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SEPSIS AND INDOMETHACIN FAILURE IN PREMATURE INFANTS WITH SYMPTOMATIC PATENT DUCTUS ARTERIOSUS
977 ANTIBODIES TO B BURGDORFERI IN SERA
SEPSIS AND INDOMETHACIN FAILURE IN PREMATURE INFANTS WITH SYMPTOMATIC PATENT DUCTUS ARTERIOSUS SiR,—Indomethacin, a potent inhibitor of prostaglandin synthetase, is commonly used to induce closure of symptomatic patent ductus arteriosus (PDA) in premature infants with hyaline membrane disease. Although therapy has improved the prognosis success rates for ductal closure vary considerably between different centres. To evaluate the influence of sepsis on the success rate of
indomethacin therapy we analysed retrospectively data from 35 premature infants (16 boys, 19 girls; median birthweight 1600 g, range 750-2350; median gestational age 32 weeks, range 27-35) with hyaline membrane disease and symptomatic PDA. After detection and haemodynamic assessment of PDA by doppler echocardiography, indomethacin therapy was given initially as a 03 mg/kg intra-arterial bolus and repeated at 12 and 24 h. Thereafter the maintenance dose was 0-15 mg/kg twice daily. High-pressure liquid chromatographyl was used to monitor plasma indomethacin: levels of more than 0.25 ug/ml were regarded as effective. Doppler echocardiography was repeated at 24 and 72 h after the start of indomethacin therapy. Plasma indomethacin concentrations were higher than 0-25 j!gjml in all 35 infants; the duct closed in only 29. All of the 6 non-responders had sepsis with positive blood-cultures growing Fscherichia coli (3 infants), Streptococcus faecalis (2 infants), and Staphylococcus aureus (1 infant). 28 of the responders had negative blood-cultures; 1 responder had a positive blood-culture for Staph aureus. This infant had the highest indomethacin plasma concentration (1 -2 ug/ml). Our data point towards a relation between sepsis and indomethacin failure in premature infants with hyaline membrane disease and symptomatic PDA. Sepsis may lead to an increased synthesis of PGE2 in premature infants.2-4 If so, indomethacin failure in septic premature infants with symptomatic PDA could be due to higher circulating PGE2 levels. The observation that the 1 responder out of 7 infants with sepsis had the highest plasma indomethacin concentration suggests that ductal closure in septic infants may require higher indomethacin concentrations, which raises questions about a higher dose regimen or surgical closure by
ligation. H. R. SALZER U. SALZER-MUHAR A. POLLAK M. WENINGER
University Paediatric Clinic, A-1090 Vienna, Austria
A, Weninger M, Salzer HR, et al. Liquid-chromatographic determination of plasma indomethacin in premature infants with patent ductus arteriosus. IRCS
1. Pollak
Med Sci 1986; 14: 813-14. 2.
Clyman RI, Brett C, Mauray F. Circulating prostaglandin E2 concentrations and incidence of patent ductus arteriosus in preterm infants with respiratory distress syndrome. Pediatrics 1980; 66: 725-28. 3. Lamont RF, Rose M, Elder MG. Effect of bacterial products on prostaglandin E production by amnion cells. Lancet 1985; ii: 1331-33. 4. Bejar P, Curbelo V, Davis C, Gluck L. Premature labour II: Bacterial sources of phospholipase. Obstet Gynecol 1981; 57: 479-82.
HORSE RESERVOIR FOR BORRELIA BURGDORFERI?
