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ETHAMSYLATE REDUCES THE INCIDENCE OF PERIVENTRICULAR HAEMORRHAGE IN VERY LOW BIRTH-WEIGHT BABIES
830
acyclovir on both skin healing and pain does not support this contention. This investigation shows that acyclovir is highly effective and non-toxic when used systemically in the treatment of acute herpes zoster. The need for intravenous administration clearly limits the use of the drug for treatment of local herpes zoster in the non-immunocompromised host. We thank the Wellcome Research Laboratories, material.
England, for advice and
Requests for reprints should be addressed to V. E., Marselisborg Hospital, Århus C., Denmark.
DK-8000
REFERENCES
herpes simplex. Lancet 1980; i: 1337-39. Elion GB, Furman PA, Fyfe J, Miranda P, Beauchamp L, Schaeffer HJ. Selectivity of action of an antiherpetic agent, 9-(2-hydroxy-ethoxymethyl) guanine. Proc Natl Acad Sci U.S.A. 1977; 74: 5716-20. Selby PJ, Powles RL, Jameson B, et al. Parenteral acyclovir therapy for herpes virus infections in man. Lancet 1979; ii: 1267-70. Mitchell CD, Bean B, Gentry SR, Groth KE, Boen JR, Balfour HH Jr Acyclovir treatment for mucocutaneous herpes simplex infections in immunocompromised patients. Lancet 1981; ii: 1389-92. Wildenhoff KE, Ipsen J, Esmann V, et al. Treatment of herpes zoster with idoxuridine ointment, including a multivariate analysis of symptoms and signs. Scand JJnf Dis
1. Editorial. Antiviral treatment of varicella zoster and 2.
3. 4.
5.
6. 7.
1979; 11: 1-9. Wildenhoff KE, Esmann V, Ipsen J, et al. Treatment oftrigeminal and thoracic zoster with idoxuridine. Scand J Inf Dis 1981; 13: 257-62. Ipsen J, Feigl P. Appropriate scores for clinical and public health variables. Am J Publ Health 1966; 56: 1287-95.
ETHAMSYLATE REDUCES THE INCIDENCE OF PERIVENTRICULAR HAEMORRHAGE IN VERY LOW BIRTH-WEIGHT BABIES M. E. I. MORGAN I. W. T. BENSON R. W. I.COOKE M. E. I. MORGAN J.
.
BENSON
Regional Neonatal Intensive Care Unit Department of Child Health, Liverpool University, Liverpool Maternity Hospital
Summary
The effect of
ethamsylate, a capillarystabilising drug, in limiting or preventing periventricular haemorrhage (PVH) in 70 very low birthweight babies was evaluated in a double-blind trial. PVH developed in 9 of the 35 infants on ethamsylate and 18 of the 35 infants who received placebo. Mortality associated with PVH was similar in both groups, but the incidence of PVH of all grades in survivors was reduced in the ethamsylate-treated group.
