pediatric hydrocephalus: systematic literature review and ......a history of intraventricular...

J Neurosurg Pediatrics (Suppl) 14:8–23, 2014

8 J Neurosurg: Pediatrics / Volume 14 / November 2014

©AANS, 2014

Although reviews have been recently published, there exists a paucity of guidelines or evidence-based recommendations for the management of

posthemorrhagic hydrocephalus (PHH) in infants.62 Ac-

Pediatric hydrocephalus: systematic literature review and evidence-based guidelines. Part 2: Management of posthemorrhagic hydrocephalus in premature infantsCatherine a. Mazzola, M.D.,1 asiM F. ChouDhri, M.D.,2,3 Kurtis i. auguste, M.D.,4 DaviD D. liMbriCK Jr., M.D., Ph.D.,5 Marta rogiDo, M.D.,6 laura MitChell, M.a.,7 anD ann Marie Flannery, M.D.8

1Division of Pediatric Neurological Surgery, Goryeb Children’s Hospital, Morristown, New Jersey; 2Departments of Radiology and Neurosurgery, University of Tennessee Health Science Center, and 3Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Memphis, Tennessee; 4Department of Neurosurgery, University of California, San Francisco, California; 5Division of Pediatric Neurosurgery, St. Louis Children’s Hospital, St. Louis, Missouri; 6Division of Neonatology, Department of Pediatrics, Goryeb Children’s Hospital, Morristown; and Rutgers New Jersey Medical School, Newark, New Jersey; 7Congress of Neurological Surgeons, Schaumburg, Illinois; and 8Department of Neurological Surgery, Saint Louis University, St. Louis, Missouri

Object. The objective of this systematic review and analysis was to answer the following question: What are the optimal treatment strategies for posthemorrhagic hydrocephalus (PHH) in premature infants?

Methods. Both the US National Library of Medicine and the Cochrane Database of Systematic Reviews were queried using MeSH head-ings and key words relevant to PHH. Two hundred thirteen abstracts were reviewed, after which 98 full-text publications that met inclusion criteria that had been determined a priori were selected and reviewed.

Results. Following a review process and an evidentiary analysis, 68 full-text articles were accepted for the evidentiary table and 30 publications were rejected. The evidentiary table was assembled linking recommendations to strength of evidence (Classes I–III).

Conclusions. There are 7 recommendations for the management of PHH in infants. Three recommendations reached Level I strength, which represents the highest degree of clinical certainty. There were two Level II and two Level III recommendations for the management of PHH.

RecommendAtion conceRning SuRgicAl tempoRizing meASuReS: I. Ventricular access devices (VADs), external ventricular drains (EVDs), ventriculosubgaleal (VSG) shunts, or lumbar punctures (LPs) are treatment options in the management of PHH. Clinical judgment is required. StRength of RecommendAtion: Level II, moderate degree of clinical certainty.

RecommendAtion conceRning SuRgicAl tempoRizing meASuReS: II. The evidence demonstrates that VSG shunts reduce the need for daily CSF aspiration compared with VADs. StRength of RecommendAtion: Level II, moderate degree of clinical certainty.

RecommendAtion conceRning Routine uSe of SeRiAl lumbAR punctuRe: The routine use of serial lumbar puncture is not recommended to reduce the need for shunt placement or to avoid the progression of hydrocephalus in premature infants. StRength of RecommendAtion: Level I, high clinical certainty.

RecommendAtion conceRning nonSuRgicAl tempoRizing AgentS: i. Intraventricular thrombolytic agents including tissue plasminogen activator (tPA), urokinase, or streptokinase are not recommended as methods to reduce the need for shunt placement in premature infants with PHH. StRength of RecommendAtion: Level I, high clinical certainty.

RecommendAtion conceRning nonSuRgicAl tempoRizing AgentS. ii. Acetazolamide and furosemide are not recommended as methods to reduce the need for shunt placement in premature infants with PHH. StRength of RecommendAtion: Level I, high clinical certainty.

RecommendAtion conceRning timing of Shunt plAcement: There is insufficient evidence to recommend a specific weight or CSF pa-rameter to direct the timing of shunt placement in premature infants with PHH. Clinical judgment is required. StRength of RecommendAtion: Level III, unclear clinical certainty.

