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Ischaemia and Haemorrhage in thePremature Brain

THE LANCET

FOUR years and two international conferences have

passed since our last editorial on intraventricular

haemorrhage.’ What have we learnt in the interim?Few would now dispute that subependymal haemor-rhage and resulting intraventricular haemorrhage(SEH-IVH) is essentially a condition of prematureinfants (although occasionally seen in babies born atfull term2) and that bleeding usually arises from fragilecapillaries of the subependymal plate with subsequentrupture into the ventricles. This bleeding is probablyof little consequence in the absence of either post-haemorrhagic ventricular dilatation or extension intothe cerebral parenchyma. The frequency of

parenchymal extension of IVH is reported to varybetween 4%4 and 27% 15-20% seems a realisticestimate of its likelihood. Intraparenchymalhaemorrhage associated with SEH-IVH, an importantcause of subsequent handicap,6 is thought to be due todirect extension from an intraventricular haemorrhagewhich bursts through the ependyma to infiltrate whitematter.’ This may not necessarily be destructive iftissue is pushed aside to allow space for theextravasated blood.8 In many cases there is no means of

saying how much of the damage is due to primaryparenchymal extension and how much to secondaryinfarction of tissue adjacent to the haematoma mass.Lately, two groups have suggested that parenchymal"haemorrhage" may be due to bleeding into a primaryischaemic lesion.9’o This important point will bereturned to later.

1. Editorial. Towards the prevention of intraventricular haemorrhage. Lancet 1980; i:

236-37.

2. Lacey DJ, Terplan K. Intraventricular haemorrhage in full-term neonates. Devel MedChild Neural 1982; 24: 332-37.

3. Hambleton G, Wigglesworth JS. Origin of intraventricular haemorrhage in the

preterm infant. Arch Dis Child 1976; 51: 651-59.4. Hawgood S, Spong J, Yu V. Intraventricular hemorrhage. Incidence and outcome in a

population of very-low-birth-weight infants. Am J Dis Child 1984; 138: 136-39.5. Kosmetatos N, Dmter C, Williams ML, Lourie H, Berne AS. Intracranial hemorrhage

m the premature. Its predictive features and outcome. Am J Dis Child 1980; 134:855-59.

6 Papile L-A, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricularhemorrhage and early childhood neurologic handicaps. J Pediatr 1983; 103:273-77.

7 Larroche J-L. Developmental pathology of the neonate. Amsterdam: Excerpta Medica,1977.

8. Rorke LB. Pathology of perinatal brain injury. New York. Raven Press, 1982.9 Flodmark O, Becker LE, Harwood-Nash DC, Fitzhardinge PM, Fitz CR, Chuang SH.

Correlation between computed tomography and autopsy in premature and full-termneonates that have suffered perinatal asphyxia. Radiology 1980; 137: 93-103.

10. Volpe JJ, Herscovitch P, Perlman JM, Raichle ME. Positron emission tomography inthe newborn: Extensive impairment of regional cerebral blood flow with intra-ventricular hemorrhage and hemorrhagic intracerebral involvement Pediatrics

1983, 72: 589-601.

Real-time ultrasound has provided a convenient andsafe technique to diagnose and study SEH-IVH but theresults, like those with computerised tomography,have been inconsistent: the reported incidence of SEH-IVH in premature infants has ranged from 32%" to90%.12 Data from recently published reports suggestan incidence, in infants ofbirthweight 1500 g or less, of40-50%. There are fewer data on smaller babies, butthe incidence in infants of birth weight 1250 g or belowis in the region of 55-65%.Almost all haemorrhages occur in the first week of

life but the precise timing is disputed. According to twogroups, about 90% of infants with SEH-IVH have bledwithin 24 hours ofbirth.12,13 One group found that 67%of lesions were present at 6 hours of age and a sub-stantial number were present within 1 hour of birth,’3implying prepartum haemorrhage. Other centres,however, claim that the onset of bleeding is distributedmore or less equally between the first, second, and third24-hour periods.14,15 In some infants bleeding may notbe a sudden event but may evolve to its maximumextent over a few days;16,17 but another possibleexplanation in such-cases is periventricular infarctionrather than primary intraparenchymal haemorrhage. Ifwe knew what mechanism prevents SEH-IVH from

arising after the first three or four days of life, we mighthave an important lead to prevention.Apart from strong associations with prematurity and

respiratory syndrome, what aetiological clues haveemerged? Disappointingly few clear factors can beelucidated. The three groups who have looked at riskfactors operating before the onset of haemorrhagesuggest that hypercapnia,18 acidosis,14 and pneumo-thorax15 are important predisposing events. These areall closely related to the severity of the lung disease.Other risk factors that may be important are birthoutside, and transfer into, a neonatal intensive careunit4>m>13-’s and coagulation defects. 15,19 Beverley et aFosuggest that, although clotting disorders are not thecause of SEH-IVH, once subependymal capillaryrupture has occurred severe coagulopathy will

predispose to extensive haemorrhage. Surprisingly, noobstetric factor other than place of birth, can

11. Clark CE, Clyman RI, Roth RS, Sniderman SH, Lane B, Ballard RA. Risk factoranalysis of intraventricular hemorrhage in low-birth-weight infants. J Pediatr 1981;99: 625-28.