hospital. One had Potter’s syndrome with pulmonary hypoplasia, the second had trisomy 18. Both infants died shortly this
at
after birth and neither was included in the trial. No other exclusions occurred. Ethamsylate (125 mg/ml) or placebo were provided by the manufacturer (’Dicynene’, Delandale Laboratories, Canterbury) m 80 numbered batches of 16 ampoules. The randomised code was held by the manufacturer until the end of the trial. Approval for the trial was obtained from the hospital ethical committee. Infants received 0 1 ml/kg of drug or placebo intramuscularly within 2 h of birth and thereafter 6-hourly for 4 days. Ultrasound brain scanning was carried out before the first dose of trial drug, and daily for the first week of life, unless the infant died earlier. An Adavanced Technology Laboratories 850A rotary mechanical sector scanner with 5 MHz transducers was used and scans were photographed on Polaroid film from a slave monitor. Parasaggital and coronal views were recorded via the anterior fontanelle.9-11 Ultrasound appearances of PVH were graded from 1 to 4 by a system based on that of Papile et al.2developed for computerised tomography scanning. Clinical data relating to factors known to be associated with the incidence of PVH, such as gestational age, weight, evidence of birth asphyxia, respiratory disease &c. were recorded. 12
Results 73 infants were entered into the trial. 3 infants were found have PVH before drug treatment began and have been considered separately. Of the remaining 70 infants, 35 received ethamsylate. 7 of the original 80 batches contained damaged vials and these were discarded during the trial. Clinical factors which may have been related to development of PVH were evenly matched in both groups; these included mode of delivery, exposure to labour, birth-weight, presence of birth asphyxia, gestational age, and growth retardation. The distribution of postnatal insults such as respiratory distress requiring ventilatory support, hypercapnia, acidosis, and development of pneumothorax were also not significantly different in the two groups (table 1). PVH developed in 9 infants in the ethamsylate-treated group and 18 in the placebo group (x2 6 - 0; p<0. 02). The distribution of haemorrhage differed between the groups, with an excess of small non-fatal bleeds in the placebo group (table n). The overall mortality in the two groups did not differ and the mean time of initial detection of haemorrhage was 48 h after birth in both groups. 3 infants had intraventricular haemorrhage (IVH) noted on the initial scan before they were 2 h old; all were small immature infants who had been delivered vaginally (2
to
=
TABLE I-CLINICAL FACTORS IN DRUG-TREATED AND PLACEBO-
Introduction
TREATED INFANTS
haemorrhage (PVH) is detected in birth-weight infants’ by non-invasive diagnostic techniques such as computerised tomography2,3or
PERIVENTRICULAR 40-50% of very low
real-time ultrasound.4 PVH is an important cause of neonatal mortality5 and also contributes substantially to late morbidity and handicap.6, 7 Anatomical studies have shown that the most usual site of origin of PVH is the capillary network of vessels supplying the germinal matrix of the developing brain.8 Because PVH is often progressive or saltatory rather than catastrophic it seemed reasonable to test the effect of a capillary-stabilising drug, ethamsylate, in limiting or preventing PVH. Patients and Methods The study was limited to patients weighing less than 1500 g and born in the Liverpool Maternity Hospital. During the 15-month trial 2 malformed infants weighing less than 1500 g were born alive
*Apgar score <3 at 1 min. Continuous positive airways
pressure or intermittent positive pressure ventilation for 1 h. kPa on any occasion from intermittent arterial blood gas. pCO2>8 Arterial pH<7’ 15 over same period. Requiring thoracocentesis. CS = caesarean section.
831 TABLE III—CAUSES OF NEONATAL DEATH IN BOTH GROUPS
TABLE II-GRADE OF HAEMORRHAGE IN DRUG-TREATED AND PLACEBO-TREATED INFANTS
and had bruising noted clinically. 2 of these infants received placebo; 1 had grade 1 IVH which extended to grade 3 at 12 h. The third infant received ethamsylate; this child had a unilateral subependymal bleed which did not extend subsequently.
