- Email: [email protected]
AGE-DISTRIBUTIONS OF MENINGOCOCCAL DISEASE AS PREDICTOR OF EPIDEMICS
1039
Letters
to
EARLIER HAEMOPERFUSION IN FULMINANT HEPATIC FAILURE
SIR,-After reading the paper from the King’s College Hospital liver unit in your issue of Sept. 25 I was left with a mixture of enthusiasm and concern. My concern is that many centres may prematurely adopt this charcoal haemoperfusion method for routine treatment offulminant hepatic failure (FHF), as happened a few years ago. Our reports in 1972 that haemoperfusion resulted in the temporary recovery of consciousness of grade IV hepatic coma patients were followed two years later by the report of Dr Williams’ group at King’s3of the efficacy of this approach for the treatment of grade IV FHF. Before further detailed clinical and laboratory research was done, the technique was taken up by many centres for the routine treatment of grade iv FHF. The results, to say the least, were confusing, especially when Williams’ team could not reproduce their clinical results because of the blood incompatibility of the haemoperfusion .device they used in their later studies. In the past five years we have tried to resolve this confusion by detailed laboratory research on galactosamine induced FHF in rats.4-7 Initial results showed that haemoperfusion significantly improved the survival rate from 30% to 70%.4 It seems that an increase in survival rate was possible only if haemoperfusions were done early on in hepatic coma, and more detailed studies with controls and different treatment regimens6,7 confirmed this. Our results in FHF rats are now supported by the clinical trial described by Gimson et al. Even so the following points should be borne in mind: (1) Drug induced FHF due to galactosamine in rats4-7 and paracetamol (acetaminophen) in man may be similar-indeed laboratory5-7 and, now, clinical results support the possible use of earlier haemoperfusion in drug induced FHF, especially since the King’s group studied 23 cases of grade III FHF and 23 cases of grade IV FHF. However, only 6 cases of grade III viral FHF were treated by earlier haemoperfusion, and much more clinical work is needed before any conclusion can be made about this treatment’s value in viral FHF. (2) Gimson et al. infused epoprostenol (prostacyclin) to prevent blood incompatibility due to their haemoperfusion device. Since prostacyclin infusion may have its own side-effects, it should be emphasised that other, more blood compatible, haemoperfusion devices are available which do not require prostacyclin infusion. (3) The effect of prostacyclin itself on the course ofFHF should be studied. Prostaglandin E2, though very different from prostacyclin, increases survival rates in FHF rats.8 Despite the promising results obtained so far, more clinical research should be done before earlier haemoperfusion can be considered as a routine treatment for FHF, especially for viral FHF.
comlete
Artficial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Quebec, Canada H3G 1Y6
AGE-DISTRIBUTIONS OF MENINGOCOCCAL DISEASE AS PREDICTOR OF EPIDEMICS
the Editor
T. M. S. CHANG
1. Chang TMS
Haemoperfusions over microencapsulated adsorbent in a patient with hepatic coma. Lancet 1972; ii: 1371-72. 2. Chang TMS, Migchelsen M Characterization of possible ’toxic’ metabolitesin uremia and hepatic coma based on the clearance spectrum for larger molecules by the ACAC microcapsule artificial kidney Trans Am Soc Artif Intern Organs 1973; 19: 314-19. 3 Gazzard BG, Weston MJ, Murray-Lyon, IM, Filax H, Record CO, Portman B, Langley, Dunlop EH, Mellon PJ, Ward MD, Williams R. Charcoal haemoperfusion in the treatment of fulminant hepatic failure Lancet 1974; i: 1301. 4. Chirito E. Reiter B, Lister C, Chang TMS, Artificial liver: the effect of ACAC microencapsulated charcoal hemoperfusion on fulminant hepatic failure. Artif Organs 1977; 1: 76-83. 5. Chang TMS, Lister C, Chirito E, O’Keefe P, Resurrection E. Effects of hemoperfusion rate and time of initiation of ACAC charcoal hemoperfusion on the survival of fulminant hepatic failure rats. Trans Am Soc Artif Intern Organs 1978; 24: 243-45.
