Chapter 11. Intracranial Hemorrhage: Germinal Matrix-Intraventricular Hemorrhage of the Premature Infant

518



UNIT IV



TABLE 11-1



INTRACRANIAL HEMORRHAGE



Years of Study



Criteria for Inclusion



Incidence



Late 1970s–1980s



Premature: several different birth weights

and gestational ages

<1500 g

<1500 g

<1500 g



40%–50%



Late 1980s

Late 1990s

Present

*



A



High Incidence of Intraventricular

Hemorrhage in Premature Infants*



Perforating

arteries



20%

15%–20%

20%–25%



See text for references; values for incidence are rounded off.



Anterior choroidal artery

Striate branches of

middle cerebral artery



A



artery (through Heubner’s artery), the middle cerebral

artery (primarily through the deep lateral striate

branches but also through penetrating branches

from surface meningeal branches), and the internal carotid artery (through the anterior choroidal artery)

(Fig. 11-2).40,41 The relative importance of these

arteries in the vascular supply to the capillaries of the

matrix is not entirely clear; different studies have attributed particular importance to Heubner’s artery40,42 and

to the lateral striate arteries.43 However, it is likely that

the terminal branches of this arterial supply constitute

a vascular end zone and thus a vulnerability to ischemic

injury (see later discussion).



Infants with intraventricular hemorrhage (%)



Capillary Network

The rich arterial supply just described feeds an elaborate capillary bed in the germinal matrix.40,42-47 This bed

generally is composed of relatively large, irregular

endothelial-lined vessels that do not exhibit the characteristics of arterioles or venules and are classified as

capillaries or channels, or both. Pape and Wigglesworth42 characterized the anatomical appearance as

‘‘a persisting immature vascular rete in the subependymal matrix which is only remodeled into a definite capillary bed when the germinal matrix disappears.’’ As

term approaches, some of the larger endothelial-lined



Heubner’s artery



Section A-A

Figure 11-2 Arterial supply. Arterial supply to the subependymal germinal matrix at 29 weeks of gestation. (From Hambleton G,

Wigglesworth JS: Origin of intraventricular haemorrhage in the preterm

infant, Arch Dis Child 51:651–659, 1976.)



vessels acquire a collagenous adventitial sheath43 and

can be categorized appropriately as veins,46 as also

described in the matrix of the monkey.48 The nature

of the endothelial-lined vessels in this microvascular

bed may be of pathogenetic importance concerning

germinal matrix hemorrhage (see later section).

Venous Drainage of Subependymal

Germinal Matrix

The rich microvascular network just described is continuous with a well-developed deep venous system.

This venous drainage eventually terminates in the

great cerebral vein of Galen (Fig. 11-3).49 In addition



Medullary v v.

35



34/108



30



Choroidal v.



51/171



25



Thalamostriate v.



20

45/285

15



Terminal v.

10



22/303



Internal cerebral v.

5



15/1083



0

<750



751-1000 1001-1250 1251-1500 1551-2250



Vein of Galen



Birth weight (g)



Figure 11-1 Incidence of intraventricular hemorrhage as a function

of birth weight of 1950 infants weighing 2250 g or less. The bars

represent the percentage of total infants in the range of birth weight,

and the numbers at the top of the bars are absolute numbers of

infants. (From Sheth RD: Trends in incidence and severity of intraventricular hemorrhage, J Child Neurol 13:261–264, 1998.)



Figure 11-3 Veins of the Galenic system, midsagittal view. Note

that the medullary, choroidal, and thalamostriate veins come to a

point of confluence to form the terminal vein. The terminal vein,

which courses through the germinal matrix, empties into the internal

cerebral vein, and the major flow of blood changes direction sharply

at that junction.



Chapter 11



Intracranial Hemorrhage: Germinal Matrix–Intraventricular Hemorrhage



519



to the matrix region, this venous system drains blood

from the cerebral white matter, choroid plexus, striatum, and thalamus through the medullary, choroidal,

thalamostriate, and terminal veins. Indeed, the terminal

vein, which runs essentially within the germinal matrix,

is the principal terminus of the medullary, choroidal,

and thalamostriate veins. The latter three vessels

course primarily anteriorly to a point of confluence at

the level of the head of the caudate nucleus to form the

terminal veins, which empty into the internal cerebral

vein that courses directly posteriorly to join the vein of

Galen. Thus, at the usual site of germinal matrix

hemorrhage, the direction of blood flow changes in a

peculiar U-turn. This feature may have pathogenetic

implications (see later section). This venous anatomy

is also relevant to the occurrence of periventricular

hemorrhagic infarction (see later discussion).



A

Site of Origin and Spread of Intraventricular

Hemorrhage

Site of Origin

The site of origin of IVH characteristically is the subependymal germinal matrix (Fig. 11-4). This cellular region

immediately ventrolateral to the lateral ventricle serves as

the source of cerebral neuronal precursors between

approximately 10 to 20 weeks of gestation and in the

third trimester provides glial precursors that become

cerebral oligodendroglia and astrocytes (see Chapter 2).

