et al. (1.2) repeatedly in our recent manuscript (3). we would like to reemphasize that some of their data parallel our own findings. However, we also believe that several important differences exist. First, while previous investigations including those by Green et al. stem from tertiary referral centers, our investigation was performed in a gastroenterological group practice that serves as a primary referral center. Second, in contrast to Green’s investigations, our study did not concern only patients undergoing resections for gastric cancer but all patients with an endoscopic diagnosis for this disease. If we extrapolate our data to patients with resectable lesions, the prevalence of EGC would be 29%. which is more than double the figure reported by Green et al. Furthermore, in contrast to Dr. Green’s observation, we did not observe an increasing incidence of early gastric cancer during more recent years (1977-1981, 21%; 1982-1986. 23%], indicating that the changing frequency of EGC may be a factor that is more physician related than patient related. Finally, the fact that lymph node metastases in EGC patients were five times commoner in the American study (2) agrees with our belief that patients reported from tertiary referral centers present with a later stage of their disease. Despite these differences in the studies from two continents, we totally agree with the conclusions of Green et al. that the concept of EGC is still not sufficiently appreciated in the Western world. We even believe that a frequency of EGC that is well below 20% indicates delayed and/or inaccurate diagnosis. VOLKERF. ECKARDT Gastroenterologisches Institut Wiesbaden, Federal Republic of Germany 1. Green PHR, O’Toole KM, Weinberg LM. Goldfarb gastric cancer. Gastroenterology 1981:81:247-256.
JP. Early
1541
Green PHR, O’Toole KM, Slonim D, Wang T, Weg A. Increasing incidence and excellent survival of patients with early gastric cancer: experience in a United States medical center. Am J Med 1988;85:658-661. Eckardt VF, GieBler W, Kanzler G, Remmele W, Bernhard G. Clinical and morphological characteristics of early gastric cancer. Gastroenterology 1990;98:708-714,
Complement Deposits in Inflammatory Bowel Disease Dear Sir: I read with interest the article by Halstensen et al. (11in which the authors show immunohistochemical evidence of complement activation in submucosal blood vessels of active inflammatory bowel disease (IBD). It is interesting to note that 10 of the 13 patients studied had extraintestinal manifestations and that C3c% was particularly high in patients with arthritis or cutaneous lesions. By using paraffin-embedded sections of colonic specimens and synovial and skin biopsy specimens of patients with IBD, I also found deposits of both IgG and C3 around intestinal vessels. Moreover, in two skin biopsy specimens of erythema nodosum and in two synovial biopsy samples I observed C3 positivity in blood vessels (2). I agree with the authors that continuous complement activation in IBD lesions is presumably related to local immune complex formation. I feel this may be of considerable immunopathogenic interest, particularly in colitis-related systemic complications of IBD. TAVARELAVELOSO Unidade de Gastroenterologia Faculdade de Medicina Hospital de S. Joao 4200 Porto, Portugal Halstensen TS, Mollnes TE, Brandtzaeg P. Persistent complement activation in submucosal blood vessels of active inflammatory bowel disease: immunohistochemical evidence. Gastroenterology 1989;97:10-19. Tavarela Veloso F, Vaz AL, Saleiro JV. Carvalho J. Immunological studies in patients with Crohn’s disease associated with arthritis and erythema nodosum (abstr). Stand J Gastroenterol 1989;24(Suppl 158):174. Reply.
The letter from Dr. Veloso raises the interesting possibility that extraintestinal manifestations of IBD are associated with vascular complement activation and are therefore perhaps immune complex mediated. The finding of vascular IgG and C3 deposition in two skin biopsy samples from erythema nodosum and in two of seven synovial biopsy specimens from arthritis, all from patients with Crohn’s disease, was taken to suggest such an immunopathogenie mechanism. However, when immunohistochemical staining for serum proteins such as IgG and C3 are performed on sections of directly fixed and paraffin-embedded tissue it is difficult to ascertain that the positivity obtained indeed represents immunologically bound components rather than a retained inflammatory exudate (1). Moreover, antisera most often used to detect C3 react with both the activated and native proteins. To overcome this problem, one may either use extensively prewashed tissue specimens from which most soluble extracellular proteins (IgG and C3) have been extracted (2) or. alternatively, a monoclonal antibody (MoAb) to a C3b activation neoepitope (3). Unfortunately, such MoAbs are seldom reactive on formalin-fixed and paraffin-embedded tissue sections. Dr. Veloso found immunohistochemical reactivity for IgG and C3 around intestinal vessels in IBD (4). For reasons explained above, this finding is difficult to interpret. We have performed immunohistochemical examination of multiple extensively prewashed mucosal
GASTROENTEROLOGY
is because they only studied four patients with secondary peritonitis compared with our 15 patients. In summary, it seems that this algorithm is valid in differentiating patients with SBP from those with secondary peritonitis in more than one patient population on more than one continent. Perhaps it should be used for this purpose everywhere. B.A. RUNYON. M.D.