RecommendAtion conceRning endoScopic thiRd VentRiculoStomy: There is insufficient evidence to recommend the use of endoscopic third ventriculostomy (ETV) in premature infants with posthemorrhagic hydrocephalus. StRength of RecommendAtion: Level III, unclear clinical certainty.(http://thejns.org/doi/abs/10.3171/2014.7.PEDS14322)

Key WorDs • hydrocephalus • infant • case management • magnetic resonance imaging • posthemorrhagic hydrocephalus • premature infant • preterm infant • ventriculomegaly •

intraventricular hemorrhage • meningitis • ventricular dilation • ventricular index • head circumference • in utero • shunt • reservoir • endoscopic third ventriculostomy • ventriculoperitoneal shunt • practice guidelines

Abbreviations used in this paper: AANS = American Association of Neurological Surgeons; CDC = Centers for Disease Control and Prevention; CNS = Congress of Neurological Surgeons; ELBW = extremely low birth weight; ETV = endoscopic third ventriculos-tomy; EVD = external ventricular drain; HUS = head ultrasound; IVH = intraventricular hemorrhage; LBW = low birth weight; LP = lumbar puncture; OFC = occipitofrontal circumference; PHH = posthemorrhagic hydrocephalus; PHVD = posthemorrhagic ventric-ular dilation; tPA = tissue plasminogen activator; VAD = ventricular access device; V/BP = ventricular/biparietal; VP = ventriculoperito-neal; VSG = ventriculosubgaleal.

Part 2: Management of posthemorrhagic hydrocephalus in infants

9J Neurosurg: Pediatrics / Volume 14 / November 2014

cording to 2007 data provided by the Division of Vital Statistics of the Centers for Disease Control and Preven-tion (CDC), infants born with very low birth weight and gestational age have a significantly higher risk of mortal-ity.49 In fact, more than 50% of all infant deaths in 2007 occurred in infants born before 32 weeks’ gestation.49 In 2008, the reported preterm birth rate declined for the second consecutive year to 12.3%, but this decrease pri-marily involved those infants born in the later preterm period (34–36 weeks).47 Low birth weight (LBW) also contributes to increased infant mortality, and the CDC has reported that the percentage of LBW infants, or in-fants born weighing less than 2500 g, increased by 24% between 1984 and 2006.47

A recent study of 15,454 extremely low birth weight (ELBW) infants, each weighing between 401 g and 1000 g, was undertaken to assess neurodevelopmental out-come.1 More than 5000 infants died while in the hospital or before the follow-up visit. Among the 7693 children in whom follow-up studies were available, 2530 (33%) had a history of intraventricular hemorrhage (IVH). The IVH was Grade III or IV for 998 (13%) of the 7693 infants. Remarkably, in only 246 (3%) of the 7693 ELBW infants with follow-up was a shunt placed for PHH.1 There are still many questions about the optimal time to intervene for infants with PHH, and there are many different opin-ions about the best temporizing mechanism for symp-tomatic infants too small or unstable for permanent shunt placement.

The objective of this systematic review and analy-sis was to answer the following question: What are the optimal treatment strategies for posthemorrhagic hydro-cephalus (PHH) in premature infants? We evaluated the current literature and constructed evidence-based recom-mendations supported by the strength of the available data for the management of PHH in premature infants. Specifically, we wanted to investigate relevant evidence for the following:

• Use of surgical temporizing methods such as ventric-ular reservoirs, external ventricular drains (EVDs), ventriculosubgaleal (VSG) shunts, and lumbar punc-tures (LPs).

• Routine use of serial LPs to reduce the need to shunt or to avoid the progression of hydrocephalus in pre-mature infants.

• Use of intraventricular thrombolytic agents, includ-ing tissue plasminogen activator (tPA), urokinase, and streptokinase, to reduce the need for shunt place-ment in premature infants with PHH.

• Use of acetazolamide or furosemide to reduce the need for shunt placement in premature infants with PHH.

• Efficacy of endoscopic third ventriculosomy (ETV) in this population.

• Specific CSF parameters to direct the timing of shunt placement in premature infants with PHH.

MethodsSearch Criteria

Both the US National Library of Medicine and the

Cochrane Database of Systematic Reviews were queried using MeSH headings and key words relevant to PHH.

Key Words. The following key words were used in this study: (((preterm[All Fields] AND Intraventricular[All Fields] AND (“haemorrhage”[All Fields] OR “hemor-rhage”[MeSH Terms] OR “hemorrhage”[All Fields])) OR ((“infant, premature”[MeSH Terms] OR (“infant”[All Fields] AND “premature”[All Fields]) OR “premature infant”[All Fields] OR (“preterm”[All Fields] AND “infant”[All Fields]) OR “preterm infant”[All Fields]) AND (“hydrocephalus”[MeSH Terms] OR “hydro ceph-alus”[All Fields]))) OR ((preterm[All Fields] AND (“heart ventricles”[MeSH Terms] OR (“heart”[All Fields] AND “ventricles”[All Fields]) OR “heart ventricles”[All Fields] OR “ventricular”[All Fields]) AND reservoir[All Fields])) AND shunt[All Fields].