For reasons discussed later, the many thin-walled vessels

in the matrix are a ready source of bleeding. The matrix

undergoes progressive decrease in size, from a width of

2.5 mm at 23 to 24 weeks, to 1.4 mm at 32 weeks, to

nearly complete involution by approximately 36 weeks.36

The matrix from 28 to 32 weeks is most prominent in the

thalamostriate groove at the level of the head of the caudate nucleus at the site of or slightly posterior to the foramen of Monro,40,50-54 and this site is the most

common for germinal matrix hemorrhage. Before

28 weeks, hemorrhage in persisting matrix over the

body of the caudate nucleus may also be found.

Hemorrhage from choroid plexus occurs in nearly 50%

of infants with germinal matrix hemorrhage and IVH,55

and, in more mature infants especially, it may be the

major site of origin of IVH (see Chapter 10).

The vascular site of origin of germinal matrix hemorrhage within the microcirculation of this region

appears most commonly to be the prominent endothelial-lined vessels described earlier, not clearly arterial or

venous.40,46,50,54,56-58 Particular importance for vessels

in free communication with the venous circulation

(e.g., capillary-venule junction or small venules) is suggested by the emergence of solution into germinal

matrix hemorrhage from postmortem injection into

the jugular veins but not from injection into the carotid

artery.56 Histochemical studies of germinal matrix vessels at the site of hemorrhage also are consistent with

an origin at the capillary-venule or small venule level.58

Multiple microcirculatory sites involving small vessels

lined only by endothelium may be involved, depending

on the clinical circumstances.



B

Figure 11-4 Germinal matrix–intraventricular hemorrhage. Coronal

sections of cerebrum. A, Germinal matrix hemorrhage (arrowheads) at

the level of the head of the caudate nucleus and foramen of Monro

(see probe), with rupture into the lateral ventricles. B, Massive intraventricular hemorrhage. Obstruction at the foramen of Monro has

caused severe, unilateral ventricular dilation.



Spread of Intraventricular Hemorrhage

In the approximately 80% of cases with germinal matrix

hemorrhage in which blood enters the lateral ventricles, spread occurs throughout the ventricular system

(Fig. 11-5).40,53,54 Blood proceeds through the foramina of Magendie and Luschka and tends to collect in the

basilar cisterns in the posterior fossa; with substantial

collections, the blood may incite an obliterative arachnoiditis over days to weeks with obstruction to cerebrospinal fluid (CSF) flow. Other sites at which

particulate blood clot may lead to impaired CSF dynamics are the aqueduct of Sylvius and the arachnoid

villi (see later discussion of hydrocephalus).



520



UNIT IV



INTRACRANIAL HEMORRHAGE



A



A



B

Figure 11-6 Periventricular hemorrhagic infarction with intraventricular hemorrhage; coronal sections of cerebrum. A, Early lesion;

note evolving hemorrhagic infarction (arrowheads) on the same side

as larger intraventricular hemorrhage. B, More advanced lesion; note

hemorrhagic necrosis with liquefaction in periventricular white matter

(arrowheads) on the same side as larger intraventricular hemorrhage.

The ependymal lining is marked by white arrows.



B

Figure 11-5 Spread of intraventricular hemorrhage. A, Coronal and,

B, sagittal views. In A, note blood in the lateral ventricles, aqueduct of

Sylvius, the fourth ventricle, and the subarachnoid space around the

cerebellum and lower brain stem. In B, note blood throughout the ventricular system (the numbers 1 to 4 refer to lateral ventricle, third

ventricle, aqueduct, and fourth ventricle, respectively).



Neuropathological Consequences

of Intraventricular Hemorrhage

Several neuropathological states occur as apparent

consequences of IVH, including, in temporal order

of occurrence, germinal matrix destruction, periventricular hemorrhagic infarction, and posthemorrhagic

hydrocephalus.

Germinal Matrix Destruction

Destruction of germinal matrix and, perhaps importantly, its glial precursor cells is a consistent and

expected feature of germinal matrix hemorrhage.50,54

The hematoma is frequently replaced by a cyst, the

walls of which include hemosiderin-laden macrophages

and reactive astrocytes. The destruction of glial precursor cells may have a deleterious influence on subsequent brain development (see later discussion).



Periventricular Hemorrhagic Infarction

Approximately 15% of very-low-birth-weight infants

with IVH also exhibit a characteristic parenchymal

lesion (i.e., a relatively large region of hemorrhagic

necrosis in the periventricular white matter) just

dorsal and lateral to the external angle of the lateral

ventricle (Fig. 11-6).13,16,39 The incidence of the

lesion increases with decreasing gestational age, such

that in infants of less than 1000 g or gestational age less

than 28 weeks, periventricular hemorrhagic infarction

accounts for approximately 15% to 20% of all cases

with IVH (see later).9,13,16,19,39,59

Large-scale ultrasonographic studies have defined

the topographic characteristics of periventricular hemorrhagic

infarction. The parenchymal hemorrhagic necrosis is

strikingly asymmetrical; in the largest early series

reported,60 67% of such lesions were exclusively

unilateral, and in virtually all the remaining cases,

lesions were grossly asymmetrical, although bilateral.

Approximately one half of the lesions were extensive

and involved the periventricular white matter from frontal to parieto-occipital regions (Fig. 11-7); the remainder

were more localized. Approximately 80% of cases were

associated with large IVH. Commonly (and mistakenly),



Chapter 11



Intracranial Hemorrhage: Germinal Matrix–Intraventricular Hemorrhage



Figure 11-7 Periventricular hemorrhagic infarction, neuropathology.