unmonitored)
Discussion
Ethamsylate is a synthetic water-soluble non-steroidal drug (diethylammonium 2,5,-dihydroxybenzenesulphonate) which is absorbed and excreted unchanged. 13 It has been used clinically to reduce capillary bleeding in ear surgery, buccal surgery,14 after prostatectomy, 15 and in menorrhagia.16 It has no known toxic effects, and in particular no association with venous thrombosis. Animal and clinical trials suggest that it increases platelet adhesiveness, and capillary resistance, while reducing the bleeding time and increasing local intrinsic thromboplastin release. 13 It is thought to have a dual action on capillary bleeding-i.e., reinforcement of the capillary basal membrane by action on the polymerisation of its constituent hyaluronic acid, and increase of platelet adhesiveness, thus maintaining the integrity of the capillary wall by platelet occlusion of endothelial lacunae.17 Its effect is known to be most evident in haemorrhage originating from capillaries, whereas it is inactive where there is a serious coagulation defect, thrombocytopenia, or rupture of a large blood-vessel. It has not previously been used clinically in premature infants. PVH in the preterm low birth-weight infant is currently thought to arise from rupture of the poorly supported capillaries in the subependymal germinal matrix. The area surrounding these vessels has a high fibrinolytic activity because of the presence of a local plasminogen activator; this may contribute to the failure of localisation of germinal
capillary haemorrhage.’8 Although abnormalities of haemostasis are common in infants with respiratory distress syndrome and PVH, there is are causal. no evidence that they However, platelet dysfunction has been seen on day 1 in a group of infants in whom PVH subsequently developed. 19 There is no evidence that administration of coagulation factors can prevent PVH; the emphasis of current hypotheses concerning its origin is on capillary haemorrhage which, in other clinical situations, can be effectively controlled by ethamsylate. In this study, ethamsylate-treated infants had half the incidence of PVH when compared with the placebo group. No complications attributable to ethamsylate were observed. The reduction in incidence of PVH was, however, mainly confined to the smaller bleeds, with mortality associated with PVH remaining similar in both groups (table III). Follow-up studies suggest that small (grade 1) bleeds are not often associated with serious neurological or developmental sequelae in survivors, at least during the first year of life.7 Larger bleeds are related to increasing risk of poor outcome. Although overall mortality in the two groups was similar (9 treated, 7 untreated); only 1 surviving infant in the treated group had
a
large PVH, but there
were
5 survivors with
grades 2-4 PVH in the placebo group. It could be argued that these results indicate that ethamsylate treatment was in some way ensuring that a grade 2-4 haemorrhage was fatal. However, a similar number of infants with a grade 2-4 bleed died in each group (6 treated, 5 placebo) making this unlikely. We believe that although the main effect of ethamsylate was as expected-to reduce the incidence of small bleeds by maintaining capillary integrity-it also reduced the occurrence of larger bleeds in survivors. The general effect of ethamsylate treatment may be to reduce the likelihood oflater handicap. The aetiology ofPVH is certainly multifactorial, and close attention to details of management of very low birth-weight -infants with respiratory disease may help to reduce its prevalence in the future. In conjunction with each management, ethamsylate can contribute to the reduction of PVH of all grades in survivors. We are grateful to Delandale Laboratories for their help in providing the drug and placebo and to the medical and nursing staffinvolved in caring for the patients for their help in recording clinical data. Requests for reprints should be addressed to R. C., Regional Neonatal Intensive Care Unit, Department of Child Health, Liverpool Maternity Hospital, Oxford Street, Liverpool L7 7BN.
REFERENCES 1. Volpe JJ. Neonatal intraventricular haemorrhage. N Engl J Med 1981; 304: 886-91. 2. Papile L-A, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular haemorrhage; a study of infants with birth weights less than 1500 g. J pediat 1978; 92: 529-34. 3. Ahmann PA, Lazzara A, Dykes FD, Brann AW Jr, Schwartz JF. Intraventricular haemorrhage in the high-risk preterm infant, incidence and outcome. Ann Neurol
1980; 7: 118-24. 4.
Pape KE, Blackwell RJ, Cusick G, Sherwood A, Huang MTW, Thorburn RJ, Reynolds EOR. Ultrasound detection of brain damage in preterm infants. Lancet 1979; i: 1261-64.
