- Email: [email protected]
Diuretics, ACE inhibitors, and cardiac failure
Group
B
streptococcus
SrR—Towers’ July 22 commentary on the problems of control of group B streptococcal (GBS) sepsis in neonates in the USA makes interesting reading. The difficulties in the UK are similar to those in that country. There are no UK guidelines on prevention of neonatal group B streptococcal infections. The US guidelines therefore provide the only basis for clinical practice. However, the situation in the UK and western Europe is different from that in the USA. The incidence of group B neonatal sepsis in the USA is about 2 per thousand livebirths,’ whereas in the UK it is estimated to be 0,3.2 This rate is in line with the reported lower incidence in other European countries.3 As a result, any nationwide screening and chemoprophylaxis programmes will be less cost-effective than in the USA3 and hence more difficult to introduce. However, the incidence of this disease may show geographical variation within a country. In Hackney, London, there are 0-8 cases per thousand livebirths (unpub-lished observations). Thus it may be justifiable to introduce such programmes locally in areas of increased incidence. We agree that rapid detection tests during labour are the best theoretical approach to this problem, and we suggest that until effective vaccines against group B streptococcus are widely available, research in this area is much needed. *A J H
Simpson, S R Heard
Department of Medical Microbiology, St Bartholomew’s Hospital Medical College, West Smithfield, London EC1A 7BE, UK
1
2
3
Edwards MS, Baker CJ. Streptococcus agalactiae (group B streptococcus). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone; 1994: 1835-45. Mayon-White RT. The incidence of neonatal group B streptococcal disease in Britain. In: Holm SE, Christensen P, eds. Basic concepts of streptococci and streptococcal diseases. Chertsey: Reedbooks, 1982: 305-06. Boyer KM. Maternal screening in prevention of neonatal infections: current status and rationale for group B streptococcal screening. J Hosp Infect 1988; 11 (suppl A): 328-33.
SiR-Towers castigates both the American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) for promulgating guidelines for the prevention of neonatal GBS infections. He charges that the very existence of these guidelines has "placed health professionals in a position of performing unrealistic tasks". By this, he means the complete "eradication of neonatal GBS sepsis", though the AAP task force explicitly stated that their strategy could not prevent all neonatal GBS infections. Towers also claims that the guidelines have "given rise to a medicolegal dimension that will work against the patient’s best interests"-implying that there were no medicolegal aspects of neonatal sepsis before publication of the AAP and ACOG guidelines! Surely this is shooting the messenger. Should the AAP and the ACOG have ignored the careful clinical studies by Boyer and colleagues’1 which demonstrated that selective intrapartum chemoprophylaxis can prevent many (but not all) neonatal GBS infections? Expert opinion remains divided about the best strategy to identify at-risk pregnancies, but there is a clear consensus that intrapartum antibiotics prevent most neonatal GBS infections in high-risk women.2,3 Multivalent vaccines now under development may prevent many (but, again not all) neonatal
GBS infections, perhaps making intrapartum chemoprophylaxis obsolete. Until then, physicians and professional societies can either ignore the data proving that intrapartum antibiotics are effective or use those data to try 700
prevent neonatal GBS sepsis. I publication of these guidelines. to
B Keith
applaud
the AAP for
English
Department of Pediatrics, University of Tennessee, Memphis, TN 38103, USA 1 Boyer KM, Gotoff SP. Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. 2
3
N Engl J Med 1986; 314: 1665-69. Committee on Infectious Diseases and Committee on Fetus and Newborn. Guidelines for prevention of group B streptococcal (GBS) infection by chemoprophylaxis. Pediatrics 1992; 90: 775-78. Group B streptococcal infections in pregnancy. ACOG Tech Bull
1992; 170: 1-5.