Horizontal section of cerebrum above the level of lateral ventricles from

a premature infant who died on the sixth postnatal day, 3 days after

severe intraventricular hemorrhage. Hemorrhagic necrosis in left cerebral white matter separated from the brain section during fixation and

revealed a shaggy margin of the hemorrhagic infarction. See text for

details.



the parenchymal hemorrhagic lesion is described as an

‘‘extension’’ of IVH. Several neuropathological studies

have shown that simple extension of blood into cerebral

white matter from germinal matrix or lateral ventricle

does not account for the periventricular hemorrhagic

necrosis.24,55,59-65 In a later ultrasonographic report of

58 infants, findings were similar: the lesion was unilateral in 74%, extensive (involving two or more lobar territories) in 67%, and associated with large IVH in

88%.66 The lobar distribution indicates that the majority of lesions involved the frontal and parietal regions.

Approximately 50% of the cases exhibited a midline



Medullary

veins

LV

Foramen

of Monro

Terminal

vein



A



LV

Germinal

matrix



B



521



shift of cerebral structures, consistent with the severity

of the lesions.

Microscopic study of the periventricular hemorrhagic necrosis just described indicates that the lesion

is a hemorrhagic infarction.24,60-65,67 The careful studies

of Gould and co-workers62 and Takashima and coworkers67 emphasized that (1) the hemorrhagic component consists usually of perivascular hemorrhages

that follow closely the fan-shaped distribution of the

medullary veins in periventricular cerebral white

matter (Fig. 11-8) and (2) the hemorrhagic component

tends to be most concentrated near the ventricular

angle where these veins become confluent and ultimately join the terminal vein in the subependymal

region. Thus, the periventricular hemorrhagic necrosis

occurring in association with large IVH is, in fact, a

venous infarction. The most common neuropathological sequela of periventricular hemorrhagic infarction is a large

porencephalic cyst at the site of the lesion, either alone

(66%) or in combination with smaller cysts (23%).66

The large cyst communicates often, although not

invariably, with the lateral ventricle.

Periventricular hemorrhagic infarction is distinguishable neuropathologically from secondary hemorrhage into periventricular leukomalacia, which is the

ischemic, usually nonhemorrhagic, and symmetrical

lesion of periventricular white matter of the premature

infant (see later discussion). Distinction of these two

lesions in vivo, however, is difficult. Indeed, because

the pathogeneses of periventricular hemorrhagic infarction and periventricular leukomalacia overlap (see

later discussion), it is to be expected that the lesions

often coexist, thereby sometimes causing confusion

in interpretation of cranial ultrasound scans.1 In

Table 11-2, I compare the basic features of these two

periventricular white matter lesions of the premature

infant.

The pathogenesis of periventricular hemorrhagic infarction appears to be related causally to the germinal

matrix hemorrhage–IVH. A direct relation to the latter

lesion seems likely on the basis of three fundamental

findings.60,66 First, 80% to 90% of the reported



Figure 11-8 Venous drainage of cerebral white matter in

schematic and actual appearances. A, Schematic diagram

shows that the medullary veins, arranged in a fan-shaped distribution, drain blood from the cerebral white matter into the

terminal vein, which courses through the germinal matrix.

B, Postmortem venogram obtained from a human newborn

shows the actual appearance of the vessels. LV, lateral ventricle. (B, From Takashima S, Mito T, Ando Y: Pathogenesis of

periventricular white matter hemorrhages in preterm infants,

Brain Dev 8:25–30, 1986.)



522



UNIT IV



TABLE 11-2



INTRACRANIAL HEMORRHAGE



Periventricular White Matter Lesions in the Premature Infant with Intraventricular Hemorrhage

LESION

Periventricular Hemorrhagic Infarction



Likely site of circulatory disturbance

Grossly hemorrhagic

Markedly asymmetrical

Evolution



Periventricular Leukomalacia



Venous

Invariable

Nearly invariable

Single large cyst



Arterial

Uncommon

Uncommon

Multiple small cysts



parenchymal lesions are observed in association with

large (and almost invariably) asymmetrical germinal

matrix hemorrhage–IVH. Second, the parenchymal

lesions invariably occurred on the same side as the

larger amount of germinal matrix and intraventricular

blood (Table 11-3). Third, in some cases, the lesions

were shown to develop and progress after the occurrence of the germinal matrix hemorrhage–IVH. More

than one-half of the lesions were detected after the

second postnatal day, when approximately 75% of

cases of IVH have already occurred (see ‘‘Diagnosis’’).

The association of large asymmetrical germinal matrix

hemorrhage–IVH with progression to ipsilateral periventricular hemorrhagic infarction has been confirmed.66,68-71 These data suggest that the IVH or its

associated germinal matrix hemorrhage leads to

obstruction of the terminal veins and thus impaired

blood flow in the medullary veins with the occurrence

of hemorrhagic venous infarction. A similar conclusion

was suggested from a neuropathological study.62 The

timing of this progression to infarction is often very

rapid because, in most cases, the severe IVH and the

periventricular hemorrhagic infarction are detected

simultaneously.