IR,—Lyme disease is caused by
a
spirochaete,
Borrelia
burgdorferi, and is transmitted by the bite of a tick.1 The tick’s hosts include deer, small mammals, and some birds in the United States
and, possibly, the UK. We report here
a case
of
Lyme
disease
possibly contracted from a horse. On Aug 10,1986, a 24-year-old man was bitten on the left side of his neck while tending sick horses in a village in a wooded area of southern Belgium. A few days later erythema chronicum migrans (ECM) developed. On Aug 18 he presented with severe arthritis of the left knee, fever, and a 6 kg weight loss. Cultures of blood, urine, joint fluid, stool, and urethral swab were negative. No crystals were found. Synovial biopsy revealed a non-specific inflammatory arthritis. The symptoms remitted slowly following articular drainage and 10 days of intravenous oxacillin. The diagnosis of Lyme disease was confirmed by specific serological tests (table). Tests for syphilis and autoantibodies were negative. The sick horses had had severe coughs for about 10 days but with
*Positive if 64 or more (- ’ = not tested). tAll sera also positive by ELISA with sonicated B burgdorferi as antigen. All the samples were negative on agglutination testing with ’Leptospira TR’ (Institut
Pasteur).
fever or obvious arthritis. The cough had not responded to geomycin or co-trimoxazole but it disappeared on the administration ofneoarsphenamine. The sera of the three horses were found to contain high-titre antibodies to B burgdorferi (table). We conclude that our patient probably contracted Lyme disease no
from a horse reservoir. Deer are common in the forests of southern
Belgium but the prevalence of specific antibodies to B burgdorferi in Belgian deer is not known. It reached 86% (39/45) in deer from two areas of Britain’ and was 24% (12/50) in selected horses from endemic areas in New England.3 Further serological studies will show whether horses constitute an important reservoir for this disease. Department of Internal Medicine, Clinique du Parc Léopold, 1040 Brussels, Belgium
L. MARCELIS P. DE MARNEFFE E. CHAIDRON
Serology Laboratory, Cliniques Universitaires St-Luc, Brussels Institute of Tropical Medicine,
Antwerp
G. BIGAIGNON P. KAGERUKA P. GOUBAU
AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal etiology of Lyme disease. N Engl J Med 1983; 308: 733-40. 2 Muhlemann MF, Wright DJM. Emerging pattern of Lyme disease in the United Kingdom and Irish Republic. Lancet 1987; i. 260-62. 3. Marcus LC, Patterson MM, Gilfillan RE, et al. Antibodies to Borrelia burgdorferi in New England horses: Serological survey. Am J Vet Res 1985; 46: 2570-71. 1. Steere
BUCCAL AND TOPICAL NITROGLYCERIN
SIR,-Your March 21 editorial (p 666) on giving drugs by the buccal route states that "it was not appreciated that nitroglycerin had no systemic effects after being swallowed (it is metabolised in the liver)". The idea that nitroglycerin has no systemic effects after being swallowed arose from animal experiments in the early 1970s but later work1 revealed high systemic levels of dinitrate metabolites after oral administration of nitroglycerin;’ these metabolites are pharmacologically active.2.3 Your editorial finds the evidence that bucally administered nitroglycerin is beneficial in heart failure in elderly patients’ unconvincing. Yet Sanghera et al4 found striking and improvement in breathlessness, fatigue, and peripheral oedema in a group of patients, more than 80 % of whom were severely incapacitated by grade III/IV heart failure. Lahiri et als (not mentioned in your editorial) evaluated 21 patients with severe congestive heart failure, using exercise testing and angiography. Mean ejection fraction rose from 14 1% (SEM 1-6%) to 19-1 (1-7%) on acute treatment with buccal nitroglycerin and to 21.6 (1 -7 %) on chronic treatment (p < 0 001 ; n = 16). Mean exercise time increased from 3-02 (0-4) min to 5-95 (06) min on chronic therapy
rapid
(p < 0-001). You also state that "long-term therapy with glyceryl trinitrate skin patches may be associated with tolerance to the actions of the drug in association with sustained high plasma concentrations". In the reference citedb Abrams commented that a major problem with transdermal nitroglycerin delivery systems is the limited plasma levels achievable with conventional dosage. He wrote: "NTG [nitroglycerin] plasma concentrations after application of up to 4 low dose units of TD NTG [transdermal nirroglycerin] were quite low. Application of 5-10 mg of NTG in 24 hours results in plasma levels well under 0-5 ng/ml". Plasma levels average 0-16 ng/ml with 5 mg doses, which is a very low concentration. It is not
