Intraventricular Hemorrhage

COMMENTARIES

913

important goal for future research. Such an

ap-proach would be greatly facilitated if decision mak-ing were based on gestational age. For that purpose,

detailed perinatal outcome data by gestational age

are needed for geographically defined populations including all very preterm live and stillbirths.

Op-timally, data concerning both neonatal and

post-neonatal mortality (through the minimum age of

12 months) should be provided, because almost 10%

of deaths that are direct consequences of prematur-ity are still postponed to infancy.’4 Besides

obser-vational studies, population-based prospective

cm-ical trials are unavoidable if efficacy of perinatal health services interventions is to be properly

meas-ured. The answer to the question in the title is

“yes”!

REFERENCES

KIR8TI M. HEINONEN, MD Children’s Hospital

University of Kuopio 70210 Kuopio, Finland

1. Greenough A, Roberton NRC. Morbidity and survival in neonates ventilated for the respiratory distress syndrome. Br Med J. 1985;290:597-600

2. Field DJ, Milner AD, Hopkin IE, et al. Changing patterns in neonate! respiratory distress. Pediatr PulmonoL 1987;3:231-235

3. Yu VYH, Zhao SM, Bajuk B. Results of intensive care for 375 very low birth weight infants. Aust Paediatr J. 1982;18:188-192

4. Yu VYH, Bajuk B, Orgill AA, et a!. Viability of infants born at 24 to 26 weeks’ gestation. Ann Aced Med. 1985;14:563-571

5. Sinclair JC, Torrance GW, Boyle MH, et al. Evaluation of neonatal-intensive-care programs. N EngI J Med. 1981;

305:489-494

6. Hakulinen A, Heinonen K, Jokela V. et al.

Prematurity-associated morbidity during the first two years of life. A population-based study. Acta Paediatr Scand. 1988;77:430-448

7. Pomerance JJ, Ukrainski CT, Ukra T, et al. Cost of living

for infants weighing 1000 grams or less at birth. Pediatrics. 1978;61:908-910

8. Sandhu B, Stevenson RC, Cooke RWI, et a!. Cost of neo-natal intensive care for very-low-birthweight infants. Lan-cet. 1986;1:600-603

9. Kitchen WH, Campbell N, Drew JH, et al. Provision of perinatal services and survival of extremely low birthweight infants in Victoria. Med JAust. 1983;2:314-318

10. Kitchen WH, Murton LI. Survival rates of infants with birth weights between 501 and 1000 g. Improvement by

excluding certain categories of cases. Am J Dix Child. 1985;139:470-471

11. Hoskins EM, Elliot E, Shennan AT, et al. Outcome of very

low birth weight infants born at a perinatal center. Am J Obstet GynecoL 1983;145:135-140

12. Yu VYH, Wong PY, Bajuk B, et a!. Outcome of extremely

low birthweight infants. Br J Obstet GynaecoL 1986;93:162-170

13. Hirata T, Epcar JT, Walsh A, et al. Survival and outcome

of infants 501 to 750 grams: a six-year experience. JPediatr.

1983;102:741-748

14. Heinonen KM, Hakulinen A, Jokela V. Survival of the smallest. Lancet. 1988;2:204-207

Intraventricular

Hemorrhage

In this issue, Philip et al’ present data concerning the declining incidence of intraventricular hemor-rhage in the premature infant in the 1980s without

planned intervention. Before discussing the

impli-cations of this work, it may be useful to review

some of the pertinent features of intraventricular hemorrhage in the neonate.

Intraventricular hemorrhage is characteristic of

the premature infant, particularly the infant less

than 32 weeks’ gestation. Bleeding typically

ema-nates from capillaries in subependymal germinal

matrix, a gelatinous area containing an elaborate

but immature capillary bed which, in turn, is

sub-served by an abundant arterial and venous supply.

