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Lactulose in the Treatment of Portal-Systemic Encephalopathy
595
COMMENTS
April 1970
7. Capper, W . M., G. R. Airth, and J. O. Kilby. 1966. A test for pyloric regurgitation. Lancel 2: 621. 8. Buckler, K. G. 1967. Effects of gastric surgery upon gastric emptying in cases of peptic ulceration. Gut 8: 137. 9. Wastell, C., P. Aylett, and 1. Wise. 1969. Gastric secretion and emptying before and
after vagotomy and pyloroplasty with and without continuous infusion of peptavlon pentagastrin. Amer. J . Dig. Dis. 14: 245. 10. Du Plessus, D. J. 1969. Alkaline reflux gastritis, p. 124-137. In H. N. Harkins and L. M. Nyhus [eds.], Surgery of the stomach and duodenum, Ed. 2. Little, Brown & Company, Boston.
LACTULOSE IN THE TREATMENT OF PORTAL-SYSTEMIC ENCEPHALOPATHY Report of a symposium
Under the chairmanship of U. P. Haemmerli (Zurich), investigators from 12 countries met at Baden near Vienna on September 8, 1969, for a working session on predominantly unpublished experiences with lactulose. Basic Action
H. Haenel (Potsdam) reported that the disaccharide lactulose (a keto analogue of lactose, 1,4-j]-galactosido-fructose) is not hydrolyzed by the small intestinal mucosa of man, rat, rabbit, and cattle. Less than 0.4% is absorbed and excreted in the urine. In the colon lactulose is broken down by lactobacilli, bacterioids, and Escherichia coli, but not by Proteus mirabilis and Streptococcus faecalis. The lactic acid produced by this breakdown of lactulose leads to a lowering of fecal pH and stimulates the growth of lactobacilli with a decrease in that of bacteroids. D. Muting (Homburg/Saar) found that addition of lactulose to cultures of E . coli and Proteus decreased the formation of ammonia and free phenols. A small portion of lactulose is probably hydrolized in the colon into its constituent monosaccharides, galactose and fructose, as evidenced by observation of A. Charbonnier (Paris) that galactosuria still occurred 4 to 8 hI' after lactulose administration. U. P. Haemmerli (Zurich) described the introduction of lactulose into the treatment of chronic hepatic encephalopathy in 1966 and pointed out that lactulose ingestion induced an artificial disaccharide malabsorption syndrome and, when given
in sufficient doses, led to a watery acid diarrhea. The osmotic effect of lactulose breakdown products in the colon was verified radiologically by S. Pertsiounis (Berne), who calculated an average increase in colon volume of about 400 ml 90 min after 20 g of lactulose. In a carefully controlled study, W. R. Ebert (Weesp, Nederland) noticed that the daily dose necessary to achieve about one soft bowel movement per day in constipated subjects varied between 15 and 30 m!. Clinical Evaluation
S. G. Elkington (West Haven, Connecticut ) treated 7 patients with chronic portal system encephalopathy in a double blind study and noted clinical improvement in 5 instances. Simultaneously lowered fecal pH and arterial ammonia values were observed. G. Rorsman (Eksjo) quantitated alterations in the electroencephalograph by plotting wavelength frequency diagrams. In each of 3 patients, significant improvement occurred during lactulose administration, although the frequency curves did not revert completely to a normal shape. One of the most detailed studies was described by R. Zeegen (London). In addition to daily stool frequency and weight, bacteriological examination of the stool, and arterial and venous blood ammonia, they had applied a method for quantitative psychometric testing, which appeared particularly suitable for the serial evaluation of patients with chronic encephalopathy. When analyzed by the cumulative sum technique, they found a
596
COMMENTS