Tabata Y, Chang TMS. Comparisons of six artificial liver support regimes in fulminant hepatic coma rats. Trans Am Soc Artif Inter Organs 1980; 26: 394-99. 7. Chang TMS. Hemoperfusion, exchange transfusion, cross circulation, liver perfusion, 6.
hormones and immobilized enzymes. In: Brunner G, Schmidt FW, eds. Artificial liver support. Berlin; Springer-Verlag, 1981; 126-33. 8 Dixit V, Chang TMS. The effects of prostaglandin E3 on the survival of fulminant hepatic failure rats. Int J Artif Organs (in press).
SIR,-Dr Peltola and colleagues (Sept. 11, p. 595) analysed the age-distribution of meningococcal disease in Finland before, during, and after the epidemic of 1973-75. The percentages of patients aged more than 4 years were 45, 70-75, and 50, respectively. They concluded that during an epidemic the age-distribution shifts towards the group aged over 4, and that an epidemic might be predicted from careful demographic surveillance. They invited others to test this idea. Because most bacteriological laboratories in the Netherlands send us meningitis-causing strains, we have the data on about 3500 meningococci at our disposal from 1959 and onwards. Except for an increase in incidence in 1966, due to serogroup B strains, no major outbreak was observed during the periods 1959-70 and 1971-81.i We used the percentage of patients aged more than 4 years and the median age as indications of the age-distribution (table). For the AGE GROUP AND SEROGROUP DISTRIBUTION OF MENINGOCOCCAL DISEASE IN THE NETHERLANDS
Nos. in parentheses refer to percentages of total. * Including cases with unknown age (about 10%). t 59% and$117% of notified cases in that period (Office of the Chief Medical Officer of
Health).
three most prevalent serogroups (A, B, and C) clear differences existed in the age distribution of the cases; this accords with other reports.2,3 These differences were seen in the first as well as in the second period. Thus useful conclusions can only be drawn from the age distribution in meningococcal disease if the relative occurrence of the serogroups is known. During the endemic years 1971-81 the distribution for group A in the Netherlands (68% over 4) was nearly equal to that during the Finnish epidemic (70-75%), which was also due to serogroup A. In the same period the age distribution for the combined serogroups in the Netherlands (45% over 4) was comparable to that in Finland during the non-epidemic years (45-50%). Because of these resemblances we suggest that in Finland, as in the Netherlands, sporadic meningococcal disease is caused mainly by group B strains,4 and that the shift in the age distribution during the epidemic has been largely due to the increase in group A prevalence (92% of all cases in 1974). Therefore we doubt whether every epidemic caused by any serogroup of Neisseria meningitidis would show the shift in age distribution described in the Finnish study. Did the increase in the percentage of the patients aged over 4 years have predictive value in 1973? We think that this shift in age distribution was mainly caused by an increase in serogroup A. The rising number of strains isolated in that5 year contrasts with the very rare isolations in the preceding years. Furthermore, in the Netherlands the median age for each serogroup increased in the two successive periods 1959-70 and 1. de Marie
S, Hoeijmakers JHJ, Poolman JT, Zanen HC. Epidemiology of Neisseria
meningitidis: Serogrouping Antonie
and
serotyping;
a
method for
large-scale serotyping.
1981, 47: 470-72. Anon. Acute meningococcal infections, 1977 Br Med J1978; i. 1560.
2. 3. The
van
Leeuwenhoek
Meningococcal Disease Surveillance Group. Analysis of endemic meningococcal disease by serogroup and evaluation of chemoprophylaxis J Infect Dis 1976; 134: 201-04. 4. Laboratorium voor de Gezondheidsleer. Bacteriële meningitis in Nederland: Jaarverslag 1980. Amsterdam, 1981. 5. Peltola H, Mäkelä PH, Käythy H, et al Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children three months to five years of age. N Engl J Med 1977; 297: 686-91.