It is a transitional zone that becomes less promi-nent during the last 12 to 16 weeks of gestation and is essentially exhausted at term.2 Current concepts

of pathogenesis of intraventricular hemorrhage

in-dude intravascular, vascular, and extravascular

factors, all of which may act in combination to

provoke intraventricular hemorrhage.2 In recent

years, it has become apparent that disturbances in

cerebral blood flow are particularly important fac-tors in causing hemorrhage. Particular importance has been attributed to fluctuations in cerebral blood flow, increases in cerebral blood flow, increases in

venous pressure, and decreases in cerebral blood

flow.2 A likely mechanism for the premature

in-fant’s propensity for dangerous alterations in cere-bral blood flow is a pressure-passive circulation,3 imparting extreme importance to events that affect the systemic blood pressure. Striking disturbances

in systemic blood pressure may occur during the

labor and delivery process and during routine

neo-natal

procedures such as suctioning and in infants with respiratory distress syndrome, pneumothorax,

and patent ductus arteriosus. Intervention

strat-egies directed at the routine care of sick premature infants to minimize perturbations in systemic blood

pressure and cerebral blood flow have focused on

(1) simple measures, such as the early intubation

of infants with respiratory distress syndrome, the

avoidance ofrapid volume infusions, minimal

hand-ling of infants, etc and (2) pharmacologic interven-tions, such as the antenatal administration of phe-nobarbital,9”#{176} the postnatal use of phenobarbital,

indomethacin, vitamin E, and ethamsylate to a

heterogenous group of mothers and/or infants, with

conflicting results.”’6 The use of muscle paralysis in a subset of intubated infants with respiratory

distress syndrome and fluctuations in cerebral

blood flow velocity has resulted in a marked reduc-tion in both the incidence and severity of intraven-tricular hemorrhage.17

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914

PEDIATRICS

Vol. 84 No. 5 November

1989

The study of Philip et al is based on a retrospec-tive review of records during 8 years. Several per-tinent observations from this study require ampli-fication. Although the incidence of intraventricular

hemorrhage declined from 39% in infants weighing

less than 1500 g at birth in 1980/1981 to 25% in

1986/1987, the incidence ofsevere hemorrhage, that

lesion that accounts for much of the brain injury in the premature infant, has not significantly changed

during the same time. The authors describe in some

detail

the changes introduced in clinical

manage-ment that may have contributed to the observed

decrease in intraventricular hemorrhage by

mini-mizing fluctuations in systemic blood pressure.

Al-though none of the pharmacologic interventions

mentioned previously are administered in their

nursery to reduce intraventricular hemorrhage, it

is of interest to note that there is an increased use of narcotic analgesics in their mechanically

venti-lated infants. The use of analgesics may be an

important contributing factor in their observed

re-duction in intraventricular hemorrhage because, in

a recent report, elimination of fluctuations in ar-terial blood pressure in infants receiving morphine

sulfate and/or fentanyl was reported.’8 This issue

clearly requires further study. It is possible that the observed decrease in intraventricular hemorrhage

is unrelated to neonatal factors but rather to a

change in obstetrical management. Thus, pertinent obstetrical data not presented by Philip et al relate to the antenatal administration of steroids, tocoly-tic agents, and barbiturates, all of which have been reported to alter either the occurrence of postnatal respiratory distress syndrome and/or intraventric-ular hemorrhage.’#{176}”2’ The role of labor and de-livery in the genesis of intraventricular hemorrhage is controversial.22’ However, in one center, early

intraventricular hemorrhage, ie, diagnosed in the

delivery room, was a common finding.’ An

incon-clusive analysis has been undertaken by Philip et

al to assess the protective role of cesarean section

in the genesis of intraventricular hemorrhage. A

definitive conclusion in this regard could only be

made if a cranial ultrasound scan was obtained near the time of delivery. In this study the cranial

ultra-sound scans were obtained “sometime” in the first

3 postnatal days. Although the apparent incidence

of respiratory distress syndrome has not changed

in Portland during the 8 years, no information is

provided regarding the severity of respiratory dis-tress syndrome. A strong association exists between respiratory distress syndrome, and in particular, severity ofrespiratory distress syndrome, and

intra-ventricular hemorrhage.6’ One could argue that

the decline in intraventricular hemorrhage during

the 8 years is a reflection of less severe pulmonary

disease. In support of this hypothesis is the obser-vation that, of the 26 infants enrolled in a surfac-tant study carried out by Philip et al (presumably the sickest infants), the incidence of

intraventric-ular hemorrhage was 34% during 1986/1987 when

the lowest overall incidence (25%) of intraventric-ular hemorrhage was observed.