This pathogenetic formulation received strong support from Doppler determinations of blood flow velocity in the terminal vein during the evolution of the

infarction in the living premature infant; obstruction

of flow in the terminal vein by the ipsilateral germinal

matrix hemorrhage–IVH was shown clearly.72,73

Moreover, the finding of elevated lactate in structures

adjacent to the germinal matrix hemorrhage, in the distribution of tributaries of the terminal vein, further

supports the occurrence of ischemia secondary to

venous obstruction by the matrix hemorrhage.74



TABLE 11-3



Hydrocephalus

A third neuropathological consequence of IVH is

progressive posthemorrhagic ventricular dilation (i.e.,



Laterality of Apparent Periventricular

Hemorrhagic Infarction and

Concurrent Asymmetrical

Intraventricular Hemorrhage



Severity of

Intraventricular

Hemorrhage

Grade III

Grades I–II



Finally, a magnetic resonance imaging (MRI) study of

acute periventricular hemorrhagic infarction has

shown an appearance consistent with a combination

of intravascular thrombi and perivascular hemorrhage

along the course of the medullary veins within the area

of infarction (Fig. 11-9).75

The pathogenetic scheme that I consider to account

for most examples of periventricular hemorrhagic infarction is shown in Figure 11-10. This scheme should

be distinguished from that operative for hemorrhagic

periventricular leukomalacia (Fig. 11-11), although the

lesions could coexist. The frequency of coexistence of

the two lesions is not known. Additionally, the two

pathogenetic schemes could operate in sequence; that

is, periventricular leukomalacia could become secondarily hemorrhagic (and perhaps a larger area of injury)

when germinal matrix hemorrhage or IVH subsequently causes venous obstruction.



Periventricular

Hemorrhagic

Infarction

Homolateral

47

5



Periventricular

Hemorrhagic

Infarction

Contralateral

0

4



Data from Guzzetta F, Shackelford GD, Volpe S, Perlman JM, et al:

Periventricular intraparenchymal echodensities in the premature

newborn: Critical determinant of neurologic outcome, Pediatrics

78:995–1006, 1986.



Figure 11-9 Periventricular hemorrhagic infarction. Coronal magnetic resonance imaging scan (fast spin-echo image) demonstrating

bilateral germinal matrix–intraventricular hemorrhages, with an apparent periventricular hemorrhagic infarction on the side of the larger

amount of germinal matrix and intraventricular blood (reader’s right).

Note the fan-shaped linear distribution of increased signal in the parenchymal lesion (reader’s right), consistent with a combination of intravascular thrombi and perivascular hemorrhage along the course of the

medullary veins. (From Counsell SJ, Maalouf EF, Rutherford MA,

Edwards AD: Periventricular haemorrhagic infarct in a preterm neonate,

Eur J Paediatr Neurol 3:25–28, 1999.)



Chapter 11



Intracranial Hemorrhage: Germinal Matrix–Intraventricular Hemorrhage



Germinal matrix–

intraventricular

hemorrhage



Periventricular venous

congestion



Periventricular ischemia



Periventricular hemorrhagic

infarction

Figure 11-10 Pathogenesis of periventricular hemorrhagic infarction.

The formulation indicates a central role for germinal matrix–intraventricular

hemorrhage in causation of the periventricular venous infarction.



hydrocephalus). The likelihood and the rapidity of evolution of hydrocephalus after IVH are related directly to

the quantity of intraventricular blood. Thus, with large

IVH, hydrocephalus may evolve over days (acute hydrocephalus), and with smaller IVH, the process evolves

usually over weeks (subacute-chronic hydrocephalus) (see

later discussion).

Acute hydrocephalus is accompanied by particulate

blood clot, readily demonstrated in life by ultrasound

scan (see later discussion). The particulate clot may

impair CSF absorption by obstruction of the arachnoid

villi. This mechanism may be particularly likely in the

newborn, in whom only microscopic arachnoid villi

(and not larger, later-appearing arachnoid granulations) are present.76-78 The possibility that endogenous

fibrinolytic mechanisms mediated by plasminogen activation are deficient in the CSF of the premature infant

Ischemia



Germinal matrix

injury



Periventricular

leukomalacia

(nonhemorrhagic

infarction)

Subsequent

reperfusion



Hemorrhagic

periventricular

leukomalacia



Intraventricular

hemorrhage



Figure 11-11 Pathogenesis of hemorrhagic periventricular leukomalacia.



523



is suggested by the findings that plasminogen levels are

extremely low in CSF of such infants,79 whereas in

infants with recent IVH, the levels of plasminogen activator inhibitor are relatively high.80,81 This combination of findings may limit the infant’s capacity to

mediate clot lysis after IVH.

Subacute-chronic hydrocephalus relates most commonly

either to an obliterative arachnoiditis in the posterior

fossa (which results in either obstruction of fourth ventricular outflow or flow through the tentorial notch) or

to aqueductal obstruction by blood clot, disrupted

ependyma, and reactive gliosis.42,50,82-84 The obliterative arachnoiditis is probably most important. Two

molecules important in fibroproliferative responses

have been shown to be up-regulated in infants with

posthemorrhagic hydrocephalus.85-88 Transforming

growth factor-beta1, derived in this setting from platelets, is a cytokine chemotactic for fibroblasts and

important in the up-regulation of genes encoding collagen, fibronectin, and other extracellular matrix proteins.85,87,88 Procollagen 1C-peptide, involved in

collagen fiber formation and tissue deposition, also

has been shown to be elevated in CSF of infants with

posthemorrhagic hydrocephalus.86

Neuropathological Accompaniments of

Intraventricular Hemorrhage

Several neuropathological states are common accompaniments of IVH, but, in contrast to the states just

described, these are apparently not caused by the IVH.