5. Pape KE, Wigglesworth JS. Haemorrhage, ischaemia and the perinatal brain. Philadelphia: J. B. Lippincott, 1979. 6. Krishnamoorhy KS, Shannon DC, DeLong GR, Todres ID, Davies KR. Neurologic sequelae in the survivors of neonatal intraventricular haemorrhage. Pediatrics 1979; 64: 233-37. 7. Thorburn RJ, Lipscomb AP, Stewart AL, Reynolds EOR, Hope PL, Pape KE. Prediction of death and major handicap in very preterm infants by brain ultrasound. Lancet 1981; i: 1119-21. 8. Hambleton G, Wigglesworth JS. Origin of intraventricular haemorrhage in the preterm infant. Arch Dis Child 1976; 51: 651-59. 9. Cooke RWI. Ultrasound examination of neonatal heads. Lancet 1979; ii: 38. 10. Cooke RWI. Diagnosis of periventricular haemorrhage by real time two dimensional ultrasound sector scanning. In: Rolfe P, ed. Fetal and neonatal monitoring. London: Pitman Medical, 1980: 344-55. 11. Cooke RWI. Factors associated with periventricular haemorrhage in very low birth weight infants. Arch Dis Child 1981; 56: 425-31. 12. Dykes FD, Lazzara A, Ahmann P, Blumenstein B, Schwartz J, Brann AW Intraventricular haemorrhage; a prospective evaluation of etiopathogenesis. Pediatrics 1980; 66: 42-49. 13. Deacock AR de C, Birley DM. The antihaemorrhagic activity of ethamsylate (dicynene). Br J Anaesth 1969; 41: 18-24. 14. Held AJ Dicynene in stomatology. International colloquium on the actions and effects of dicynene, Geneva, OM Laboratories, 1966. 15. Symes JM, Offen DN, Lyttle JA, Blandy JP, Chapitt de Saintonge DM. The effect of dicynene on blood loss during and after transurethral resection of the prostate. Br J Urol 1975; 47: 203-07. 16. Harrison RF, Campbell S. A double blind trial of ethamsylate in the treatment of primary and intrauterine-device menorrhagia. Lancet 1976; ii: 283-85. 17. Huguet G, Thomas J, Raynaud G. Action of cylonamine, a haemostatic drug, on capillary premeability and resistance. Therapie 1969; 24: 429-50. 18. Gilles FH, Price RA, Kevy SV, Berenberg W. Fibrinolytic activity in the ganglionic eminence of the premature human brain. Biol Neonate 1971; 18: 426-32. 19. Setzer ES, Webb IB, Wassenaar JW, Reeder JD, Mehta PS, Eitzman DV. Platelet dysfunction: an etiologic factor in intraventricular haemorrhage in the premature. Paediat Res 1981; 15: 1423.
acyclovir on both skin healing and pain does not support this contention. This investigation shows that acyclovir is highly effective and non-toxic when used systemically in the treatment of acute herpes zoster. The need for intravenous administration clearly limits the use of the drug for treatment of local herpes zoster in the non-immunocompromised host. We thank the Wellcome Research Laboratories, material.
England, for advice and
Requests for reprints should be addressed to V. E., Marselisborg Hospital, Århus C., Denmark.
DK-8000
REFERENCES
herpes simplex. Lancet 1980; i: 1337-39. Elion GB, Furman PA, Fyfe J, Miranda P, Beauchamp L, Schaeffer HJ. Selectivity of action of an antiherpetic agent, 9-(2-hydroxy-ethoxymethyl) guanine. Proc Natl Acad Sci U.S.A. 1977; 74: 5716-20. Selby PJ, Powles RL, Jameson B, et al. Parenteral acyclovir therapy for herpes virus infections in man. Lancet 1979; ii: 1267-70. Mitchell CD, Bean B, Gentry SR, Groth KE, Boen JR, Balfour HH Jr Acyclovir treatment for mucocutaneous herpes simplex infections in immunocompromised patients. Lancet 1981; ii: 1389-92. Wildenhoff KE, Ipsen J, Esmann V, et al. Treatment of herpes zoster with idoxuridine ointment, including a multivariate analysis of symptoms and signs. Scand JJnf Dis
1. Editorial. Antiviral treatment of varicella zoster and 2.
3. 4.
5.
6. 7.
1979; 11: 1-9. Wildenhoff KE, Esmann V, Ipsen J, et al. Treatment oftrigeminal and thoracic zoster with idoxuridine. Scand J Inf Dis 1981; 13: 257-62. Ipsen J, Feigl P. Appropriate scores for clinical and public health variables. Am J Publ Health 1966; 56: 1287-95.