These notes represent an attempt to place the

study of Philip et al in perspective. They should

not detract from the basic value of the work. Their data raise several important issues. First, the

mci-dence of intraventricular hemorrhage may vary

substantially from institution to institution. This variation may not be related to any specific practice

but rather to the particular patient population.

Thus, in our experience, the incidence of

hemor-rhage in nonmechanically ventilated or

mechani-cally ventilated preterm infants with minimal

res-piratory distress syndrome is less than 10%. The

incidence increases markedly with the severity of

the lung disease and/or its complications.

More-over, in our experience, the incidence of

hemor-rhage is greater (approximately 60%) and the onset

earlier (10 ± 8 hours) in the extremely small

pre-mature infant, ie, less than 700 g, compared with

the incidence (approximately 20%) in “larger” birth weight infant, ie, greater than 1000 g, with an onset usually in the second or third postnatal day.27 This raises the distinct possibility that the pathogenesis

of intraventricular hemorrhage may be different in

infants of differing gestational ages. Thus, before

embarking on a prevention study, some ofthe

afore-mentioned factors should be taken into

considera-tion. Moreover, identifying the infants who are at

highest risk for the subsequent development of

intraventricular hemorrhage would reduce the

po-tential risk of administering a variety of

pharma-cologic agents unnecessary to a large group of

in-fants. Our own data indicate that infants at highest risk for intraventricular hemorrhage can be identi-fled before the onset of hemorrhage by the presence

of fluctuations in arterial blood pressure and/or

cerebral blood flow velocity.6 The former

observa-tion can easily be made at the bedside from the

arterial

blood pressure monitor. Elimination of these fluctuations is associated with a reduction not

only in the incidence but more importantly the

severity of intraventricular hemorrhage.’7 Because the fluctuations are tightly linked to the infant’s

own respiratory effect, intervention strategies

should be focused on minimizing the infant’s own

respiratory effort during the time of greatest vul-nerabiity, ie, the first 72 hours of life.

Presently, the most important contribution

ap-parent from this report should be to stimulate

everyone involved in the care of the critically ill

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COMMENTARIES

915

neonate to review their own experience and, in the

event of embarking on pharmacologic

interven-tions, to focus on those infants at highest risk for severe intraventricular hemorrhage.

REFERENCES

JEFFREY M. PERLMAN, MD Dept of Pediatrics

University of Texas

Southwestern Medical Center

Dallas, Texas

1. Philip AGS, Allan WC, Tito AM, Wheeler LR. Intraven-tricular hemorrhage in perterm infants: declining incidence in the 1980s. Pediatrics. 1989:84:797-801

2. Volpe JJ. Neurology of the Newborn. 2nd ad. Philadelphia, PA: WB Saunders Co; 1987

3. Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregula-tion of cerebral blood flow in the distressed newborn infant.

J Pediatr. 1979;94:118-124

4. Newton TH, Gooding CA. Compression of superior sagittal

sinus by neonatal calvarial moulding Radiology.

1979;115:635-639

5. Perlman JM, Volpe JJ. The effects of suctioning on cerebral blood flow velocity, intracranial and systemic blood pressure in the preterm infant. Pediatrics. 1983;72:329-334

6. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating

cere-bral blood flow velocity in respiratory distress syndrome:

relationship to the development of intraventricular

hemor-rhage. N Engi J Med. 1983;309:209-213

7. Hill A, Perlman JM, Volpe JJ. Relationship of

pneumotho-rax to occurrence of intraventricular hemorrhage in the premature infant. Pediatrics. 1982;69:144-149

8. Perlman JM, Hill A, Volpe JJ. The effect of patent ductus arteriosus on the anterior cerebral arteries: ducts.! steal in the premature newborn infant. J Pediatr. 1981;99:767-772 9. Shankaran 5, Cepeda E, Ilagan N, et a!. Antenatal

pheno-barbital for the prevention of neonatal intracerebral

hem-orrhage. Am J Obstet GynecoL 1986;154:53-57

10. Morales WJ, Koerten J. Prevention ofintraventricular hem-orrhage in very low birthweight infants by maternally ad-ministered phenobarbital. Obstet GynecoL 1986;68:295-299 11. Donn S, Roloff D, Goldstein G. Prevention of

intraventric-ular hemorrhage in preterin infants with phenobarbitone.