significant clinical response in 3 of 7 patients and a tendency toward Improvement in 2 of the nonresponders. The difference in response remained unexplained; stool frequency and weight were comparable in responders and nonresponders. One of the nonresponders improved when given neomycin. Two long term results were satisfactory for 17 and 24 months. During the ensuing discussion, M. Helms (Freiburgh i. Br.) showed significant improvement of portal systemic encephalopathy in 2 of 10 patients on lactulose and J. Bircher (Zurich) reported clinically convincing improvements in 6 patients who had remained in a steady state during the various trial periods. H. Brown (Boston, Massachusetts) described a double blind trial in 4 patients with cirrhosis and a portacaval shunt which comprised a total of 25 months of lactulose and 15 months of placebo treatment with sorbitol. All patients were relatively well on lactulose. On sorbitol, 1 remained well, 2 did poorly, and 1 died before it was started. B. Combes (Dallas, Texas) evaluated long term protein tolerance in portal systemic encephalopathy and showed an increase in certain patients when lactulose was given for long periods, although sorbitol should, on occasions, be equally effective. L. Demeulenaere (Gent) treated acute episodes of portal systemic encephalopathy by retention enemas (300 ml of lactulose syrup and 700 ml of water retained for 1 hr), repeated, if necessary, three times. Dramatic improvement in the level of consciousness, in the electroencephalogram changes, and in the hyperammonemia occurred often within hours. The improvement was too rapid to be a consequence of the breakdown of lactulose and might be related to rapid acidification of colonic contents from the syrup which had a pH of 3.8. H. Siebner (Hamburg) successfully treated 5 patients with acute coma by 111tragastric administration of lactulose. Mechanism of Effect
H. Haenel (Potsdam) showed that untreated patients with cirrhosis had, com-
Vol. 58, No.4
pared with the healthy population, an increase in total anaerobic organisms, E. coli, Proteus, aerobic lactobacilli, and streptococci, with a definite decrease of Lactobacillus bifidus. D. Muting found an increased growth of lactobacilli and decrease of E. coli and Proteus vulgaris in cirrhotic patients treated with lactulose. The effect on coma was best when the reduction in blood ammonia and free serum phenols was most marked. H. O. Conn (West Haven, Connecticut) could find no significant change in the bacteriological flora of the stools of cirrhotic patients treated with lactulose, despite significant clinical improvement, and neither could' R. Zeegen (London). J. Bircher (Zurich) showed that some unselected hQspital patients with various disorders had significantly decreased fecal pH, total bacterial counts, E. coli and bacteroids under lactulose treatment, although lactobacilli increased only proportionally. Fecal ammonia levels remained unchanged. In cirrhotic subj ects clinical improvement of encephalopathy occurred 7 to 20 days before the bacteriological changes were well established and lactulose could be effective even in patients without lactobacilli in the stools after previous neomycin therapy. U. Gmunder (Zurich) could not find a decrease in colonic bacterial urease activity in rats pretreated with lactulose. Thus, even though unanimity on bacteriological findings was not reached, it was felt that changes in fecal flora could not account for the clinical effects of lactulose. O. H. Braun (Pforzheim) observed increased lysozyme excretion in children treated with lactulose, an effect which was independent of changes in fecal flora. L. Demeulenaere (Gent) gave 100 mEq of NH 4 CI intravenously over 1 hr to 10 patients with cirrhosis before and after lactulose therapy. Electroencephalogram changes were less marked after lactulose and blood ammonia rose to only about 60% of values in the control periods. This suggested increased clearance of ammonia and not decreased absorption. J. Bircher (Berne) studied ammonia absorption in the dog colon, assuming non ionic diffusion and, therefore, dependence upon luminal pH.
Llpril 1970
COMMENTS
Under control conditions, ammonia transport occurred from the lumen to the blood. Acidification of colonic contents to below pH 6 resulted in movement of ammonia from the blood to the lumen. Finally, M. Knoblauch (Zurich) reported that the trisaccharide raffinose was equally effective as lactulose in 1 patient with chronic coma. During a concluding discussion with a panel of J. P. Benhamou (Paris), L. Chiandussi (Torino), J. De Groote (Leuven), W. H. J. Summerskill (Rochester, Minnesota), N. Tygstrup (Copenhagen), and Roger Williams (London), the following were agreed upon: 1. Lactulose therapy did have a beneficial effect in some cases of chronic portosystemic encephalopathy. The nonresponders were, in general, mild cases and a good response usually was obtained in patients with encephalopathy following a portacaval shunt.