12. Bejar R, Curbelo V, Coen RW, Leopold G, James H, Gluck L. Diagnosis and follow-upof intraventricular and mtracerebral hemorrhages by ultrasound studies of infant’sbrain through the fontanelle and sutures. Pediatrics 1980; 66: 661-73.

13. de Crespigny LCh, MacKay R, Muston LJ, Roy RND, Robinson PH. Timing ofneonatal cerebroventricular haemorrhage with ultrasound. Arch Dis Child 1982; 57:231-33.

14. Levene MI, Fawer C-L, Lamont RF. Risk factors in the development of intra-ventricular haemorrhage Arch Dis Child 1982; 57: 410-17.

15. Thorburn RJ, Lipscomb AP, Stewart AL, Reynolds EOR, Hope PL Timing andantecedents of periventricular haemorrhage and of cerebral atrophy in very preterminfants. Early Hum Devel 1982; 7: 221-38.

16. Levene MI, de Vries L Extension of neonatal intraventricular haemorrhage Arch DisChild 1984; 59: 631-36.

17. Szymonowicz W, Yu V. Timing and evolution of periventricular haemorrhage ininfants weighing 1250g or less at birth Arch Dis Child 1984; 59: 7-12.

18 Szymonowicz W, Yu V, Wilson FE. Antecedents of periventricular haemorrhage ininfants weighing 1250g or less at birth. Arch Dis Child 1984, 59: 13-17.

19 Setzer ES, Webb IB, Wassenaar JW, Reeder JD, Mehta PS, Eitzman DV. Plateletdysfunction and coagulopathy in intraventricular hemorrhage in the prematureinfant. J Pediatr 1982; 100: 599-605.

20. Beverley DW, Chance GW, Inwood MJ, Schaus M, O’Keefe B. Intraventricularhaemorrhage and haemostasis defects Arch Dis Child 1984, 59: 444-48.

848

convincingly be argued to predispose to this form ofhaemorrhage.The use of drugs to prevent SEH-IVH has been

much discussed but after initial enthusiasm this areahas become confused by a series of poorly designedstudies. To date, five different drugs have been testedin this context-phenobarbitone, 21-21 indomethacin (inanimals),25 ethamsylate,26 vitamin E,z’ and tranexamicacid.28 Donn et al reported in 1981 that early treatmentwith phenobarbitone significantly reduced theincidence of IVH, but no subsequent study hasconfirmed this. The only controlled and double-blindinvestigation revealed no difference in the overallincidence of haemorrhage between the treated anduntreated groups.24 Ethamsylate, a drug that reducescapillary bleeding time, has been shown by Morgan etaF6 to reduce the incidence of IVH, and in a follow-upstudy these workers claim that the drug reduceshandicap detected between one and three years ofage.29This verdict must be treated with reserve because of theuncontrolled manner infants were included in the

follow-up study. Furthermore, the investigators wenton to test tranexamic acid 28 for its ability to preventIVH- suggesting a certain lack of faith in ethamsylate.Chiswick et a 117 claim that vitamin E significantlyreduced the incidence of IVH but their investigationhas been criticised on methodological ground.10 Atpresent we cannot recommend routine administrationof any drug in this context.SEH-IVH is not the only acquired lesion of vascular

origin in the perinatal brain. Although Kowitz in1914 was the first to report IVH in the newbornbrain,31 Parrot some 41 years earlier had describedperiventricular infarction,32 a lesion later termed

periventricular leucomalacia.33 This condition occursin infants with circulatory instability similar to that inSEH-IVH,34 and the two are best regarded as facets ofthe same pathophysiological process. Lately PVL has-21. Donn S, RoloffD, Goldstein G. Prevention of intraventricular haemorrhage in preterm

infants by phenobarbitone. Lancet 1981; ii: 215-17.22. Morgan MEI, Massey RF, Cooke RWI. Does phenobarbitone prevent periventricular

hemorrhage in very-low-birth-weight babies?: A controlled trial. Pediatrics 1982;70: 186-89.

23. Bedard MP, Shankaran S, Slovis TL, Pantoja A, Dayal B, Poland RL. Effect ofprophylactic phenobarbital on intraventricular hemorrhage in high-risk infants.Pediatrics 1984; 73: 435-39.

24 Whitelaw A, Placzek M, Dubowitz LMS, Lary S, Levene MI Phenobarbitone forprevention of periventricular haemorrhage in very-low-birth-weight infants. Lancet1983; ii: 1168-70

25. Ment LR, Stewart WB, Scott DT, Duncan CC. Beagle puppy model of intraventricularhemorrhage: Randomized indomethacin prevention trial. Neurology 1983; 33:179-84.

26. Morgan MEI, Benson JWT, Cooke RWI. Ethamsylate reduces the incidence ofperiventricular haemorrhage in very low birth-weight babies. Lancet 1981; ii:830-31.

27. Chiswick ML, Johnson M, Woodhall C, et al Protective effect of vitamin E (dl-alpha-tocopherol) against intraventricular haemorrhage in premature babies. Br Med J1983; 287: 81-84.