SEPSIS AND INDOMETHACIN FAILURE IN PREMATURE INFANTS WITH SYMPTOMATIC PATENT DUCTUS ARTERIOSUS SiR,—Indomethacin, a potent inhibitor of prostaglandin synthetase, is commonly used to induce closure of symptomatic patent ductus arteriosus (PDA) in premature infants with hyaline membrane disease. Although therapy has improved the prognosis success rates for ductal closure vary considerably between different centres. To evaluate the influence of sepsis on the success rate of
indomethacin therapy we analysed retrospectively data from 35 premature infants (16 boys, 19 girls; median birthweight 1600 g, range 750-2350; median gestational age 32 weeks, range 27-35) with hyaline membrane disease and symptomatic PDA. After detection and haemodynamic assessment of PDA by doppler echocardiography, indomethacin therapy was given initially as a 03 mg/kg intra-arterial bolus and repeated at 12 and 24 h. Thereafter the maintenance dose was 0-15 mg/kg twice daily. High-pressure liquid chromatographyl was used to monitor plasma indomethacin: levels of more than 0.25 ug/ml were regarded as effective. Doppler echocardiography was repeated at 24 and 72 h after the start of indomethacin therapy. Plasma indomethacin concentrations were higher than 0-25 j!gjml in all 35 infants; the duct closed in only 29. All of the 6 non-responders had sepsis with positive blood-cultures growing Fscherichia coli (3 infants), Streptococcus faecalis (2 infants), and Staphylococcus aureus (1 infant). 28 of the responders had negative blood-cultures; 1 responder had a positive blood-culture for Staph aureus. This infant had the highest indomethacin plasma concentration (1 -2 ug/ml). Our data point towards a relation between sepsis and indomethacin failure in premature infants with hyaline membrane disease and symptomatic PDA. Sepsis may lead to an increased synthesis of PGE2 in premature infants.2-4 If so, indomethacin failure in septic premature infants with symptomatic PDA could be due to higher circulating PGE2 levels. The observation that the 1 responder out of 7 infants with sepsis had the highest plasma indomethacin concentration suggests that ductal closure in septic infants may require higher indomethacin concentrations, which raises questions about a higher dose regimen or surgical closure by
ligation. H. R. SALZER U. SALZER-MUHAR A. POLLAK M. WENINGER
University Paediatric Clinic, A-1090 Vienna, Austria
A, Weninger M, Salzer HR, et al. Liquid-chromatographic determination of plasma indomethacin in premature infants with patent ductus arteriosus. IRCS
1. Pollak
Med Sci 1986; 14: 813-14. 2.
Clyman RI, Brett C, Mauray F. Circulating prostaglandin E2 concentrations and incidence of patent ductus arteriosus in preterm infants with respiratory distress syndrome. Pediatrics 1980; 66: 725-28. 3. Lamont RF, Rose M, Elder MG. Effect of bacterial products on prostaglandin E production by amnion cells. Lancet 1985; ii: 1331-33. 4. Bejar P, Curbelo V, Davis C, Gluck L. Premature labour II: Bacterial sources of phospholipase. Obstet Gynecol 1981; 57: 479-82.
HORSE RESERVOIR FOR BORRELIA BURGDORFERI?
IR,—Lyme disease is caused by
a
spirochaete,
Borrelia
burgdorferi, and is transmitted by the bite of a tick.1 The tick’s hosts include deer, small mammals, and some birds in the United States
and, possibly, the UK. We report here
a case
of
Lyme
disease
possibly contracted from a horse. On Aug 10,1986, a 24-year-old man was bitten on the left side of his neck while tending sick horses in a village in a wooded area of southern Belgium. A few days later erythema chronicum migrans (ECM) developed. On Aug 18 he presented with severe arthritis of the left knee, fever, and a 6 kg weight loss. Cultures of blood, urine, joint fluid, stool, and urethral swab were negative. No crystals were found. Synovial biopsy revealed a non-specific inflammatory arthritis. The symptoms remitted slowly following articular drainage and 10 days of intravenous oxacillin. The diagnosis of Lyme disease was confirmed by specific serological tests (table). Tests for syphilis and autoantibodies were negative. The sick horses had had severe coughs for about 10 days but with
*Positive if 64 or more (- ’ = not tested). tAll sera also positive by ELISA with sonicated B burgdorferi as antigen. All the samples were negative on agglutination testing with ’Leptospira TR’ (Institut
Pasteur).