597
2. The dose needed had to be adjusted carefully in each individual to avoid diarrhea and varied from 30 to 120 ml daily. Two to three soft bowel motions, with a stool pH of 5.5 or less (checked with pH paper) , should be the aim. 3. Independent of minor bacteriological changes, the most likely mechanism of action is a decreased ammonia absorption and increased NHa excretion in the colon. Other substances with a high pk, such as amines, may be similarly affected. J. BIRCHER, M.D. Institut fur klinische Pharmakologie, Universitiit Bern, Switzerland U. P. HAEMMERLI, M.D. Stadtspital Triemli, Zurich, Switzerland ROGER WILLIAMS, M.D. King's College Hospital London, England
CRITIQUE OF TESTS OF MAXIMAL GASTRIC ACID SECRETION INCLUDING INSULIN Kayl was the first to propose a maximal gastric secretory test on a dose per weight basis using histamine as the stimulant. In his test, 0.04 mg of histamine acid phosphate per kilogram of body weight produced a maximal gastric acid response in normal and duodenal ulcer patients over a wide range of resultant HCI values. An antihistaminic was used to prevent histamine reactions. Several assumptions underlie such determinations of a maximal response on a dose per weight basis, the first being that organ size is proportional to the lean body mass. For the stomach, this also assumes that the parietal cell mass (PCM) in a homogenous group of subjects, e.g., normals, is proportional to body weight. Therefore, the PCM should be approximately equal in size in normal subjects of equal weight. Such tests assume that the PCM is functionally and anatomically stable and also that the agent used acts as a pure stimulant and never a depressant. Let us examine some of these assump-
tions. In human subjects, it is very unlikely that gross stomach size (area and volume) is related to body weight and this is even less true of the PCM.2 Endoscopic experience clearly demonstrates that it is not. Within all weight groups and age groups, one encounters normal mucosa, mucosal atrophy, and a hypertrophic hypersecretory mucosa 3 ,4 and, consequently, PCM varies widely in human subj ects. Yet, according to Kay the same dose by weight (0.04 mg per kg) of histamine produces a maximal response over this wide range of PCM sIze. Two recent studies from India are pertinent to this problem. Goyal et a1. 5 reported that there was no correlation between body weight and acid secretion under basal condition.> and after maximal histamine stimulation. Stated simply this means that large people did not necessarily produce more acid than smaller people on a maximal test on a dose-weight basis. Another study by Desai and co-workers 6 demonstrated that in subjects weighing less than
COMMENTS
April 1970
7. Capper, W . M., G. R. Airth, and J. O. Kilby. 1966. A test for pyloric regurgitation. Lancel 2: 621. 8. Buckler, K. G. 1967. Effects of gastric surgery upon gastric emptying in cases of peptic ulceration. Gut 8: 137. 9. Wastell, C., P. Aylett, and 1. Wise. 1969. Gastric secretion and emptying before and
after vagotomy and pyloroplasty with and without continuous infusion of peptavlon pentagastrin. Amer. J . Dig. Dis. 14: 245. 10. Du Plessus, D. J. 1969. Alkaline reflux gastritis, p. 124-137. In H. N. Harkins and L. M. Nyhus [eds.], Surgery of the stomach and duodenum, Ed. 2. Little, Brown & Company, Boston.
LACTULOSE IN THE TREATMENT OF PORTAL-SYSTEMIC ENCEPHALOPATHY Report of a symposium
Under the chairmanship of U. P. Haemmerli (Zurich), investigators from 12 countries met at Baden near Vienna on September 8, 1969, for a working session on predominantly unpublished experiences with lactulose. Basic Action
H. Haenel (Potsdam) reported that the disaccharide lactulose (a keto analogue of lactose, 1,4-j]-galactosido-fructose) is not hydrolyzed by the small intestinal mucosa of man, rat, rabbit, and cattle. Less than 0.4% is absorbed and excreted in the urine. In the colon lactulose is broken down by lactobacilli, bacterioids, and Escherichia coli, but not by Proteus mirabilis and Streptococcus faecalis. The lactic acid produced by this breakdown of lactulose leads to a lowering of fecal pH and stimulates the growth of lactobacilli with a decrease in that of bacteroids. D. Muting (Homburg/Saar) found that addition of lactulose to cultures of E . coli and Proteus decreased the formation of ammonia and free phenols. A small portion of lactulose is probably hydrolized in the colon into its constituent monosaccharides, galactose and fructose, as evidenced by observation of A. Charbonnier (Paris) that galactosuria still occurred 4 to 8 hI' after lactulose administration. U. P. Haemmerli (Zurich) described the introduction of lactulose into the treatment of chronic hepatic encephalopathy in 1966 and pointed out that lactulose ingestion induced an artificial disaccharide malabsorption syndrome and, when given
in sufficient doses, led to a watery acid diarrhea. The osmotic effect of lactulose breakdown products in the colon was verified radiologically by S. Pertsiounis (Berne), who calculated an average increase in colon volume of about 400 ml 90 min after 20 g of lactulose. In a carefully controlled study, W. R. Ebert (Weesp, Nederland) noticed that the daily dose necessary to achieve about one soft bowel movement per day in constipated subjects varied between 15 and 30 m!. Clinical Evaluation