Diuretics, ACE inhibitors, and cardiac failure SIR—Waterer and Donaldson (July 22, p 254) report that the use of high-dose frusemide is an effective and safe approach to management of severe cardiac failure resistant to an optimum dose of an angiotensin-converting-enzyme (ACE) inhibitor and low-dose frusemide. They investigated 15 geriatric patients with cardiac failure. On admission mean serum creatinine was 161 IlmoVL (56-7-325-0), showing that several subjects had renal insufficiency, some of them with advanced renal disease. An oedematous patient can be judged resistant to diuretics when treatment with a potent drug (generally a loop diuretic) in moderate doses fails to reduce the extracellular fluid volume to the desired level.’ Loop diuretics are the most powerful natriuretics. However, several factors can hamper diuretic activity, including chronic renal failure (CRF) and cardiac failure. In CRF, such resistance can arise from various mechanisms.I,2 First, the surviving nephrons are already in a condition of enhanced diuresis because of increased osmotic load; and, second, the organic anions accumulated in CRF compete with the same tubular secreting mechanisms that carry diuretics to their site of action in the lumen. On the other hand, cardiac failure can modify diuretic disposition and responsiveness. Diuretic kinetics can become severely abnormal in cardiac failure, with a restriction in the peak urinary diuretic concentration. The most important factor contributing to this abnormality is reduced renal blood flow decreased cardiac output. On the basis of these data, it seems logical that patients with severe cardiac failure and renal insufficiency need higher’ diuretic doses. The maximum effective doses of loop diuretics have been empirically derived from studies in patients with different oedematous states. In cardiac failure and advanced renal disease (glomerular filtration rate below 20 mL/min) the maximum effective dose of intravenous frusemide can be as high as 200 mg.’ Larger doses (higher than 500 mg) have been used in cases of congestive heart failure with diuretic resistance, but they are associated with an increased risk of ototoxicity and permanent deafness.‘-3 In the patients who need very large doses, continuous diuretic infusion has been effective in overcoming diuretic resistance.’ Constant diuretic infusion of frusemide (up to 1 mg/kg per h) limits the ability of the kidney to retain sodium chloride when blood concentrations of drug are low, and, furthermore, it prevents periods of postdiuretic sodium chloride retention.2,3 This modification of traditional bolus therapy might be safer, with a low frequency of side-effects, despite the large doses at which the drug is infused.’ Also of interest in patients with severe cardiac failure is chronic treatment with ACE inhibitors. Although the advent of effective vasodilator therapy has produced a substantial improvement in the treatment of patients with heart failure, they should be used with caution. ACE inhibitors can produce a decrease in renal blood flow mediated by a decrement in systemic pressure. Sodium excretion varies
directly with renal perfusion pressure via pressure natriuresis. Thus, a reduction in systemic blood pressure can decrease sodium excretion.’ Furthermore, ACE inhibitors produce a reduction in the postglomerular capillary resistance by a decrease in angiotensin-11-mediated efferent arteriolar tone.’ Therefore, patients with heart failure could be at risk of a decline in renal function on long-term ACEinhibitor therapy, since in chronic cardiac failure angiotensinII-mediated systemic and renal vasoconstriction is a main factor in the maintenance of renal perfusion pressure. The use of combined afterload reduction with ACE inhibitors and diuretics in patients with severe cardiac failure may improve functional class and prolong life. However, too much of either the vasodilator or the diuretic can lead to renal insufficiency or further sodium-chloride retention. *J F Navarro González, J J García Pérez
1 Rose BD. Nephrology forum: diuretics. Kidney Int 1991; 39: 336-52. 2 Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991; 114: 886-94. 3 Ellison DH. Diuretic drugs and the treatment of edema: from clinic to bench and back again. Am J Kidney Dis 1994; 23: 623-43. 4 Rudy DW, Voelker JR, Green PK, Esparza FA, Brater DC Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann Intern Med 1991; 115: 360-66. 5 Brunner HR, Waeber B, Nussberger J. Renal effects of converting enzyme inhibition. J Cardiovasc Pharmacol 1987; 3 (suppl): S6-S13.
Replacement of drug treatment for insomnia by ambient odour are
frequently prescribed long-term
medication for insomnia. This could be potentially important in reducing side-effects. Although our results are preliminary, being based on only four patients, it might be worthwhile to investigate this effect more formally under controlled situations. Mark
Hardy, Michael D Kirk-Smith, *David D Stretch
Millaton House Nursing Home, Bridestowe, Okehampton; School of Management, University of Ulster, Newtownabbey Co Antrim, UK; and *Greenwood Institute of Child Health, University of Leicester, Westcotes House, Leicester LE3 0QU, UK
Teuscher E,
Melzig M, Villmann E, Moritz KU. Untersuchungen zum Wirkungsmechanismus atherischer Ole. Phytotherapie 1990; 11: 87-92. 2 Buchbauer G, Jirovetz L, Jager W, Plank C, Dietrich H. Fragrance compounds and essential oils with sedative effects upon inhalation. J Pharm Sci 1993; 82: 660-64. 3 Buchbauer G, Jirovetz L, Jager W, Dietrich H, Plank C, Karamat E. Aromatherapy: evidence for sedative effects of the essential oil of lavender after inhalation. Zeitschrift fur naturforschung c-a. J Biosciences 1991; 46c: 1067-72. 4 Chen YW, Su KSE, Chang S. Nasal systemic drug delivery. New York: Marcel Dekker, 1989.