28. Hensey OJ, Morgan MEI, Cooke RWI. Tranexamic acid in the prevention of peri-ventricular haemorrhage. Arch Dis Child 1984; 59: 719-21.

29. Cooke RWI, Morgan MEI. Prophylactic ethamsylate for periventricular haemorrhage.Arch Dis Child 1984; 59: 82-83.

30. Levene MI. Protective effect of vitamin E against intraventricular haemorrhage inpremature babies. Br Med J 1983; 287: 617.

31. Kowitz HL. Intrakranielle Bluntungen und Pachymeningitis haemorrhagia chronicainterna bis neugeborenen und Sauglingen Virchows Arch Path Anat Physiol 1914;215: 233-46.

32. Parrot MJ. Etude sur le ramollissement de l’encephale chez le nouveau-né. Arch PhysiolNorm Pathol (Paris) 1873; 5: 59-73.

33. Banker BQ, Larroche J-L. Periventricular leukomalacia of infancy. A form of neonatalanoxic encephalopathy. Arch Neurol 1962; 7: 386-410.

34. Pape KE, Wigglesworth JS. Haemorrhage, ischaemia and the perinatal brain (ClinDevel Med 69/70) London: Spastics International Medical Publications, 1979.

been diagnosed by real-time ultrasound,35-37 and

necropsy correlation 38 has been good. Preliminaryfollow-up data suggest that ischaemic cerebral lesionsleading to periventricular infarction are associated withsevere cerebral palsy and mental retardation in mostinfants surviving this condition.39Volpe and his colleagues using positron emission

tomography in premature infants, suggested an

important link between haemorrhage and ischaemia.They studied six infants all with intraparenchymalhaemorrhage following IVH, and in each there was astriking reduction in cerebral blood flow involving amuch wider area of periventricular white matter thanthat occupied by the intracerebral haemorrhage. Theysuggest that intracerebral haemorrhage is only a

component of a much larger lesion, ischaemic inbasic nature. Necropsy data support the suggestionthat haemorrhage commonly arises in areas of

periventricular infarction;4O but it is equally possiblethat infarction (either venous or arterial) has beensecondary to massive haemorrhage. To determinewhether ischaemia is primary or secondary in thedevelopment of intraparenchymal haemorrhage, weneed safe and reliable methods for measuring cerebralblood flow before, during, and after

haemorrhagic/ischaemic insults.

Diagnosing Obstruction in Renal FailureTHE routine retrograde pyelogram was king under

this heading until Schwartz et all showed in 1963 thatthe intravenous urogram was a practicable alternative.Over the next ten years intravenous urographyestablished itself as the standard test in renal failure for

demonstrating kidney size, and for finding or rulingout urinary obstruction as the cause. This work was ledin Britain by Fry and his colleagues at StBartholomew’s Hospital. 2,3 The technique came undera cloud in the 1970s because of reports that renal

impairment might be worsened; but, with properassessment and preparation of patients, this hazardnow seems slight.35 The arrival of ultrasound scanningin the same decade, however, had already offered a non-

35. Hill A, Nelson GL, Clark HB, Volpe JJ. Hemorrhagic periventricular leukomalacia.Diagnosis by real-time ultrasound and correlation with autopsy findings. Pediatrics1982; 69: 282-84.

36. Levene MI, Wigglesworth JS, Dubowitz V. Hemorrhagic periventricular leukomalaciain the neonate: A real-time ultrasound study. Pediatrics 1983; 71: 794-97.

37. Dolfin T, Skidmore MB, Fong KW, Hoskins EM, Shennan AT, Hill A. Diagnosis andevolution of periventricular leukomalacia: A study with real-time ultrasound. EarlyHum Devel 1984; 9: 105-09.

38. Nwaesei CG, Pape KE, Martin DJ, Becker LE, Fitz CR. Periventricular infarctiondiagnosed by ultrasound: A postmortem correlation. J Pediatr 1984; 105: 106-10.

39. Levene MI, Dubowitz LMS, de Crespigny LCh Classifying intraventricular

haemorrhage. Lancet 1983; ii: 49.40. Armstrong D, Norman MG. Periventricular leucomalacia in neonates. Complications

and sequelae. Arch Dis Child 1974; 49: 367-75.1 Schwartz WB, Hurwit A, Ettinger A. Intravenous urography in the patient with renal

insufficiency. N Engl J Med 1963; 269: 277-83.2. Brown CB, Glancy JJ, Fry IK, Cattell WR. High-dose excretion urography in oliguric

renal failure Lancet 1970; ii: 952-55.3. Fry IK, Cattell WR. Excretion urography in advanced renal failure. Br J Radiol 1971,

44: 198-202.

4 Rahimi A, Edmondson RPS, Jones NF. Effect of radiocontrast media on kidneys ofpatients with renal disease. Br Med J 1981; 282: 1194-95.

5. Webb JAW, Reznek RH, Cattell WR, Fry IK. Renal function after high doseurography in patients with renal failure. Br J Radiol 1981; 54: 479-83.