University of Southern California Liver Unit Downey, California 1. Akriviadis EA, Runyon BA. The utility of an algorithm in differentiating spontaneous from secondary peritonitis. Gastroenterology 1990;98:127-133.
Hemodynamic Infusion
Status During Famotidine
Dear Sir: We read with great interest the article by Kirch et al. (1) on the possible interaction of famotidine and nifedipine in noninvasive parameters of cardiac performance. While impedance cardiography, electrocardiog raphy, and phonocardiography may be used for the noninvasive measurement of cardiac performance, they each have large inherent problems of inaccuracy and error. We performed an invasive, double-blind, placebo-controlled study of eleven critically ill but hemodynamically stable intensive care patients who were receiving famotidine. Measurements were performed via a Swan-Ganz catheter and an intraarterial line after a 2-minute bolus injection of either famotidine or placebo at l-. 3-. 5-, and lo-minute intervals. Parameters measured included cardiac output, cardiac index, left and right ventricular stroke work indexes, mean arterial pressure, heart rate, pulmonary capillary wedge pressure, right atria1 pressure, and pulmonary arterial pressure. Using analysis of variance (P < 0.05), no clinical or statistically significant change was noted in any of the invasively measured or calculated parameters of cardiac performance (submitted for publication). In addition, Omote et al. (2) compared hemodynamic parameters of intensive care patients receiving cimetidine. ranitidine. and famotidine and found no significant change in hemodynamics with the use of famotidine. Ohnishi et al. (3) studied hepatic hemodynamits in 20 patients with peptic ulcers and chronic liver disease. These invasive studies showed no changes in portal or hepatic blood flow, cardiac output, or gradient between wedged hepatic vein pressure and free hepatic vein pressure. In conclusion, famotidine seems to show no significant changes in hemodynamics measured by invasive techniques of cardiac performance. This lack of change was confirmed in critically ill patients who would have had the most risk of hemodynamic instability. DARELL E. HEISELMAN. D.O. MARK MALIK. M.D. LYNN J. WHITE, MS.
Department of Critical Care Medicine Akron General Medical Center 400 Wabash Avenue Akron, Ohio 44307 1. Kirch W, Halabi A, Linde M, Santos SR. Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 1989:96: 1388-1392. 2. Omote K, Namiki A, Sumita S, Takahashi T, Ujike Y, Hagiwara T. Comparative studies on hemodynamic effects of intravenous cimetidine, ranitidine and famotidine in intensive care unit patients. Masui 1987;36:940-947.
Vol. 99, No. 5
3. Ohnishi K, Saito M, Normura F. Okuda K, Suzuki N, Ohtsuki T, Goto N, Takashi M. Effect of famotidine on hepatic hemodynamits and peptic ulcer. Am ] Gastroenterol1987;82:415-418. Reply. It is questionable to determine hemodynamic effects of famotidine in patients in an intensive care unit because these critically ill subjects are mostly under concurrent treatment with various drugs, e.g., positive inotropic substances such as dopamine or dobutamine (1). This was the case in the studies of Omote et al. and Matsukawa et al. (2,3), who invasively investigated hemodynamic parameters following IV administration of famotidine in these patients. The study presented by Heiselmann et al. lacks any information on concurrent treatment of the critically ill patients to whom famotidine was administered. Furthermore, because of the circumstances of an intensive care unit, patients are under maximum sympathomimetic stimulation. This additionally leads to alteration of the results of hemodynamic measurements. Both invasive and noninvasive techniques for the measurement of cardiac performance have disadvantages with inherent problems of inaccuracy and errors. These largely depend on the investigator’s experience and on the conditions under which the subjects are studied. Thus, in our opinion, hemodynamic data found with famotidine are not dependent on the measurement of invasive or noninvasive methods but rather on the study design used. Thus, in conclusion, most probably the circumstances under which patients were investigated are responsible (critically ill patients of an intensive care unit) for the results found by Heiselman et al. and the Japanese groups (2,3). Finally, one should be aware that HZ-antagonists have been shown to exert negative inotropic effects also in vitro (4). whereas famotidine at higher concentrations causes an unsurmountable HZ-receptor antagonism 151. W. KIRCH A. HALABI H. HINRICHSEN
Christian-Albrechts-Universitiit Schittenhelmstrasse 12 D-2300 Kiel, Federal Republic of Germany 1. Kirch W, Halabi A, Linde M, Santos SR, Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 1989;96: 1388-1392.