Aseptic meningitis caused by measlesmumps-rubella vaccine in Japan SIR-Since
measles-mumps-rubella (MMR) vaccine was Japan in April, 1989, a number of cases of post-vaccination aseptic meningitis have been reported and
introduced into to
relieve insomnia in psychogeriatric patients, despite recommendations that they are for short-term use only. They can have serious side-effects, and long-term prescription indicates the difficulty in treating this condition effectively. Pharmacological and animal studies indicate that the main components of lavender oil have a light sedative effect We studied whether lavender oil could replace drug treatment for insomnia. The hours of sleep of each of four psychogeriatric patients were measured for 6 weeks. Patient 1 had been on 10 mg temazepam for 1 year; patient 2 on 25 mg promazine hydrochloride for 3 years; patient 3 on one capsule chlormethiazole for 7 months; and patient 4 on no previous medication. After 2 weeks of measurement (phase 1), medication was withdrawn; for the middle 2 weeks (phase 2), measurement of hours asleep was done (the 2week period being long enough to overcome any rebound insomnia); and for the final 2 weeks (phase 3) ambient lavender oil was introduced into their ward with an odour diffuser. The results (table) suggest that the amount of time spent asleep was significantly reduced after withdrawal of medication, but that amount of time asleep returned to the same level with ambient odour under medication as
Times are median (interquartile range) h spent asleep/night, and probability levels give probabilities with which such differences between medians could arise if due only to chance-differences between the 3 conditions (Kruskal-Wallis). Post-hoc comparisons indicate all pairwise differences, except those between phases 1 and 3. were significant.
Table : Median sleep times
also
continued
1
Department of Nephrology, Hospital Ntra Sra de Candelaria, 38010 S/C de Tenerife, Canary Islands, Spain
SiR-Hypnotic drugs
in all patients by post-hoc comparisons.) Patients reported to be less restless during sleep. This exposure to odour could potentially be more economic than current medication. The study suggests that ambient lavender oil might be used as a temporary relief from
(confirmed
were
these have been attributed to use of Urabe Am9 mumps vaccine.1,2 The incidence of disease associated with vaccine has increased with time; various mumps vaccines may be implicated, and the problem has been reported from other countries.3,4 In Japan, the Ministry of Health and Welfare (MHW) withdrew the domestically produced MMR vaccine in April, 1993.’ To determine the incidence of vaccine-associated aseptic meningitis in Japan, we conducted a prospective study in Fukuoka district between October, 1990, and April, 1993, in collaboration with the MHW Vaccination Study Group. The criteria for inclusion of a case of aseptic meningitis in this study were symptoms of meningitis and pleocytosis in the cerebrospinal fluid. When our study began, only the MHW version of MMR vaccine was available. Because the incidence of meningeal disease associated with the MHW version was found to be high during the first 18 months of the study, three additional vaccine products were later included in our surveillance protocol, in the hope that we would see a decrease in disease incidence: Takeda, Biken, and Kitasato versions became available in October, 1991 (see table). Our study was facilitated by the use of case cards to record observations for 35 days by the vaccinated children’s parents, whose informed consents were obtained by family physicians before inoculation. Vaccinations were given according to a schedule prescribed by the Japanese Vaccination Law. Participants were instructed to consult their doctors if symptoms occurred and further examinations were done only if needed. We did not recommend routine prospective examinations to prove pleocytosis in the cerebrospinal fluid of the vaccinated children. 11800 participants in the Fukuoka district were vaccinated and 10 148 case cards were recovered. MMR versions, MMR virus strains identified, and the incidence of confirmed vaccine-associated aseptic meningitis are summarised in the table. Among the three MMR versions (Biken excepted) the incidences of disease were 701