1040 1971-81. This pattern is partly due to the decrease in the percentage of children aged 4 years or less in the Dutch population (9 - 9% in 1965 and 7-5% in 1975; Netherlands Central Bureau of Statistics). Thus the age distributions from different periods cannot be compared without standardisation, at least not in the Netherlands. Laboratory of Hygiene, Dutch Reference Laboratory of Bacterial Meningitis, University of Amsterdam, 1092 AD
L. SPANJAARD P. BOL S. DE MARIE H. C. ZANEN
Amsterdam, Netherlands
INTRAUTERINE CONTRACEPTIVE DEVICES FOR DIABETICS
SIR,-Contrary
to
the
suggestion
from Professor
Thiery
and
colleagues (Oct. 16, p. 883) our report of a high failure rate in insulin-dependent diabetics with IUCDs was not the first such observation. In 1974 Wiese2from Copenhagen reported a 15% failure rate (5 out of 33), although in a later series he found a failure rate of only 3% with an expulsion rate of 11 %. 3 Lawless and Vessey4 in a small group of 10 insulin-dependent diabetics had a 10% failure rate. Our findings I that insulin-dependent diabetics have a different endometrial response to IUCDs is also not an isolated report. In 1977 Larssonssuggested that the lack of increase in fibrinolytic activity seen in the diabetic endometrium in the presence of an IUCD might be related to decreased efficacy. The risk of pelvic inflammatory disease in the presence of an IUCD is generally accepted and one would expect the incidence of this complication to be increased in diabetics. The frequency of pelvic inflammatory disease was 3% in our series, 5% in Thiery’s group, and 10% in Vessey’s. Even in non-diabetics IUCDs are not the most effective form of contraception, and pregnancies occurring with an IUCD in situ can give rise to further problems. There can be other unpleasant side-effects of IUCDs. For all these reasons we make no apologies for questioning the suitability of IUCDs for women with insulindependent diabetes. We agree with Thiery et al. that further studies are urgently required since their data and those from Copenhagen show no evidence of an increased failure rate ofIUCDs in insulin-dependent diabetes. Our own positive findings in this respect could be due to chance alone. Since raising the issue we have received several reports of cases in which IUCDs have proved ineffective in diabetics. There is a danger in drawing conclusions from small series or from anecdotal evidence, and it is essential to obtain unselected data. We feel it is important to stress that the risk of pregnancy with an IUCD is greatest in the first year, or possibly two, and hence a failure rate expressed in terms of women-years can be misleading. If 10 women are fitted with IUCD’s and 5 become pregnant within a year, while 5 go for ten years without pregnancy the attendant risk can either be expressed as "1pregnancy in 11I women-years" or "a 50% chance of becoming pregnant in the first year". As a practical guide the latter would be a more realistic way of looking at the problem. It seems that there are certain women (whether or not they are diabetic) who are more liable than others to become pregnant with an IUCD in situ, and further work should be done to identify the risk factor or factors. While accepting that our findings of a high failure rate of IUCDs in insulin-dependent diabetics may not be generally applicable we do not agree that it is "dangerous to alert doctors and patients at this stage by even suggesting, let alone concluding, that IUCDs are less effective in diabetics". Presumably Thiery and his colleagues see dangers in diabetics being encouraged to use alternative forms of contraception. We have published evidence of an increased risk of vascular disease in insulin-dependent diabetic women taking the 1. Gosden C, Steel J, Ross A, Springbett A. Intrauterine contraceptive devices in diabetic women. Lancet 1982; i: 530. 2. Wiese J. Contraception in diabetic patients. Acta Endocrinol 1974; suppl 182: 87-94. 3. Wiese J. Intra-uterine contraception in diabetic women. Fertil Steril 1977; 28: 422. 4. Lawless M, Vessey MP. Intrauterine devices for diabetics. Lancet 1982; i: 807. 5. Larrson B. Fibrinolytic activity of the endometrium in diabetic women using copper IUCD’s. Contraception 1977; 15: 711-16. 6. Skouby SO, Mølsted-Pedersen L. IUCDs for diabetics. Lancet 1982; i: 968.