2. Omote K, Namiki A, Sumita S, Takahashi T, Ujike Y, Hagiwara T. Comparative studies on hemodynamic effects of intravenous cimetidine, ranitidine, and famotidine in intensive care unit patients. Masui 1987;36:940-947. 3. Matsukawa S, Hoshi K. Kaise A, Sasaki I, Hashimoto Y, Amaha K. The cardiovascular effect of famotidine in intensive care patients. J Intensive Care Med 1986;10:763-767. 4. Bertaccini G. Coruzzi G, Poli E, Adami M. Pharmacology of the novel HZ-antagonist famotidine: in vitro studies. Agents Actions 1986:19:180-187, 5. Pendleton RG, Torchiama ML, Chung C. Cook P, Wiese S, Clineschmidt BV. Studies on MK-208 (YM-11170) a new slowly dissociable HZ-receptor antagonist. Arch Int Pharmacodyn Ther 1983;266:4-16.
Geopathology
of Early Gastric Cancer
Dear Sir: Eckardt et al. (1) report their experience with early gastric cancer (EGC] in Germany. They showed a 21.2% incidence of EGC and an 83.4% crude 5-year survival rate. This survival rate was comparable to a group of patients with benign gastric ulcers. They point out that
November
CORRESPONDENCE
1990
EGC may be underestimated in Western countries and that 5-year survival rates do not reach those reported for Japanese patients. We have, however, reported a series of patients with EGC treated at Columbia Presbyterian Medical Center in New York [2) in whom we showed a >97% 5-year survival rate (age-adjusted). Thisgroup of patients in fact have a survival rate comparable to the U.S. population (1980 census]. This survival rate is comparable to the age-adjusted 5-year survival rate of Japanese patients with EGC (3). This is the survival rate in our patients despite the presence of lymph node involvement in 28%. We have also noted an increasing incidence with an annual incidence approaching 30% of resections for gastric cancer. Early gastric cancer in the U.S. resembles that found in Japan in every way (morphology, clinical presentation, and curability]. The maJor difference lies in the fact that the concept of early gastric cancer is not widely appreciated by endoscopists or surgeons in this country. PETER H. R. GREEN, M.D. K. M. O’TOOLE,M.D. D. SLONIM Departments of Medicine and Pathology Columbia Presbyterian Medical Center New York, New York 10032 Eckardt V, GieBler W, Kanzler G, Remmele W, Bernhard G. Clinical and morphological characteristics of early gastric cancer. A case-control study. Gastroenterology 1990;98:708-714. Green PHR, O’Toole KM, Slonim D, Wang T, Weg A. Increasing incidence and excellent survival of patients with early gastric cancer: experience in a United States medical center. Am J Med 1988;85:658-661. Kidoro T. Frequency of resection, metastases and five year survival rate of early gastric cancer in a surgical clinic. Jpn J Cancer Res 1971;11:45-49. Reply.