B
streptococcus
SrR—Towers’ July 22 commentary on the problems of control of group B streptococcal (GBS) sepsis in neonates in the USA makes interesting reading. The difficulties in the UK are similar to those in that country. There are no UK guidelines on prevention of neonatal group B streptococcal infections. The US guidelines therefore provide the only basis for clinical practice. However, the situation in the UK and western Europe is different from that in the USA. The incidence of group B neonatal sepsis in the USA is about 2 per thousand livebirths,’ whereas in the UK it is estimated to be 0,3.2 This rate is in line with the reported lower incidence in other European countries.3 As a result, any nationwide screening and chemoprophylaxis programmes will be less cost-effective than in the USA3 and hence more difficult to introduce. However, the incidence of this disease may show geographical variation within a country. In Hackney, London, there are 0-8 cases per thousand livebirths (unpub-lished observations). Thus it may be justifiable to introduce such programmes locally in areas of increased incidence. We agree that rapid detection tests during labour are the best theoretical approach to this problem, and we suggest that until effective vaccines against group B streptococcus are widely available, research in this area is much needed. *A J H
Simpson, S R Heard
Department of Medical Microbiology, St Bartholomew’s Hospital Medical College, West Smithfield, London EC1A 7BE, UK
1
2
3
Edwards MS, Baker CJ. Streptococcus agalactiae (group B streptococcus). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone; 1994: 1835-45. Mayon-White RT. The incidence of neonatal group B streptococcal disease in Britain. In: Holm SE, Christensen P, eds. Basic concepts of streptococci and streptococcal diseases. Chertsey: Reedbooks, 1982: 305-06. Boyer KM. Maternal screening in prevention of neonatal infections: current status and rationale for group B streptococcal screening. J Hosp Infect 1988; 11 (suppl A): 328-33.
SiR-Towers castigates both the American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) for promulgating guidelines for the prevention of neonatal GBS infections. He charges that the very existence of these guidelines has "placed health professionals in a position of performing unrealistic tasks". By this, he means the complete "eradication of neonatal GBS sepsis", though the AAP task force explicitly stated that their strategy could not prevent all neonatal GBS infections. Towers also claims that the guidelines have "given rise to a medicolegal dimension that will work against the patient’s best interests"-implying that there were no medicolegal aspects of neonatal sepsis before publication of the AAP and ACOG guidelines! Surely this is shooting the messenger. Should the AAP and the ACOG have ignored the careful clinical studies by Boyer and colleagues’1 which demonstrated that selective intrapartum chemoprophylaxis can prevent many (but not all) neonatal GBS infections? Expert opinion remains divided about the best strategy to identify at-risk pregnancies, but there is a clear consensus that intrapartum antibiotics prevent most neonatal GBS infections in high-risk women.2,3 Multivalent vaccines now under development may prevent many (but, again not all) neonatal
GBS infections, perhaps making intrapartum chemoprophylaxis obsolete. Until then, physicians and professional societies can either ignore the data proving that intrapartum antibiotics are effective or use those data to try 700
prevent neonatal GBS sepsis. I publication of these guidelines. to
B Keith
applaud
the AAP for
English
Department of Pediatrics, University of Tennessee, Memphis, TN 38103, USA 1 Boyer KM, Gotoff SP. Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. 2
3
N Engl J Med 1986; 314: 1665-69. Committee on Infectious Diseases and Committee on Fetus and Newborn. Guidelines for prevention of group B streptococcal (GBS) infection by chemoprophylaxis. Pediatrics 1992; 90: 775-78. Group B streptococcal infections in pregnancy. ACOG Tech Bull
1992; 170: 1-5.