contraceptive pill.7 but have found that the progestagen-only pill and mechanical methods of contraception, if used correctly, are effective alternatives.8 We observed no changes in plasma lipids in patients taking the progestagen only pill, and in our experience to date (in over 100 patients) only I pregnancy has occurred, and that was in a patient who had stopped taking the pill; this form of contraception has not been associated with any serious combined oral
side-effects. Diabetic and Dietetic
Royal Infirmary, Edinburgh EH3 9YW
Department,
J. M. STEEL L. J. P. DUNCAN C. M. GOSDEN
PROPRANOLOL IN DECOMPENSATED ALCOHOLIC CIRRHOSIS
SIR,-Propranolol at dose levels which reduce the resting heart by 25% decreases portal venous pressure in alcoholic cirrhotic patients with portal hypertension and well compensated hepatocellular function.9 One explanation is reduced intestinal blood flow secondary to decreased cardiac output, although extracardiac factors may also be involved.1o A placebo controlled trial in cirrhotic patients with portal hypertension concluded that regular oral propranolol significantly decreased the incidence of recurrent bleeding.11 In all three studies9-11 patients with jaundice, severe biochemical liver dysfunction, or ascites were excluded. We have examined the acute effects of propranolol on portal venous pressure and systemic haemodynamics in alcoholic cirrhotic patients with decompensated liver function. Twelve male alcoholics were admitted to hospital with endoscopically confirmed bleeding from oesophageal varices or with massive ascites, jaundice, and liver failure. All patients had consumed more than 120 g of alcohol daily for over twelve years and alcoholic cirrhosis was confirmed histologically in seven of the patients. Impaired haemostasis precluded liver biopsy in the other rate
five, all of whom had the clinical and biochemical features of advanced alcoholic liver disease. After a 6 h fast, hepatic vein catheterisation was performed and the gradient between wedged and free hepatic venous pressure measured, wedging being checked by the absence of reflux after. injection of contrast medium.
Propranolol was then administered orally-40 mg to seven patients and 160 mg five-and the pressure gradient was measured every 15 min for 120 min. Cardiac output was measured by the CO, rebreathing method,12,13 expired CO, being collected in a Tissot spirometer and analysed with a fast response CO, analyser (Gould-Godart). Mixed venous pCO, was measured by the equilibrium rebreathing technique. Arterial pCO, was measured directly from a radial artery sample. 14,15 Propranolol was assayed in plasma by a fluorimetric method. The results are expressed as means ±SEM with Student’s t test for statistical comparisons. All studies accorded with the Helsinki Declaration. to
In both propranolol groups the basal haemodynamic status was similar (table). The portal and systemic haemodynamic changes after 40 or 160 mg propranolol were not significantly different. A peak effect was evident at 60 min (table) and was still present at 120 min. Cardiac output and resting heart rate fell after propranolol but wedged and free hepatic vein pressures and the corrected wedged hepatic vein pressure did not. Steel JM, Duncan LJP Contraception for the insulin dependent diabetic. Diabetes Car? 1980; 3: 557-60. 8. Steel JM, Duncan LJP. Experience with the progestogen only contraceptive pill, Micronor, in insulin dependent diabetics Br J Family Planning 1981; 6: 108-10 9. Lebrec D, Nouel O, Corbic M, Benhamou JP. Propranolol—a medical treatment for portal hypertension? Lancet 1980; ii: 180-82. 10. Lebrec D, Hillon P, Munoz C, Jungers M, Goldfarb G, Benhamou JP. Comparison of the effects of cardioselective and non-selective beta blocker on portal hypertension in 7.
patients with cirrhosis. Hepatology 1982; 1: 155. 11. Lebrec D, Poynard, T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study N Engl J Med 1981; 305: 1371-74. 12. Jones NL, Campbell EJM, Edwards RHT, Robertson DG. Clinical exercise testing. Philadelphia: W. B. Saunders, 1975. 13. Franciosa JA, Ragan DO, Rubenstone SJ. Validation of the CO2 rebreathing method for measuring cardiac output in patients with hypertension or heart failure J Lab Clin Med 1976; 88: 672-682. 14. Shand DG, Nuckolls EM, Oates JA. Plasma propranolol levels in adults with observations in four children, Clin Pharmacol Ther 1970; 11: 112-20. 15. McLean AJ, Skews H, Bobik A, Dudley FJ. Interaction between oral propranolol and hydrallazine. Clin Pharmacol Ther 1980; 27: 726-32.