The two most common accompaniments are periventricular leukomalacia and selective neuronal necrosis.

Periventricular Leukomalacia

Periventricular leukomalacia, the generally symmetrical,

nonhemorrhagic, and apparently ischemic white matter injury of the premature infant (see Chapters 8 and

9), was observed to some degree in 75% of one series of

infants who died with IVH.55 The frequent association

of classic necrotic/cystic periventricular leukomalacia

and IVH also was emphasized in three other neuropathological reports,63,67,89 as well as in two large ultrasonographic studies.16,39 Although it has been

reported that approximately 25% of examples of periventricular leukomalacia become hemorrhagic,55,90

especially when associated coagulopathy is present,

this figure includes examples that have been accompanied by large IVH and that probably represent the

venous infarction discussed earlier as periventricular

hemorrhagic infarction. Takashima and co-workers67

suggested that the two lesions (i.e., periventricular

hemorrhagic infarction and hemorrhagic periventricular leukomalacia) may be distinguishable in part on the

basis of topography. Thus, hemorrhagic periventricular

leukomalacia has a predilection for periventricular arterial border zones, particularly in the region near the

trigone of the lateral ventricles. Venous infarction,

especially its most hemorrhagic component, is particularly prominent more anteriorly; that is, the lesion radiates from the periventricular region at the site of

confluence of the medullary and terminal veins and



524



UNIT IV



INTRACRANIAL HEMORRHAGE



assumes a roughly triangular, fan-shaped appearance

in periventricular white matter. The potential role of

IVH in contributing to the occurrence of periventricular leukomalacia is discussed later (see ‘‘Mechanisms of

Brain Injury’’).

Selective Neuronal Necrosis

Selective neuronal necrosis, secondary to hypoxia-ischemia

in the premature infant, particularly involves the pons,

deep nuclear structures, especially, thalamus and basal

ganglia, and hippocampus (see Chapter 8). Although

each of these lesions is more commonly encountered

in association with IVH, the relationship is particularly

notable for pontine neuronal necrosis. In two carefully

studied neuropathological series,55,89 46% and 71% of

infants with IVH exhibited pontine neuronal necrosis.

Accompanying neuronal necrosis in the subiculum of

the hippocampus is common but not invariable.23,42,77,89,91,92 All the infants with IVH accompanied

by pontine neuronal necrosis in the series of Armstrong

and co-workers55 died of respiratory failure; previous

investigations had suggested that the pontine lesion is

related to hypoxic-ischemic insult, hyperoxia, and hypocarbia (see Chapter 8).77,93 Involvement of the inferior

olivary nucleus often accompanies the pontine disturbance, and thus cerebellar afferent systems are often

affected. This involvement could be related causally to

the decreased volume of cerebellum observed by volumetric MRI in infants after severe IVH.94



TABLE 11-4



Pathogenesis of Germinal Matrix–

Intraventricular Hemorrhage:

Intravascular Factors



Fluctuating Cerebral Blood Flow

Ventilated preterm infant with respiratory distress syndrome

Increase in Cerebral Blood Flow

Systemic hypertension: importance of pressure-passive

circulation

Rapid volume expansion

Hypercarbia

Decreased hematocrit

Decreased blood glucose

Increase in Cerebral Venous Pressure

Venous anatomy: U-turn in direction of venous flow

Labor and vaginal delivery

Respiratory disturbances

Decrease in Cerebral Blood Flow (Followed by

Reperfusion)

Systemic hypotension: importance of pressure-passive

circulation

Platelet and Coagulation Disturbance



first day of life: a stable pattern and a fluctuating pattern

(Fig. 11-12). The stable pattern was characterized by equal

peaks and troughs of systolic and diastolic flow velocity

Cerebral blood flow velocity



PATHOGENESIS



1 sec

Arterial blood pressure

mm Hg



The pathogenesis of IVH is considered best in terms of

intravascular, vascular, and extravascular factors.

Clearly, the pathogenesis of IVH is multifactorial, and

to some extent different combinations of these factors

are operative in different patients. Nevertheless, several

of the factors are important in every patient, as discussed in the following sections.



55



25

1 sec



Intravascular Factors



A



Intravascular factors are those that relate primarily to

the regulation of blood flow, pressure, and volume

in the microvascular bed of the germinal matrix

(Table 11-4). Factors that relate to platelet-capillary

function and to blood clotting capability may play a

contributory pathogenetic role in certain patients.



1 sec

Arterial blood pressure

55



mm Hg



Fluctuating Cerebral Blood Flow

Major importance for fluctuating cerebral blood flow in

the pathogenesis of IVH was shown by a study by

Perlman and co-workers95 of ventilated preterm infants

with respiratory distress syndrome. Employing the

Doppler technique at the anterior fontanelle to insonate

the pericallosal branch of the anterior cerebral artery

(the latter an important source of blood supply to the

germinal matrix), we asked whether alterations in cerebral blood flow velocity in the first hours and days of life

could be identified and related to the subsequent development of IVH. The findings were decisive. Two patterns of cerebral blood flow velocity were noted on the



Cerebral blood flow velocity



25



1 sec



B

Figure 11-12 Cerebral blood flow velocity in ventilated premature

infant with respiratory distress syndrome. The upper trace of each

pair is the cerebral blood flow velocity, obtained at the anterior fontanelle, and the lower trace is the simultaneous blood pressure obtained

using an umbilical artery catheter. A, Stable pattern, and B, fluctuating

pattern. See text for description.