ETHAMSYLATE REDUCES THE INCIDENCE OF PERIVENTRICULAR HAEMORRHAGE IN VERY LOW BIRTH-WEIGHT BABIES M. E. I. MORGAN I. W. T. BENSON R. W. I.COOKE M. E. I. MORGAN J.
.
BENSON
Regional Neonatal Intensive Care Unit Department of Child Health, Liverpool University, Liverpool Maternity Hospital
Summary
The effect of
ethamsylate, a capillarystabilising drug, in limiting or preventing periventricular haemorrhage (PVH) in 70 very low birthweight babies was evaluated in a double-blind trial. PVH developed in 9 of the 35 infants on ethamsylate and 18 of the 35 infants who received placebo. Mortality associated with PVH was similar in both groups, but the incidence of PVH of all grades in survivors was reduced in the ethamsylate-treated group.
hospital. One had Potter’s syndrome with pulmonary hypoplasia, the second had trisomy 18. Both infants died shortly this
at
after birth and neither was included in the trial. No other exclusions occurred. Ethamsylate (125 mg/ml) or placebo were provided by the manufacturer (’Dicynene’, Delandale Laboratories, Canterbury) m 80 numbered batches of 16 ampoules. The randomised code was held by the manufacturer until the end of the trial. Approval for the trial was obtained from the hospital ethical committee. Infants received 0 1 ml/kg of drug or placebo intramuscularly within 2 h of birth and thereafter 6-hourly for 4 days. Ultrasound brain scanning was carried out before the first dose of trial drug, and daily for the first week of life, unless the infant died earlier. An Adavanced Technology Laboratories 850A rotary mechanical sector scanner with 5 MHz transducers was used and scans were photographed on Polaroid film from a slave monitor. Parasaggital and coronal views were recorded via the anterior fontanelle.9-11 Ultrasound appearances of PVH were graded from 1 to 4 by a system based on that of Papile et al.2developed for computerised tomography scanning. Clinical data relating to factors known to be associated with the incidence of PVH, such as gestational age, weight, evidence of birth asphyxia, respiratory disease &c. were recorded. 12
Results 73 infants were entered into the trial. 3 infants were found have PVH before drug treatment began and have been considered separately. Of the remaining 70 infants, 35 received ethamsylate. 7 of the original 80 batches contained damaged vials and these were discarded during the trial. Clinical factors which may have been related to development of PVH were evenly matched in both groups; these included mode of delivery, exposure to labour, birth-weight, presence of birth asphyxia, gestational age, and growth retardation. The distribution of postnatal insults such as respiratory distress requiring ventilatory support, hypercapnia, acidosis, and development of pneumothorax were also not significantly different in the two groups (table 1). PVH developed in 9 infants in the ethamsylate-treated group and 18 in the placebo group (x2 6 - 0; p<0. 02). The distribution of haemorrhage differed between the groups, with an excess of small non-fatal bleeds in the placebo group (table n). The overall mortality in the two groups did not differ and the mean time of initial detection of haemorrhage was 48 h after birth in both groups. 3 infants had intraventricular haemorrhage (IVH) noted on the initial scan before they were 2 h old; all were small immature infants who had been delivered vaginally (2
to
=
TABLE I-CLINICAL FACTORS IN DRUG-TREATED AND PLACEBO-
Introduction
TREATED INFANTS
haemorrhage (PVH) is detected in birth-weight infants’ by non-invasive diagnostic techniques such as computerised tomography2,3or
PERIVENTRICULAR 40-50% of very low
real-time ultrasound.4 PVH is an important cause of neonatal mortality5 and also contributes substantially to late morbidity and handicap.6, 7 Anatomical studies have shown that the most usual site of origin of PVH is the capillary network of vessels supplying the germinal matrix of the developing brain.8 Because PVH is often progressive or saltatory rather than catastrophic it seemed reasonable to test the effect of a capillary-stabilising drug, ethamsylate, in limiting or preventing PVH. Patients and Methods The study was limited to patients weighing less than 1500 g and born in the Liverpool Maternity Hospital. During the 15-month trial 2 malformed infants weighing less than 1500 g were born alive
*Apgar score <3 at 1 min. Continuous positive airways
pressure or intermittent positive pressure ventilation for 1 h. kPa on any occasion from intermittent arterial blood gas. pCO2>8 Arterial pH<7’ 15 over same period. Requiring thoracocentesis. CS = caesarean section.