Letters
to
EARLIER HAEMOPERFUSION IN FULMINANT HEPATIC FAILURE
SIR,-After reading the paper from the King’s College Hospital liver unit in your issue of Sept. 25 I was left with a mixture of enthusiasm and concern. My concern is that many centres may prematurely adopt this charcoal haemoperfusion method for routine treatment offulminant hepatic failure (FHF), as happened a few years ago. Our reports in 1972 that haemoperfusion resulted in the temporary recovery of consciousness of grade IV hepatic coma patients were followed two years later by the report of Dr Williams’ group at King’s3of the efficacy of this approach for the treatment of grade IV FHF. Before further detailed clinical and laboratory research was done, the technique was taken up by many centres for the routine treatment of grade iv FHF. The results, to say the least, were confusing, especially when Williams’ team could not reproduce their clinical results because of the blood incompatibility of the haemoperfusion .device they used in their later studies. In the past five years we have tried to resolve this confusion by detailed laboratory research on galactosamine induced FHF in rats.4-7 Initial results showed that haemoperfusion significantly improved the survival rate from 30% to 70%.4 It seems that an increase in survival rate was possible only if haemoperfusions were done early on in hepatic coma, and more detailed studies with controls and different treatment regimens6,7 confirmed this. Our results in FHF rats are now supported by the clinical trial described by Gimson et al. Even so the following points should be borne in mind: (1) Drug induced FHF due to galactosamine in rats4-7 and paracetamol (acetaminophen) in man may be similar-indeed laboratory5-7 and, now, clinical results support the possible use of earlier haemoperfusion in drug induced FHF, especially since the King’s group studied 23 cases of grade III FHF and 23 cases of grade IV FHF. However, only 6 cases of grade III viral FHF were treated by earlier haemoperfusion, and much more clinical work is needed before any conclusion can be made about this treatment’s value in viral FHF. (2) Gimson et al. infused epoprostenol (prostacyclin) to prevent blood incompatibility due to their haemoperfusion device. Since prostacyclin infusion may have its own side-effects, it should be emphasised that other, more blood compatible, haemoperfusion devices are available which do not require prostacyclin infusion. (3) The effect of prostacyclin itself on the course ofFHF should be studied. Prostaglandin E2, though very different from prostacyclin, increases survival rates in FHF rats.8 Despite the promising results obtained so far, more clinical research should be done before earlier haemoperfusion can be considered as a routine treatment for FHF, especially for viral FHF.
comlete
Artficial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Quebec, Canada H3G 1Y6
AGE-DISTRIBUTIONS OF MENINGOCOCCAL DISEASE AS PREDICTOR OF EPIDEMICS
the Editor
T. M. S. CHANG
1. Chang TMS
Haemoperfusions over microencapsulated adsorbent in a patient with hepatic coma. Lancet 1972; ii: 1371-72. 2. Chang TMS, Migchelsen M Characterization of possible ’toxic’ metabolitesin uremia and hepatic coma based on the clearance spectrum for larger molecules by the ACAC microcapsule artificial kidney Trans Am Soc Artif Intern Organs 1973; 19: 314-19. 3 Gazzard BG, Weston MJ, Murray-Lyon, IM, Filax H, Record CO, Portman B, Langley, Dunlop EH, Mellon PJ, Ward MD, Williams R. Charcoal haemoperfusion in the treatment of fulminant hepatic failure Lancet 1974; i: 1301. 4. Chirito E. Reiter B, Lister C, Chang TMS, Artificial liver: the effect of ACAC microencapsulated charcoal hemoperfusion on fulminant hepatic failure. Artif Organs 1977; 1: 76-83. 5. Chang TMS, Lister C, Chirito E, O’Keefe P, Resurrection E. Effects of hemoperfusion rate and time of initiation of ACAC charcoal hemoperfusion on the survival of fulminant hepatic failure rats. Trans Am Soc Artif Intern Organs 1978; 24: 243-45.