Diuretics, ACE inhibitors, and cardiac failure SIR—Waterer and Donaldson (July 22, p 254) report that the use of high-dose frusemide is an effective and safe approach to management of severe cardiac failure resistant to an optimum dose of an angiotensin-converting-enzyme (ACE) inhibitor and low-dose frusemide. They investigated 15 geriatric patients with cardiac failure. On admission mean serum creatinine was 161 IlmoVL (56-7-325-0), showing that several subjects had renal insufficiency, some of them with advanced renal disease. An oedematous patient can be judged resistant to diuretics when treatment with a potent drug (generally a loop diuretic) in moderate doses fails to reduce the extracellular fluid volume to the desired level.’ Loop diuretics are the most powerful natriuretics. However, several factors can hamper diuretic activity, including chronic renal failure (CRF) and cardiac failure. In CRF, such resistance can arise from various mechanisms.I,2 First, the surviving nephrons are already in a condition of enhanced diuresis because of increased osmotic load; and, second, the organic anions accumulated in CRF compete with the same tubular secreting mechanisms that carry diuretics to their site of action in the lumen. On the other hand, cardiac failure can modify diuretic disposition and responsiveness. Diuretic kinetics can become severely abnormal in cardiac failure, with a restriction in the peak urinary diuretic concentration. The most important factor contributing to this abnormality is reduced renal blood flow decreased cardiac output. On the basis of these data, it seems logical that patients with severe cardiac failure and renal insufficiency need higher’ diuretic doses. The maximum effective doses of loop diuretics have been empirically derived from studies in patients with different oedematous states. In cardiac failure and advanced renal disease (glomerular filtration rate below 20 mL/min) the maximum effective dose of intravenous frusemide can be as high as 200 mg.’ Larger doses (higher than 500 mg) have been used in cases of congestive heart failure with diuretic resistance, but they are associated with an increased risk of ototoxicity and permanent deafness.‘-3 In the patients who need very large doses, continuous diuretic infusion has been effective in overcoming diuretic resistance.’ Constant diuretic infusion of frusemide (up to 1 mg/kg per h) limits the ability of the kidney to retain sodium chloride when blood concentrations of drug are low, and, furthermore, it prevents periods of postdiuretic sodium chloride retention.2,3 This modification of traditional bolus therapy might be safer, with a low frequency of side-effects, despite the large doses at which the drug is infused.’ Also of interest in patients with severe cardiac failure is chronic treatment with ACE inhibitors. Although the advent of effective vasodilator therapy has produced a substantial improvement in the treatment of patients with heart failure, they should be used with caution. ACE inhibitors can produce a decrease in renal blood flow mediated by a decrement in systemic pressure. Sodium excretion varies
directly with renal perfusion pressure via pressure natriuresis. Thus, a reduction in systemic blood pressure can decrease sodium excretion.’ Furthermore, ACE inhibitors produce a reduction in the postglomerular capillary resistance by a decrease in angiotensin-11-mediated efferent arteriolar tone.’ Therefore, patients with heart failure could be at risk of a decline in renal function on long-term ACEinhibitor therapy, since in chronic cardiac failure angiotensinII-mediated systemic and renal vasoconstriction is a main factor in the maintenance of renal perfusion pressure. The use of combined afterload reduction with ACE inhibitors and diuretics in patients with severe cardiac failure may improve functional class and prolong life. However, too much of either the vasodilator or the diuretic can lead to renal insufficiency or further sodium-chloride retention. *J F Navarro González, J J García Pérez
1 Rose BD. Nephrology forum: diuretics. Kidney Int 1991; 39: 336-52. 2 Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991; 114: 886-94. 3 Ellison DH. Diuretic drugs and the treatment of edema: from clinic to bench and back again. Am J Kidney Dis 1994; 23: 623-43. 4 Rudy DW, Voelker JR, Green PK, Esparza FA, Brater DC Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy. Ann Intern Med 1991; 115: 360-66. 5 Brunner HR, Waeber B, Nussberger J. Renal effects of converting enzyme inhibition. J Cardiovasc Pharmacol 1987; 3 (suppl): S6-S13.
Replacement of drug treatment for insomnia by ambient odour are
frequently prescribed long-term
medication for insomnia. This could be potentially important in reducing side-effects. Although our results are preliminary, being based on only four patients, it might be worthwhile to investigate this effect more formally under controlled situations. Mark
Hardy, Michael D Kirk-Smith, *David D Stretch
Millaton House Nursing Home, Bridestowe, Okehampton; School of Management, University of Ulster, Newtownabbey Co Antrim, UK; and *Greenwood Institute of Child Health, University of Leicester, Westcotes House, Leicester LE3 0QU, UK
Teuscher E,
Melzig M, Villmann E, Moritz KU. Untersuchungen zum Wirkungsmechanismus atherischer Ole. Phytotherapie 1990; 11: 87-92. 2 Buchbauer G, Jirovetz L, Jager W, Plank C, Dietrich H. Fragrance compounds and essential oils with sedative effects upon inhalation. J Pharm Sci 1993; 82: 660-64. 3 Buchbauer G, Jirovetz L, Jager W, Dietrich H, Plank C, Karamat E. Aromatherapy: evidence for sedative effects of the essential oil of lavender after inhalation. Zeitschrift fur naturforschung c-a. J Biosciences 1991; 46c: 1067-72. 4 Chen YW, Su KSE, Chang S. Nasal systemic drug delivery. New York: Marcel Dekker, 1989.