S. G. Elkington (West Haven, Connecticut ) treated 7 patients with chronic portal system encephalopathy in a double blind study and noted clinical improvement in 5 instances. Simultaneously lowered fecal pH and arterial ammonia values were observed. G. Rorsman (Eksjo) quantitated alterations in the electroencephalograph by plotting wavelength frequency diagrams. In each of 3 patients, significant improvement occurred during lactulose administration, although the frequency curves did not revert completely to a normal shape. One of the most detailed studies was described by R. Zeegen (London). In addition to daily stool frequency and weight, bacteriological examination of the stool, and arterial and venous blood ammonia, they had applied a method for quantitative psychometric testing, which appeared particularly suitable for the serial evaluation of patients with chronic encephalopathy. When analyzed by the cumulative sum technique, they found a
596
COMMENTS
significant clinical response in 3 of 7 patients and a tendency toward Improvement in 2 of the nonresponders. The difference in response remained unexplained; stool frequency and weight were comparable in responders and nonresponders. One of the nonresponders improved when given neomycin. Two long term results were satisfactory for 17 and 24 months. During the ensuing discussion, M. Helms (Freiburgh i. Br.) showed significant improvement of portal systemic encephalopathy in 2 of 10 patients on lactulose and J. Bircher (Zurich) reported clinically convincing improvements in 6 patients who had remained in a steady state during the various trial periods. H. Brown (Boston, Massachusetts) described a double blind trial in 4 patients with cirrhosis and a portacaval shunt which comprised a total of 25 months of lactulose and 15 months of placebo treatment with sorbitol. All patients were relatively well on lactulose. On sorbitol, 1 remained well, 2 did poorly, and 1 died before it was started. B. Combes (Dallas, Texas) evaluated long term protein tolerance in portal systemic encephalopathy and showed an increase in certain patients when lactulose was given for long periods, although sorbitol should, on occasions, be equally effective. L. Demeulenaere (Gent) treated acute episodes of portal systemic encephalopathy by retention enemas (300 ml of lactulose syrup and 700 ml of water retained for 1 hr), repeated, if necessary, three times. Dramatic improvement in the level of consciousness, in the electroencephalogram changes, and in the hyperammonemia occurred often within hours. The improvement was too rapid to be a consequence of the breakdown of lactulose and might be related to rapid acidification of colonic contents from the syrup which had a pH of 3.8. H. Siebner (Hamburg) successfully treated 5 patients with acute coma by 111tragastric administration of lactulose. Mechanism of Effect
H. Haenel (Potsdam) showed that untreated patients with cirrhosis had, com-
Vol. 58, No.4
pared with the healthy population, an increase in total anaerobic organisms, E. coli, Proteus, aerobic lactobacilli, and streptococci, with a definite decrease of Lactobacillus bifidus. D. Muting found an increased growth of lactobacilli and decrease of E. coli and Proteus vulgaris in cirrhotic patients treated with lactulose. The effect on coma was best when the reduction in blood ammonia and free serum phenols was most marked. H. O. Conn (West Haven, Connecticut) could find no significant change in the bacteriological flora of the stools of cirrhotic patients treated with lactulose, despite significant clinical improvement, and neither could' R. Zeegen (London). J. Bircher (Zurich) showed that some unselected hQspital patients with various disorders had significantly decreased fecal pH, total bacterial counts, E. coli and bacteroids under lactulose treatment, although lactobacilli increased only proportionally. Fecal ammonia levels remained unchanged. In cirrhotic subj ects clinical improvement of encephalopathy occurred 7 to 20 days before the bacteriological changes were well established and lactulose could be effective even in patients without lactobacilli in the stools after previous neomycin therapy. U. Gmunder (Zurich) could not find a decrease in colonic bacterial urease activity in rats pretreated with lactulose. Thus, even though unanimity on bacteriological findings was not reached, it was felt that changes in fecal flora could not account for the clinical effects of lactulose. O. H. Braun (Pforzheim) observed increased lysozyme excretion in children treated with lactulose, an effect which was independent of changes in fecal flora. L. Demeulenaere (Gent) gave 100 mEq of NH 4 CI intravenously over 1 hr to 10 patients with cirrhosis before and after lactulose therapy. Electroencephalogram changes were less marked after lactulose and blood ammonia rose to only about 60% of values in the control periods. This suggested increased clearance of ammonia and not decreased absorption. J. Bircher (Berne) studied ammonia absorption in the dog colon, assuming non ionic diffusion and, therefore, dependence upon luminal pH.