Tabata Y, Chang TMS. Comparisons of six artificial liver support regimes in fulminant hepatic coma rats. Trans Am Soc Artif Inter Organs 1980; 26: 394-99. 7. Chang TMS. Hemoperfusion, exchange transfusion, cross circulation, liver perfusion, 6.
hormones and immobilized enzymes. In: Brunner G, Schmidt FW, eds. Artificial liver support. Berlin; Springer-Verlag, 1981; 126-33. 8 Dixit V, Chang TMS. The effects of prostaglandin E3 on the survival of fulminant hepatic failure rats. Int J Artif Organs (in press).
SIR,-Dr Peltola and colleagues (Sept. 11, p. 595) analysed the age-distribution of meningococcal disease in Finland before, during, and after the epidemic of 1973-75. The percentages of patients aged more than 4 years were 45, 70-75, and 50, respectively. They concluded that during an epidemic the age-distribution shifts towards the group aged over 4, and that an epidemic might be predicted from careful demographic surveillance. They invited others to test this idea. Because most bacteriological laboratories in the Netherlands send us meningitis-causing strains, we have the data on about 3500 meningococci at our disposal from 1959 and onwards. Except for an increase in incidence in 1966, due to serogroup B strains, no major outbreak was observed during the periods 1959-70 and 1971-81.i We used the percentage of patients aged more than 4 years and the median age as indications of the age-distribution (table). For the AGE GROUP AND SEROGROUP DISTRIBUTION OF MENINGOCOCCAL DISEASE IN THE NETHERLANDS
Nos. in parentheses refer to percentages of total. * Including cases with unknown age (about 10%). t 59% and$117% of notified cases in that period (Office of the Chief Medical Officer of
Health).
three most prevalent serogroups (A, B, and C) clear differences existed in the age distribution of the cases; this accords with other reports.2,3 These differences were seen in the first as well as in the second period. Thus useful conclusions can only be drawn from the age distribution in meningococcal disease if the relative occurrence of the serogroups is known. During the endemic years 1971-81 the distribution for group A in the Netherlands (68% over 4) was nearly equal to that during the Finnish epidemic (70-75%), which was also due to serogroup A. In the same period the age distribution for the combined serogroups in the Netherlands (45% over 4) was comparable to that in Finland during the non-epidemic years (45-50%). Because of these resemblances we suggest that in Finland, as in the Netherlands, sporadic meningococcal disease is caused mainly by group B strains,4 and that the shift in the age distribution during the epidemic has been largely due to the increase in group A prevalence (92% of all cases in 1974). Therefore we doubt whether every epidemic caused by any serogroup of Neisseria meningitidis would show the shift in age distribution described in the Finnish study. Did the increase in the percentage of the patients aged over 4 years have predictive value in 1973? We think that this shift in age distribution was mainly caused by an increase in serogroup A. The rising number of strains isolated in that5 year contrasts with the very rare isolations in the preceding years. Furthermore, in the Netherlands the median age for each serogroup increased in the two successive periods 1959-70 and 1. de Marie
S, Hoeijmakers JHJ, Poolman JT, Zanen HC. Epidemiology of Neisseria
meningitidis: Serogrouping Antonie
and
serotyping;
a
method for
large-scale serotyping.
1981, 47: 470-72. Anon. Acute meningococcal infections, 1977 Br Med J1978; i. 1560.
2. 3. The
van
Leeuwenhoek
Meningococcal Disease Surveillance Group. Analysis of endemic meningococcal disease by serogroup and evaluation of chemoprophylaxis J Infect Dis 1976; 134: 201-04. 4. Laboratorium voor de Gezondheidsleer. Bacteriële meningitis in Nederland: Jaarverslag 1980. Amsterdam, 1981. 5. Peltola H, Mäkelä PH, Käythy H, et al Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children three months to five years of age. N Engl J Med 1977; 297: 686-91.