831 TABLE III—CAUSES OF NEONATAL DEATH IN BOTH GROUPS
TABLE II-GRADE OF HAEMORRHAGE IN DRUG-TREATED AND PLACEBO-TREATED INFANTS
and had bruising noted clinically. 2 of these infants received placebo; 1 had grade 1 IVH which extended to grade 3 at 12 h. The third infant received ethamsylate; this child had a unilateral subependymal bleed which did not extend subsequently.
unmonitored)
Discussion
Ethamsylate is a synthetic water-soluble non-steroidal drug (diethylammonium 2,5,-dihydroxybenzenesulphonate) which is absorbed and excreted unchanged. 13 It has been used clinically to reduce capillary bleeding in ear surgery, buccal surgery,14 after prostatectomy, 15 and in menorrhagia.16 It has no known toxic effects, and in particular no association with venous thrombosis. Animal and clinical trials suggest that it increases platelet adhesiveness, and capillary resistance, while reducing the bleeding time and increasing local intrinsic thromboplastin release. 13 It is thought to have a dual action on capillary bleeding-i.e., reinforcement of the capillary basal membrane by action on the polymerisation of its constituent hyaluronic acid, and increase of platelet adhesiveness, thus maintaining the integrity of the capillary wall by platelet occlusion of endothelial lacunae.17 Its effect is known to be most evident in haemorrhage originating from capillaries, whereas it is inactive where there is a serious coagulation defect, thrombocytopenia, or rupture of a large blood-vessel. It has not previously been used clinically in premature infants. PVH in the preterm low birth-weight infant is currently thought to arise from rupture of the poorly supported capillaries in the subependymal germinal matrix. The area surrounding these vessels has a high fibrinolytic activity because of the presence of a local plasminogen activator; this may contribute to the failure of localisation of germinal
capillary haemorrhage.’8 Although abnormalities of haemostasis are common in infants with respiratory distress syndrome and PVH, there is are causal. no evidence that they However, platelet dysfunction has been seen on day 1 in a group of infants in whom PVH subsequently developed. 19 There is no evidence that administration of coagulation factors can prevent PVH; the emphasis of current hypotheses concerning its origin is on capillary haemorrhage which, in other clinical situations, can be effectively controlled by ethamsylate. In this study, ethamsylate-treated infants had half the incidence of PVH when compared with the placebo group. No complications attributable to ethamsylate were observed. The reduction in incidence of PVH was, however, mainly confined to the smaller bleeds, with mortality associated with PVH remaining similar in both groups (table III). Follow-up studies suggest that small (grade 1) bleeds are not often associated with serious neurological or developmental sequelae in survivors, at least during the first year of life.7 Larger bleeds are related to increasing risk of poor outcome. Although overall mortality in the two groups was similar (9 treated, 7 untreated); only 1 surviving infant in the treated group had
a
large PVH, but there
were
5 survivors with
grades 2-4 PVH in the placebo group. It could be argued that these results indicate that ethamsylate treatment was in some way ensuring that a grade 2-4 haemorrhage was fatal. However, a similar number of infants with a grade 2-4 bleed died in each group (6 treated, 5 placebo) making this unlikely. We believe that although the main effect of ethamsylate was as expected-to reduce the incidence of small bleeds by maintaining capillary integrity-it also reduced the occurrence of larger bleeds in survivors. The general effect of ethamsylate treatment may be to reduce the likelihood oflater handicap. The aetiology ofPVH is certainly multifactorial, and close attention to details of management of very low birth-weight -infants with respiratory disease may help to reduce its prevalence in the future. In conjunction with each management, ethamsylate can contribute to the reduction of PVH of all grades in survivors. We are grateful to Delandale Laboratories for their help in providing the drug and placebo and to the medical and nursing staffinvolved in caring for the patients for their help in recording clinical data. Requests for reprints should be addressed to R. C., Regional Neonatal Intensive Care Unit, Department of Child Health, Liverpool Maternity Hospital, Oxford Street, Liverpool L7 7BN.