Chapter 11

TABLE 11-5



Relation of Fluctuating Cerebral Blood Flow

Velocity to Subsequent Development of

Intraventricular Hemorrhage



Cerebral Blood Flow

Velocity Pattern

Fluctuating

Stable



Intracranial Hemorrhage: Germinal Matrix–Intraventricular Hemorrhage



Subsequent

IVH

21

7*



No IVH

2

20



*Other provocative factors (e.g., pneumothorax) present in four patients.

IVH, intraventricular hemorrhage.



(see Fig. 11-12A). In contrast, the fluctuating pattern was

characterized by marked, continuous alterations in both

systolic and diastolic flow velocities (see Fig. 11-12B).

The cerebral blood flow velocity tracings closely reflected similar patterns of arterial blood pressure, simultaneously obtained from the abdominal aorta through an

umbilical artery catheter (see Fig. 11-12). A striking relationship of the fluctuating pattern of cerebral blood flow

velocity to the subsequent occurrence of IVH was

defined when the infants were studied by serial cranial

ultrasound scans (Table 11-5).

The aforementioned observations were important

for two reasons. First, they identified a subset of infants

with respiratory distress syndrome at extreme risk for

the subsequent occurrence of IVH and, therefore,

prime candidates for preventive interventions (see

later discussion). Second, they suggested a rational

pathogenetic mechanism for the development of IVH

with the respiratory distress syndrome (i.e., continuous

fluctuations of blood flow in the vulnerable matrix

microvessels, leading to rupture of these vessels). The

relationship between fluctuating cerebral blood flow

velocity and occurrence of major IVH was later confirmed.96 Two studies97,98 in which fluctuations in flow

velocity were less than 10% (coefficient of variation) did

not show a correlation of fluctuations with the occurrence of IVH, consistent with the earlier observation of

Perlman and co-workers95 that fluctuations of this

small degree do not lead to IVH.

The cause of the fluctuations in both the systemic

and cerebral circulations is related primarily to the

mechanics of ventilation.99-103 This notion is supported

by the observations that the fluctuations are nearly

invariable in infants who breathe out of synchrony

with the ventilator and that elimination of the infant’s

respiratory efforts by muscle paralysis eliminates the

fluctuations in the systemic and cerebral circulations

(see later discussion). In separate studies, hypercarbia,

hypovolemia, hypotension, ‘‘restlessness,’’ patent ductus arteriosus, and relatively high inspired oxygen concentrations also have correlated with the occurrence of

fluctuations in cerebral blood flow velocity.96,102-106

The effect of these rapid fluctuations is unrelated to

the presence or absence of cerebrovascular autoregulation (see later), because the response time of the latter

system (%5 to 15 seconds) is too slow.

Increases in Cerebral Blood Flow: Importance

of Pressure-Passive Circulation

The close temporal correlation between the occurrence

of IVH and abrupt increases in arterial blood pressure,



525



apparent cerebral blood flow (jugular venous occlusion plethysmography), and cerebral blood flow velocity100,107-112 has supported the earlier suggestion40 that

increases in cerebral blood flow play an important

pathogenetic role in IVH. A particularly likely cause of

the premature infant’s apparent propensity for dangerous

elevations of cerebral blood flow is a pressure-passive state of

the cerebral circulation.94,113-122 As discussed in Chapter

6, severely impaired cerebrovascular autoregulation

was identified in approximately 50% of ventilated

very-low-birth-weight infants studied by near-infrared

spectroscopy in the first several days of life.122 Using a

more sophisticated approach with the same methodology, Soul and co-workers117 showed that fully 87 of 90

infants studied in the first 5 days of life had pressure-passive

periods, and for the total group these periods accounted for a

mean of 20% of the time. Indeed, some infants exhibited

the pressure-passive state more than 50% of the time.

Additionally, hypercarbia and, perhaps, decreased hematocrit or decreased blood glucose may contribute to

severe enough elevations in cerebral blood flow in the

premature infant to provoke IVH (see later discussion).

The developmental aspects of autoregulation and the

regulatory factors involved are discussed in detail in

Chapter 6.

Elevations of Arterial Blood Pressure and PressurePassive Cerebral Circulation. Concerning the role

of elevations in arterial blood pressure, the presence

of a pressure-passive cerebral circulation would be

expected to lead to an increase in cerebral blood flow

in association with increases in blood pressure, with

the potential consequence being rupture of vulnerable

germinal matrix vessels. The striking increase in cerebral blood flow associated with increases in blood pressure can be shown in real time by near-infrared

spectroscopy (Fig. 11-13). A decisive demonstration

of the relation between pressure-passive cerebral circulation and the occurrence of IVH was obtained from a

classic study of 57 preterm infants supported by

mechanical ventilation during at least the first 48

hours of life (Fig. 11-14). Infants in whom ultrasonographic signs of severe IVH developed had prior

evidence of a pressure-passive cerebral circulation,

whereas those with intact cerebrovascular autoregulation developed either no hemorrhage or only mild