fever or obvious arthritis. The cough had not responded to geomycin or co-trimoxazole but it disappeared on the administration ofneoarsphenamine. The sera of the three horses were found to contain high-titre antibodies to B burgdorferi (table). We conclude that our patient probably contracted Lyme disease no
from a horse reservoir. Deer are common in the forests of southern
Belgium but the prevalence of specific antibodies to B burgdorferi in Belgian deer is not known. It reached 86% (39/45) in deer from two areas of Britain’ and was 24% (12/50) in selected horses from endemic areas in New England.3 Further serological studies will show whether horses constitute an important reservoir for this disease. Department of Internal Medicine, Clinique du Parc Léopold, 1040 Brussels, Belgium
L. MARCELIS P. DE MARNEFFE E. CHAIDRON
Serology Laboratory, Cliniques Universitaires St-Luc, Brussels Institute of Tropical Medicine,
Antwerp
G. BIGAIGNON P. KAGERUKA P. GOUBAU
AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal etiology of Lyme disease. N Engl J Med 1983; 308: 733-40. 2 Muhlemann MF, Wright DJM. Emerging pattern of Lyme disease in the United Kingdom and Irish Republic. Lancet 1987; i. 260-62. 3. Marcus LC, Patterson MM, Gilfillan RE, et al. Antibodies to Borrelia burgdorferi in New England horses: Serological survey. Am J Vet Res 1985; 46: 2570-71. 1. Steere
BUCCAL AND TOPICAL NITROGLYCERIN
SIR,-Your March 21 editorial (p 666) on giving drugs by the buccal route states that "it was not appreciated that nitroglycerin had no systemic effects after being swallowed (it is metabolised in the liver)". The idea that nitroglycerin has no systemic effects after being swallowed arose from animal experiments in the early 1970s but later work1 revealed high systemic levels of dinitrate metabolites after oral administration of nitroglycerin;’ these metabolites are pharmacologically active.2.3 Your editorial finds the evidence that bucally administered nitroglycerin is beneficial in heart failure in elderly patients’ unconvincing. Yet Sanghera et al4 found striking and improvement in breathlessness, fatigue, and peripheral oedema in a group of patients, more than 80 % of whom were severely incapacitated by grade III/IV heart failure. Lahiri et als (not mentioned in your editorial) evaluated 21 patients with severe congestive heart failure, using exercise testing and angiography. Mean ejection fraction rose from 14 1% (SEM 1-6%) to 19-1 (1-7%) on acute treatment with buccal nitroglycerin and to 21.6 (1 -7 %) on chronic treatment (p < 0 001 ; n = 16). Mean exercise time increased from 3-02 (0-4) min to 5-95 (06) min on chronic therapy
rapid
(p < 0-001). You also state that "long-term therapy with glyceryl trinitrate skin patches may be associated with tolerance to the actions of the drug in association with sustained high plasma concentrations". In the reference citedb Abrams commented that a major problem with transdermal nitroglycerin delivery systems is the limited plasma levels achievable with conventional dosage. He wrote: "NTG [nitroglycerin] plasma concentrations after application of up to 4 low dose units of TD NTG [transdermal nirroglycerin] were quite low. Application of 5-10 mg of NTG in 24 hours results in plasma levels well under 0-5 ng/ml". Plasma levels average 0-16 ng/ml with 5 mg doses, which is a very low concentration. It is not