Aseptic meningitis caused by measlesmumps-rubella vaccine in Japan SIR-Since
measles-mumps-rubella (MMR) vaccine was Japan in April, 1989, a number of cases of post-vaccination aseptic meningitis have been reported and
introduced into to
relieve insomnia in psychogeriatric patients, despite recommendations that they are for short-term use only. They can have serious side-effects, and long-term prescription indicates the difficulty in treating this condition effectively. Pharmacological and animal studies indicate that the main components of lavender oil have a light sedative effect We studied whether lavender oil could replace drug treatment for insomnia. The hours of sleep of each of four psychogeriatric patients were measured for 6 weeks. Patient 1 had been on 10 mg temazepam for 1 year; patient 2 on 25 mg promazine hydrochloride for 3 years; patient 3 on one capsule chlormethiazole for 7 months; and patient 4 on no previous medication. After 2 weeks of measurement (phase 1), medication was withdrawn; for the middle 2 weeks (phase 2), measurement of hours asleep was done (the 2week period being long enough to overcome any rebound insomnia); and for the final 2 weeks (phase 3) ambient lavender oil was introduced into their ward with an odour diffuser. The results (table) suggest that the amount of time spent asleep was significantly reduced after withdrawal of medication, but that amount of time asleep returned to the same level with ambient odour under medication as
Times are median (interquartile range) h spent asleep/night, and probability levels give probabilities with which such differences between medians could arise if due only to chance-differences between the 3 conditions (Kruskal-Wallis). Post-hoc comparisons indicate all pairwise differences, except those between phases 1 and 3. were significant.
Table : Median sleep times
also
continued
1
Department of Nephrology, Hospital Ntra Sra de Candelaria, 38010 S/C de Tenerife, Canary Islands, Spain
SiR-Hypnotic drugs
in all patients by post-hoc comparisons.) Patients reported to be less restless during sleep. This exposure to odour could potentially be more economic than current medication. The study suggests that ambient lavender oil might be used as a temporary relief from
(confirmed
were
these have been attributed to use of Urabe Am9 mumps vaccine.1,2 The incidence of disease associated with vaccine has increased with time; various mumps vaccines may be implicated, and the problem has been reported from other countries.3,4 In Japan, the Ministry of Health and Welfare (MHW) withdrew the domestically produced MMR vaccine in April, 1993.’ To determine the incidence of vaccine-associated aseptic meningitis in Japan, we conducted a prospective study in Fukuoka district between October, 1990, and April, 1993, in collaboration with the MHW Vaccination Study Group. The criteria for inclusion of a case of aseptic meningitis in this study were symptoms of meningitis and pleocytosis in the cerebrospinal fluid. When our study began, only the MHW version of MMR vaccine was available. Because the incidence of meningeal disease associated with the MHW version was found to be high during the first 18 months of the study, three additional vaccine products were later included in our surveillance protocol, in the hope that we would see a decrease in disease incidence: Takeda, Biken, and Kitasato versions became available in October, 1991 (see table). Our study was facilitated by the use of case cards to record observations for 35 days by the vaccinated children’s parents, whose informed consents were obtained by family physicians before inoculation. Vaccinations were given according to a schedule prescribed by the Japanese Vaccination Law. Participants were instructed to consult their doctors if symptoms occurred and further examinations were done only if needed. We did not recommend routine prospective examinations to prove pleocytosis in the cerebrospinal fluid of the vaccinated children. 11800 participants in the Fukuoka district were vaccinated and 10 148 case cards were recovered. MMR versions, MMR virus strains identified, and the incidence of confirmed vaccine-associated aseptic meningitis are summarised in the table. Among the three MMR versions (Biken excepted) the incidences of disease were 701