hemorrhage (see Fig. 11-14).114,115 The work of Tsuji

and co-workers122 showed that 47% of infants with

impaired cerebrovascular autoregulation developed

IVH (or periventricular leukomalacia, or both), whereas

only 13% of those with intact autoregulation developed

these lesions.122 Consistent with a potential role for

arterial hypertension in this setting is the demonstration of a relationship between maximum systolic blood

pressure above a threshold value and subsequent

occurrence of IVH.123 The limit for the highest tolerable peak systolic blood pressure was markedly lower for

the smaller infants.123 A particular role for minuteto-minute alterations in blood pressure has also been

demonstrated.124 Moreover, as discussed in Chapter 6,

the upper limit of the normal autoregulatory range in

the infant is dangerously close to the upper limit of the



526



UNIT IV



INTRACRANIAL HEMORRHAGE



58

3.8



HbDiff



48



38



MAP (mm Hg)



NIRS change (μMol)



Figure 11-13 Changes in blood

pressure (mean arterial pressure

[MAP]) and cerebral perfusion(hemoglobin difference [HbDiff]) during a

diaperchange.Simultaneous tracings

were obtained from a premature

infant (30 weeks of gestational age).

Note the marked, parallel increase in

cerebral perfusion, determined by

near-infrared spectroscopy (NIRS),

and in arterial blood pressure,

obtained from an umbilical artery catheter. (Courtesy of Dr. Adre du

Plessis.)



MAP

28



–1.2



45 Seconds



range of normal blood pressure. Studies in developing

animals indicate that the receptor number for specific

vasoconstricting prostaglandins, which are important

in setting the upper limit of the autoregulatory range

in the adult, are low early in maturation and thereby

impair protection of the cerebral circulation from

increases in blood pressure.125

Whether the pressure-passive cerebral circulatory

state relates to dysfunctional autoregulation per se, to

maximal vasodilation caused by hypercarbia or hypoxemia (or both), to the cranial trauma of even a ‘‘normal’’

vaginal delivery, or to ‘‘normal’’ arterial blood pressures

in the premature infant that are dangerously close

to the upslope of a normal autoregulatory curve remains unclear. Experimental support for these several

possibilities is available (see Chapter 6).40,100,116,125-132



Whatever the mechanism, however, the balance of current data imparts particular importance to events that

cause elevations in arterial blood pressure, especially

abrupt elevations, in the small premature infant.

Causes of Increased Arterial Blood Pressure in the

Human Newborn. The causes of abrupt elevations in

arterial blood pressure sometimes shown to be accompanied by increased cerebral blood flow velocity by the

Doppler technique, or increased cerebral blood volume

by near-infrared spectroscopy in the premature infant,

are clearly important to detect (and to prevent, whenever

possible) (Table 11-6). These causes include the following: such ‘‘physiological’’ events as rapid eye movement

(REM) sleep and the first minutes and hours after birth;

such ‘‘caretaking’’ concomitants as inadvertent noxious



CBF-MABP reactivity

(% Change CBF/mm Hg change MABP)



10

8

6

4

2

0

−2

−4

−6



Persistently

normal ultrasound

scans later

A



Mild intracranial

hemorrhage

later



Severe intracranial

hemorrhage later



B



C



Groups A, B, C — preterm infants

Figure 11-14 Cerebral blood flow (CBF)–mean arterial blood pressure (MABP) reactivities (percentage of change in CBF per millimeter of

mercury change in MABP) in premature infants before intracranial hemorrhage. CBF-MABP reactivities were obtained in the first 2 days of life

(primarily in the first 24 hours) in 57 mechanically ventilated preterm infants who had normal ultrasound scans at the time of the reactivity measurements and who were followed subsequently by ultrasonography. Groups A, B, and C were determined by the results of the subsequent scans. The

average reactivity and 95% confidence limits for each group are shown. Intact autoregulation (i.e., zero value for CBF-MABP reactivity) was present in

those infants who had subsequent scans that were normal or showed only mild hemorrhage. Infants who later developed severe hemorrhage had a

pressure-passive cerebral circulation. (Redrawn from Pryds O, Greisen G, Lou H, Friis-Hansen B: Heterogeneity of cerebral vasoreactivity in preterm

infants supported by mechanical ventilation, J Pediatr 115:638–645, 1989.)



Chapter 11



Although the degree to which these events contribute to the pathogenesis of IVH requires further quantitation and probably depends on concomitant clinical

circumstances, particular importance can be attributed

to pneumothorax.97,160-165 In one earlier study of nine

infants, pneumothorax was accompanied consistently

by abrupt elevations of systemic blood pressure and

cerebral blood flow velocity, and these circulatory

changes were followed within hours by IVH.161

Studies in newborn dogs documented abrupt increases

in arterial blood pressure on rapid evacuation of pneumothorax.162 Thus, both clinical and experimental data

emphasize the potentially deleterious circulatory effects

of neonatal pneumothorax.



Major Causes of Increased Blood

Pressure or Cerebral Blood Flow in

the Premature Infant*



TABLE 11-6



527



Intracranial Hemorrhage: Germinal Matrix–Intraventricular Hemorrhage



Related to ‘‘Physiological’’ Events

Postpartum status

Rapid eye movement sleep

Related to Caretaking Procedures

Noxious stimulation

Motor activity: spontaneous or with handling

Tracheal suctioning

Instillation of mydriatics

Related to Systemic Complications

Pneumothorax

Rapid volume expansion: exchange transfusion, other rapid

colloid infusion

Ligation of patent ductus arteriosus

Related to Neurological Complications

Seizure

*See text for references.