1040 1971-81. This pattern is partly due to the decrease in the percentage of children aged 4 years or less in the Dutch population (9 - 9% in 1965 and 7-5% in 1975; Netherlands Central Bureau of Statistics). Thus the age distributions from different periods cannot be compared without standardisation, at least not in the Netherlands. Laboratory of Hygiene, Dutch Reference Laboratory of Bacterial Meningitis, University of Amsterdam, 1092 AD
L. SPANJAARD P. BOL S. DE MARIE H. C. ZANEN
Amsterdam, Netherlands
INTRAUTERINE CONTRACEPTIVE DEVICES FOR DIABETICS
SIR,-Contrary
to
the
suggestion
from Professor
Thiery
and
colleagues (Oct. 16, p. 883) our report of a high failure rate in insulin-dependent diabetics with IUCDs was not the first such observation. In 1974 Wiese2from Copenhagen reported a 15% failure rate (5 out of 33), although in a later series he found a failure rate of only 3% with an expulsion rate of 11 %. 3 Lawless and Vessey4 in a small group of 10 insulin-dependent diabetics had a 10% failure rate. Our findings I that insulin-dependent diabetics have a different endometrial response to IUCDs is also not an isolated report. In 1977 Larssonssuggested that the lack of increase in fibrinolytic activity seen in the diabetic endometrium in the presence of an IUCD might be related to decreased efficacy. The risk of pelvic inflammatory disease in the presence of an IUCD is generally accepted and one would expect the incidence of this complication to be increased in diabetics. The frequency of pelvic inflammatory disease was 3% in our series, 5% in Thiery’s group, and 10% in Vessey’s. Even in non-diabetics IUCDs are not the most effective form of contraception, and pregnancies occurring with an IUCD in situ can give rise to further problems. There can be other unpleasant side-effects of IUCDs. For all these reasons we make no apologies for questioning the suitability of IUCDs for women with insulindependent diabetes. We agree with Thiery et al. that further studies are urgently required since their data and those from Copenhagen show no evidence of an increased failure rate ofIUCDs in insulin-dependent diabetes. Our own positive findings in this respect could be due to chance alone. Since raising the issue we have received several reports of cases in which IUCDs have proved ineffective in diabetics. There is a danger in drawing conclusions from small series or from anecdotal evidence, and it is essential to obtain unselected data. We feel it is important to stress that the risk of pregnancy with an IUCD is greatest in the first year, or possibly two, and hence a failure rate expressed in terms of women-years can be misleading. If 10 women are fitted with IUCD’s and 5 become pregnant within a year, while 5 go for ten years without pregnancy the attendant risk can either be expressed as "1pregnancy in 11I women-years" or "a 50% chance of becoming pregnant in the first year". As a practical guide the latter would be a more realistic way of looking at the problem. It seems that there are certain women (whether or not they are diabetic) who are more liable than others to become pregnant with an IUCD in situ, and further work should be done to identify the risk factor or factors. While accepting that our findings of a high failure rate of IUCDs in insulin-dependent diabetics may not be generally applicable we do not agree that it is "dangerous to alert doctors and patients at this stage by even suggesting, let alone concluding, that IUCDs are less effective in diabetics". Presumably Thiery and his colleagues see dangers in diabetics being encouraged to use alternative forms of contraception. We have published evidence of an increased risk of vascular disease in insulin-dependent diabetic women taking the 1. Gosden C, Steel J, Ross A, Springbett A. Intrauterine contraceptive devices in diabetic women. Lancet 1982; i: 530. 2. Wiese J. Contraception in diabetic patients. Acta Endocrinol 1974; suppl 182: 87-94. 3. Wiese J. Intra-uterine contraception in diabetic women. Fertil Steril 1977; 28: 422. 4. Lawless M, Vessey MP. Intrauterine devices for diabetics. Lancet 1982; i: 807. 5. Larrson B. Fibrinolytic activity of the endometrium in diabetic women using copper IUCD’s. Contraception 1977; 15: 711-16. 6. Skouby SO, Mølsted-Pedersen L. IUCDs for diabetics. Lancet 1982; i: 968.