REFERENCES 1. Volpe JJ. Neonatal intraventricular haemorrhage. N Engl J Med 1981; 304: 886-91. 2. Papile L-A, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular haemorrhage; a study of infants with birth weights less than 1500 g. J pediat 1978; 92: 529-34. 3. Ahmann PA, Lazzara A, Dykes FD, Brann AW Jr, Schwartz JF. Intraventricular haemorrhage in the high-risk preterm infant, incidence and outcome. Ann Neurol
1980; 7: 118-24. 4.
Pape KE, Blackwell RJ, Cusick G, Sherwood A, Huang MTW, Thorburn RJ, Reynolds EOR. Ultrasound detection of brain damage in preterm infants. Lancet 1979; i: 1261-64.
5. Pape KE, Wigglesworth JS. Haemorrhage, ischaemia and the perinatal brain. Philadelphia: J. B. Lippincott, 1979. 6. Krishnamoorhy KS, Shannon DC, DeLong GR, Todres ID, Davies KR. Neurologic sequelae in the survivors of neonatal intraventricular haemorrhage. Pediatrics 1979; 64: 233-37. 7. Thorburn RJ, Lipscomb AP, Stewart AL, Reynolds EOR, Hope PL, Pape KE. Prediction of death and major handicap in very preterm infants by brain ultrasound. Lancet 1981; i: 1119-21. 8. Hambleton G, Wigglesworth JS. Origin of intraventricular haemorrhage in the preterm infant. Arch Dis Child 1976; 51: 651-59. 9. Cooke RWI. Ultrasound examination of neonatal heads. Lancet 1979; ii: 38. 10. Cooke RWI. Diagnosis of periventricular haemorrhage by real time two dimensional ultrasound sector scanning. In: Rolfe P, ed. Fetal and neonatal monitoring. London: Pitman Medical, 1980: 344-55. 11. Cooke RWI. Factors associated with periventricular haemorrhage in very low birth weight infants. Arch Dis Child 1981; 56: 425-31. 12. Dykes FD, Lazzara A, Ahmann P, Blumenstein B, Schwartz J, Brann AW Intraventricular haemorrhage; a prospective evaluation of etiopathogenesis. Pediatrics 1980; 66: 42-49. 13. Deacock AR de C, Birley DM. The antihaemorrhagic activity of ethamsylate (dicynene). Br J Anaesth 1969; 41: 18-24. 14. Held AJ Dicynene in stomatology. International colloquium on the actions and effects of dicynene, Geneva, OM Laboratories, 1966. 15. Symes JM, Offen DN, Lyttle JA, Blandy JP, Chapitt de Saintonge DM. The effect of dicynene on blood loss during and after transurethral resection of the prostate. Br J Urol 1975; 47: 203-07. 16. Harrison RF, Campbell S. A double blind trial of ethamsylate in the treatment of primary and intrauterine-device menorrhagia. Lancet 1976; ii: 283-85. 17. Huguet G, Thomas J, Raynaud G. Action of cylonamine, a haemostatic drug, on capillary premeability and resistance. Therapie 1969; 24: 429-50. 18. Gilles FH, Price RA, Kevy SV, Berenberg W. Fibrinolytic activity in the ganglionic eminence of the premature human brain. Biol Neonate 1971; 18: 426-32. 19. Setzer ES, Webb IB, Wassenaar JW, Reeder JD, Mehta PS, Eitzman DV. Platelet dysfunction: an etiologic factor in intraventricular haemorrhage in the premature. Paediat Res 1981; 15: 1423.