70



60



60



50



50



40



40



30



30



20



20



20



20



10



10



10



0



70

60

0



Zb 491



Calib.



Suction



50

40



Feeding



Feeding



30



Manipulation



Apnea



Apnea



Apnea

Zb 491



10 Min.

0



70

60

50

40



Temp. meas.



30

0



Mean arterial pressure (mm Hg)



80



70



Zb 491



100

90



80



80



90



10



stimulation, abdominal examination, handling (see

Fig. 11-13; Fig. 11-15), instillation of mydriatics, and

tracheal suctioning (Fig. 11-16); such systemic complications as pneumothorax, exchange transfusion, and

rapid infusion of colloid; and such neurological complications as seizures.107,108,111,133-159



Relevant Experimental Studies: Role of Hypertension. The particular importance of abrupt increases

in systemic blood pressure and cerebral blood flow in

pathogenesis has been demonstrated conclusively in

elegant experimental studies in the newborn beagle

puppy129,166-174 and in the preterm sheep fetus.175

The newborn puppy, which has been studied most

extensively, has a subependymal germinal matrix

approximately comparable to that of the human premature infant of 30 to 32 weeks of gestation.176 Germinal

matrix hemorrhage–IVH is produced most readily in

this animal by a sequence of hypotension and



Figure 11-15 Increases of arterial blood pressure in the small premature infant. Continuous recording of mean aortic pressure in a 20-hour-old

premature infant weighing 880 g. Note the marked and sustained increase with manipulation. The infant subsequently developed an intraventricular

hemorrhage. (From Lou HC, Lassen NA, Friis-Hansen B: Is arterial hypertension crucial for the development of cerebral haemorrhage in premature

infants? Lancet 1:1215–1217, 1979.)



528



UNIT IV



INTRACRANIAL HEMORRHAGE



60



55



80



60



55



50



45



45



40



40



35



35



Blood flow (mL/100 g/min)



50



Mean blood pressure (mm Hg)



Mean blood pressure (mm Hg)



70

60

50

40

30

20

10

35

30



25



30



Rest



25



Changes in blood pressure

with suctioning

Figure 11-16 Changes in blood pressure with tracheal suctioning in

premature infants. Note the increase in blood pressure that accompanied suctioning in all but one infant.



hypertension produced by blood removal and volume

reinfusion (Fig. 11-17). The marked increase in

germinal matrix flow provoked by hypertension

has been demonstrated strikingly by autoradiography

(Fig. 11-18).129



Figure 11-17 Intraventricular hemorrhage in the newborn beagle

puppy. Gross intraventricular hemorrhage with dilation of the lateral

ventricle (arrow) in cerebrum of a 24-hour-old puppy subjected to hypertension. (From Goddard J, Lewis RM, Armstrong DL, Zeller RS:

Moderate, rapidly induced hypertension as a cause of intraventricular

hemorrhage in the newborn beagle model, J Pediatr 96:1057–1060,

1980.)



45



55



65



75



85



95



105



Mean arterial pressure (mm Hg)

Figure 11-18 Increase in blood flow to germinal matrix with

increase in arterial blood pressure in the newborn dog. Blood pressure was elevated by infusion of phenylephrine. Blood flow to the germinal matrix was measured by 14C-iodoantipyrine autoradiography.

(From Pasternak JF, Groothuis DR: Autoregulation of cerebral blood

flow in the newborn beagle puppy, Biol Neonate 48:100–109, 1985.)



Rapid Volume Expansion. The role of rapid volume

expansion (see Table 11-4) involves not only the administration of blood or other colloid, as described in

relation to systemic hypertension, but also the administration of hyperosmolar materials, such as hypertonic

sodium bicarbonate. Pressure-passive cerebral circulation may not be the sole or even the principal means

by which such infusions may lead to IVH, particularly

in the case of sodium bicarbonate. Although the dangers

of rapid infusion of hyperosmolar solutions had been

noted for many years, an association of IVH in the

premature infant administered sodium bicarbonate

was emphasized initially by Simmons and coworkers177 from study of an autopsy population. The

association was later confirmed in a CT study of premature infants, and the importance of rapidity of infusion was made apparent.178 Conflicting reports on the

pathogenetic role of sodium bicarbonate163,179-186

relate in part to the failure to take into account such

factors as rapidity of administration and also to the

problems of extrapolating data to living infants from

studies of dead infants, particularly in the case of

IVH. At any rate, the mechanism for the effect of

rapid infusion of hyperosmolar sodium bicarbonate

on intracranial hemorrhage may relate in part to the

abrupt elevation of arterial pressure of carbon dioxide

(PaCO2) that results in the poorly ventilated or nonventilated patient from the buffering effect of the bicarbonate. The elevated PaCO2 would then act on cerebral

arterioles, by causing an increase in perivascular hydrogen ion (H+) concentration, to increase cerebral perfusion as outlined next.

Hypercarbia. The role of hypercarbia in causing

increases in cerebral blood flow of pathogenetic importance for IVH may be appreciable in selected infants.