contraceptive pill.7 but have found that the progestagen-only pill and mechanical methods of contraception, if used correctly, are effective alternatives.8 We observed no changes in plasma lipids in patients taking the progestagen only pill, and in our experience to date (in over 100 patients) only I pregnancy has occurred, and that was in a patient who had stopped taking the pill; this form of contraception has not been associated with any serious combined oral
side-effects. Diabetic and Dietetic
Royal Infirmary, Edinburgh EH3 9YW
Department,
J. M. STEEL L. J. P. DUNCAN C. M. GOSDEN
PROPRANOLOL IN DECOMPENSATED ALCOHOLIC CIRRHOSIS
SIR,-Propranolol at dose levels which reduce the resting heart by 25% decreases portal venous pressure in alcoholic cirrhotic patients with portal hypertension and well compensated hepatocellular function.9 One explanation is reduced intestinal blood flow secondary to decreased cardiac output, although extracardiac factors may also be involved.1o A placebo controlled trial in cirrhotic patients with portal hypertension concluded that regular oral propranolol significantly decreased the incidence of recurrent bleeding.11 In all three studies9-11 patients with jaundice, severe biochemical liver dysfunction, or ascites were excluded. We have examined the acute effects of propranolol on portal venous pressure and systemic haemodynamics in alcoholic cirrhotic patients with decompensated liver function. Twelve male alcoholics were admitted to hospital with endoscopically confirmed bleeding from oesophageal varices or with massive ascites, jaundice, and liver failure. All patients had consumed more than 120 g of alcohol daily for over twelve years and alcoholic cirrhosis was confirmed histologically in seven of the patients. Impaired haemostasis precluded liver biopsy in the other rate
five, all of whom had the clinical and biochemical features of advanced alcoholic liver disease. After a 6 h fast, hepatic vein catheterisation was performed and the gradient between wedged and free hepatic venous pressure measured, wedging being checked by the absence of reflux after. injection of contrast medium.
Propranolol was then administered orally-40 mg to seven patients and 160 mg five-and the pressure gradient was measured every 15 min for 120 min. Cardiac output was measured by the CO, rebreathing method,12,13 expired CO, being collected in a Tissot spirometer and analysed with a fast response CO, analyser (Gould-Godart). Mixed venous pCO, was measured by the equilibrium rebreathing technique. Arterial pCO, was measured directly from a radial artery sample. 14,15 Propranolol was assayed in plasma by a fluorimetric method. The results are expressed as means ±SEM with Student’s t test for statistical comparisons. All studies accorded with the Helsinki Declaration. to
In both propranolol groups the basal haemodynamic status was similar (table). The portal and systemic haemodynamic changes after 40 or 160 mg propranolol were not significantly different. A peak effect was evident at 60 min (table) and was still present at 120 min. Cardiac output and resting heart rate fell after propranolol but wedged and free hepatic vein pressures and the corrected wedged hepatic vein pressure did not. Steel JM, Duncan LJP Contraception for the insulin dependent diabetic. Diabetes Car? 1980; 3: 557-60. 8. Steel JM, Duncan LJP. Experience with the progestogen only contraceptive pill, Micronor, in insulin dependent diabetics Br J Family Planning 1981; 6: 108-10 9. Lebrec D, Nouel O, Corbic M, Benhamou JP. Propranolol—a medical treatment for portal hypertension? Lancet 1980; ii: 180-82. 10. Lebrec D, Hillon P, Munoz C, Jungers M, Goldfarb G, Benhamou JP. Comparison of the effects of cardioselective and non-selective beta blocker on portal hypertension in 7.
patients with cirrhosis. Hepatology 1982; 1: 155. 11. Lebrec D, Poynard, T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study N Engl J Med 1981; 305: 1371-74. 12. Jones NL, Campbell EJM, Edwards RHT, Robertson DG. Clinical exercise testing. Philadelphia: W. B. Saunders, 1975. 13. Franciosa JA, Ragan DO, Rubenstone SJ. Validation of the CO2 rebreathing method for measuring cardiac output in patients with hypertension or heart failure J Lab Clin Med 1976; 88: 672-682. 14. Shand DG, Nuckolls EM, Oates JA. Plasma propranolol levels in adults with observations in four children, Clin Pharmacol Ther 1970; 11: 112-20. 15. McLean AJ, Skews H, Bobik A, Dudley FJ. Interaction between oral propranolol and hydrallazine. Clin Pharmacol Ther 1980; 27: 726-32.