Lancet. 1981;2:215-217

12. Kuban KCK, Leviton A, Krishnamoorthy KS, et al.

Neo-natal intracranial hemorrhage and phenobarbital. Pediat-rics. 1986;77:443-450

13. Ment LR, Duncan CC, Ehrenkrantz RA, et aL Randomized

low dose indomethacin trial for prevention of intraventric-ular hemorrhage in very low birthweight infants. J Pediatr.

1988;112:948-955

14. Hanigan WC, Kennedy G, Roemisch F. Administration of indomethacin for the prevention of

periventricular-intra-ventricular hemorrhage in high-risk neonates. J Pediatr.

1988;112:941-947

15. Sinha S, Davies J, Toner N, et al. Vitamin E supplementa-tion reduces the frequency of periventricular hemorrhage in very preterm babies. Lancet. 1987;1:466-471

16. Benson JW, Drayton MR, Hayward C, et al. Multicentre trial of ethamsylate for prevention of periventricular hem-orrhage in very low birthweight infants. Lancet. 1986; 2:1297-1300

17. Perlman JM, Goodman S, Kreusser KL, et al. Reduction in

intraventricular hemorrhage by elimination of fluctuating

cerebral blood flow velocity in preterm infants with

respi-ratory distress syndrome. N Engi J Med. 1985;312:1253-1257

18. Goldstein RF, Coffins KA, Brazy JE. Narcotic sedation stabilizes arterial blood pressure fluctuations in infants with

respiratory distress syndrome. Pediatr Res. 1988;23:409A. Abstract

19. Clarke CE, Clyman RI, Roth RS, et al. Risk factor analysis of intraventricular hemorrhage in newborn infants. J

Pe-diatr. 1981;99:625-628

20. Horbar JD, Leahy K, Lucen JF. The incidence of perinatal

intracranial hemorrhage (ICH) following maternal

admin-istration of Isosuxphrine and betamethasone. Pediatr Res. 1981;15:664

21. Avery ME. The argument for prenatal administration of dexamethasone to prevent respiratory distress syndrome. J

Pediatr. 1984;104:240

22. Horbar JD, Pasnick M, McAuliffe C, et al. Obstetric events

and risk ofperiventricular hemorrhage in premature infants.

Am J Die Child. 1983;137:678-681

23. Tejani N, Rebod B, Tuck 5, et a!. Obstetric factors in the causation of early periventricular-intraventricular hemor-rhage. Obstet GynecoL 1984:64:510-514

24. Anderson GD, Bade HS, Sibai B. The relationship between

labor and route ofdelivery and intraventricular hemorrhage

in the preterm infant. Am J Obstet GynecoL 1988;158:1382-1390

25. Dykes FD, Lazzarra A, Ahmann P, et a!. Intraventricular hemorrhage: a prospective evaluation of etiopathogenesis. Pediatrics. 1980;66:42-49

26. Levene M, Fawer CL, Lamont HF. Risk factors in the development of intraventricular hemorrhage in the

prema-ture neonate. Arch Die ChikL 1982;57:410-417

27. Perlman JM, Volpe JJ. Intraventricular hemorrhage in

ex-tremely small premature infants. Am J Dis Child. 1986;

140:1122-1124

Respiratory

Distress

Syndrome

and Intracranial

Hemorrhage:

Cause

or

Association?

Inferences

From

Surfactant

Clinical

Trials

Among preterm newborns, those with respiratory distress syndrome are at increased risk of

intracra-nial hemorrhage.’’ Three hypotheses have been

offered as explanation for this association.

In the biology hypothesis, respiratory distress

syndrome in one way or another increases the risk

of intracranial hemorrhage. Variations on this

hy-pothesis

incorporate

specific adverse effects of

res-piratory

distress,

such as grunting (ie, increased

intrathoracic pressure leads to increased cranial

intravascular pressure), impaired cerebral blood

flow, and acidosis.’’#{176}

In the second

hypothesis,

treatment of respira-tory distress increases the risk of intracranial

hem-orrhage. For example, rapid infusion of buffer for

treatment of acidosis was once thought to influence the risk of bleeding into the brain,” although sub-stantiation has not been provided.’2 Because babies

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1989;84;913

Pediatrics

JEFFREY M. PERLMAN

Intraventricular Hemorrhage

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