Llpril 1970
COMMENTS
Under control conditions, ammonia transport occurred from the lumen to the blood. Acidification of colonic contents to below pH 6 resulted in movement of ammonia from the blood to the lumen. Finally, M. Knoblauch (Zurich) reported that the trisaccharide raffinose was equally effective as lactulose in 1 patient with chronic coma. During a concluding discussion with a panel of J. P. Benhamou (Paris), L. Chiandussi (Torino), J. De Groote (Leuven), W. H. J. Summerskill (Rochester, Minnesota), N. Tygstrup (Copenhagen), and Roger Williams (London), the following were agreed upon: 1. Lactulose therapy did have a beneficial effect in some cases of chronic portosystemic encephalopathy. The nonresponders were, in general, mild cases and a good response usually was obtained in patients with encephalopathy following a portacaval shunt.
597
2. The dose needed had to be adjusted carefully in each individual to avoid diarrhea and varied from 30 to 120 ml daily. Two to three soft bowel motions, with a stool pH of 5.5 or less (checked with pH paper) , should be the aim. 3. Independent of minor bacteriological changes, the most likely mechanism of action is a decreased ammonia absorption and increased NHa excretion in the colon. Other substances with a high pk, such as amines, may be similarly affected. J. BIRCHER, M.D. Institut fur klinische Pharmakologie, Universitiit Bern, Switzerland U. P. HAEMMERLI, M.D. Stadtspital Triemli, Zurich, Switzerland ROGER WILLIAMS, M.D. King's College Hospital London, England
CRITIQUE OF TESTS OF MAXIMAL GASTRIC ACID SECRETION INCLUDING INSULIN Kayl was the first to propose a maximal gastric secretory test on a dose per weight basis using histamine as the stimulant. In his test, 0.04 mg of histamine acid phosphate per kilogram of body weight produced a maximal gastric acid response in normal and duodenal ulcer patients over a wide range of resultant HCI values. An antihistaminic was used to prevent histamine reactions. Several assumptions underlie such determinations of a maximal response on a dose per weight basis, the first being that organ size is proportional to the lean body mass. For the stomach, this also assumes that the parietal cell mass (PCM) in a homogenous group of subjects, e.g., normals, is proportional to body weight. Therefore, the PCM should be approximately equal in size in normal subjects of equal weight. Such tests assume that the PCM is functionally and anatomically stable and also that the agent used acts as a pure stimulant and never a depressant. Let us examine some of these assump-
tions. In human subjects, it is very unlikely that gross stomach size (area and volume) is related to body weight and this is even less true of the PCM.2 Endoscopic experience clearly demonstrates that it is not. Within all weight groups and age groups, one encounters normal mucosa, mucosal atrophy, and a hypertrophic hypersecretory mucosa 3 ,4 and, consequently, PCM varies widely in human subj ects. Yet, according to Kay the same dose by weight (0.04 mg per kg) of histamine produces a maximal response over this wide range of PCM sIze. Two recent studies from India are pertinent to this problem. Goyal et a1. 5 reported that there was no correlation between body weight and acid secretion under basal condition.> and after maximal histamine stimulation. Stated simply this means that large people did not necessarily produce more acid than smaller people on a maximal test on a dose-weight basis. Another study by Desai and co-workers 6 demonstrated that in subjects weighing less than