Although we have cited the work of Dr. Green et al. (1.2) repeatedly in our recent manuscript (3). we would like to reemphasize that some of their data parallel our own findings. However, we also believe that several important differences exist. First, while previous investigations including those by Green et al. stem from tertiary referral centers, our investigation was performed in a gastroenterological group practice that serves as a primary referral center. Second, in contrast to Green’s investigations, our study did not concern only patients undergoing resections for gastric cancer but all patients with an endoscopic diagnosis for this disease. If we extrapolate our data to patients with resectable lesions, the prevalence of EGC would be 29%. which is more than double the figure reported by Green et al. Furthermore, in contrast to Dr. Green’s observation, we did not observe an increasing incidence of early gastric cancer during more recent years (1977-1981, 21%; 1982-1986. 23%], indicating that the changing frequency of EGC may be a factor that is more physician related than patient related. Finally, the fact that lymph node metastases in EGC patients were five times commoner in the American study (2) agrees with our belief that patients reported from tertiary referral centers present with a later stage of their disease. Despite these differences in the studies from two continents, we totally agree with the conclusions of Green et al. that the concept of EGC is still not sufficiently appreciated in the Western world. We even believe that a frequency of EGC that is well below 20% indicates delayed and/or inaccurate diagnosis. VOLKERF. ECKARDT Gastroenterologisches Institut Wiesbaden, Federal Republic of Germany 1. Green PHR, O’Toole KM, Weinberg LM. Goldfarb gastric cancer. Gastroenterology 1981:81:247-256.
JP. Early
1541
Green PHR, O’Toole KM, Slonim D, Wang T, Weg A. Increasing incidence and excellent survival of patients with early gastric cancer: experience in a United States medical center. Am J Med 1988;85:658-661. Eckardt VF, GieBler W, Kanzler G, Remmele W, Bernhard G. Clinical and morphological characteristics of early gastric cancer. Gastroenterology 1990;98:708-714,
Complement Deposits in Inflammatory Bowel Disease Dear Sir: I read with interest the article by Halstensen et al. (11in which the authors show immunohistochemical evidence of complement activation in submucosal blood vessels of active inflammatory bowel disease (IBD). It is interesting to note that 10 of the 13 patients studied had extraintestinal manifestations and that C3c% was particularly high in patients with arthritis or cutaneous lesions. By using paraffin-embedded sections of colonic specimens and synovial and skin biopsy specimens of patients with IBD, I also found deposits of both IgG and C3 around intestinal vessels. Moreover, in two skin biopsy specimens of erythema nodosum and in two synovial biopsy samples I observed C3 positivity in blood vessels (2). I agree with the authors that continuous complement activation in IBD lesions is presumably related to local immune complex formation. I feel this may be of considerable immunopathogenic interest, particularly in colitis-related systemic complications of IBD. TAVARELAVELOSO Unidade de Gastroenterologia Faculdade de Medicina Hospital de S. Joao 4200 Porto, Portugal Halstensen TS, Mollnes TE, Brandtzaeg P. Persistent complement activation in submucosal blood vessels of active inflammatory bowel disease: immunohistochemical evidence. Gastroenterology 1989;97:10-19. Tavarela Veloso F, Vaz AL, Saleiro JV. Carvalho J. Immunological studies in patients with Crohn’s disease associated with arthritis and erythema nodosum (abstr). Stand J Gastroenterol 1989;24(Suppl 158):174. Reply.
The letter from Dr. Veloso raises the interesting possibility that extraintestinal manifestations of IBD are associated with vascular complement activation and are therefore perhaps immune complex mediated. The finding of vascular IgG and C3 deposition in two skin biopsy samples from erythema nodosum and in two of seven synovial biopsy specimens from arthritis, all from patients with Crohn’s disease, was taken to suggest such an immunopathogenie mechanism. However, when immunohistochemical staining for serum proteins such as IgG and C3 are performed on sections of directly fixed and paraffin-embedded tissue it is difficult to ascertain that the positivity obtained indeed represents immunologically bound components rather than a retained inflammatory exudate (1). Moreover, antisera most often used to detect C3 react with both the activated and native proteins. To overcome this problem, one may either use extensively prewashed tissue specimens from which most soluble extracellular proteins (IgG and C3) have been extracted (2) or. alternatively, a monoclonal antibody (MoAb) to a C3b activation neoepitope (3). Unfortunately, such MoAbs are seldom reactive on formalin-fixed and paraffin-embedded tissue sections. Dr. Veloso found immunohistochemical reactivity for IgG and C3 around intestinal vessels in IBD (4). For reasons explained above, this finding is difficult to interpret. We have performed immunohistochemical examination of multiple extensively prewashed mucosal