StrategyTwo hundred thirteen abstracts were reviewed, after

which 98 publications that met the inclusion criteria were selected. In addition to the overall inclusion/exclusion cri-teria specified in the Methods section of the Guidelines (Part 1), additional inclusion criteria included studies in which infants younger than 12 months with all forms of hydrocephalus—both congenital and acquired—were evaluated to ensure that the maximum number of studies were reviewed. The analysis focused on studies evaluat-ing infants with PHH because of the treatment strategies and challenges unique to this patient population.

As a result of the US National Library of Medicine’s search engine functionalities, additional search terms (heart ventricles) not relevant to topics addressed in this chapter were added to the search strategy. Although these search terms remained in the search strategy, we did not recall any references retrieved using them for full-text review. We excluded those references because they were not relevant to the overall scope of this project or the pa-tient population addressed in this chapter and, therefore, did not meet the article inclusion criteria specified in the methodology section of this guideline (Part 1).23

Following an evidentiary analysis and a review of the 98 full-text articles, 68 publications were accepted for in-clusion in the evidentiary table and 30 publications were excluded.2,7,12–14,21,22,27,30,33,35,38,48,50–53,55,57,58,62–64,66–68,70,73,75 The evidentiary table was assembled linking recommen-dations to the strength of the evidence (Levels I–III).

Search ResultsOf the 98 full-text articles selected for review, 30

full-text publications were rejected based on the criteria listed above and only 68 articles were used to construct the evidentiary table (Fig. 1). The criteria for the decision to treat were quite variable among different institutions and different study groups. For example, we evaluated 1 Class II study in which hydrocephalus was defined as the atrium of the lateral ventricle measuring > 10 mm on the horizontal plane of a head ultrasound (HUS) study or the body of the lateral ventricle at the level of the midthala-mus measuring > 10 mm on a sagittal ultrasound image.10 We reviewed another Class III study in which hydroceph-

C. A. Mazzola et al.


alus was defined as anterior cortical mantle thickness < 20 mm at an average postnatal age of 21 days along with increasing occipitofrontal circumference (OFC) as an in-dicator of hydrocephalus that should be treated.5 Bada et al.5 reported that of 10 infants requiring shunts, 5 (50%) experienced normal development, which was defined by physical and neurological assessment and evaluation us-ing the Denver developmental screening tool. Evan’s ra-tio, which is described as the lateral measurement of the ventricle across the frontal horns divided by the lateral measurement across the brain (biparietal diameter; also known as the ventricular/biparietal [V/BP] ratio) can also be used to describe the severity of PHH.16 The majority of studies that were evaluated based on an initial diag-nosis of PHH on HUS, CT, and MRI studies were also used. Choudhury described mild hydrocephalus as a V/BP ratio of 0.26–0.40, moderate hydrocephalus as a V/BP ratio of 0.40–0.60, severe hydrocephalus as a V/BP ratio of 0.60–0.90, and extreme hydrocephalus as a V/BP ratio of 0.91–1.0.16 These authors also reported that the thickness of the cortical mantle was not a statistically significant indicator of outcome because several infants with extreme hydrocephalus displayed normal motor de-velopment.16 One Class II and 1 Class III study indicated that when ventriculoperitoneal (VP) shunts were placed,

even in cases of severe or extreme hydrocephalus, there were some infants with normal development and motor outcome (50 of 82 patients in the Choudhury study).5,16 Numerous studies have reported that good neurodevelop-mental outcomes may be seen if and when infants with hydrocephalus are aggressively treated and cortical man-tle thickness is restored.

ResultsSurgical Temporizing Measures

RecommendAtion: Ventricular access devices (VADs), external ventricular drains (EVDs), ventriculosubgaleal (VSG) shunts, or lumbar punctures (LPs) are treatment op-tions in the management of PHH. Clinical judgment is re-quired. StRength of RecommendAtion: Level II, moderate degree of clinical certainty.

RecommendAtion: The evidence demonstrates that VSG shunts reduce the need for daily CSF aspiration compared with VADs. StRength of RecommendAtion: Level II, moderate degree of clinical certainty.

The evidence demonstrates that VADs reduce mor-bidity and mortality compared with EVDs. Three Class II and 7 Class III studies were included as evidence to sup-port the first recommendation, and these lower-quality

Fig. 1. Flowchart showing the process involved in identifying relevant literature. The criteria for “records excluded” and “full-text articles excluded with reasons” are detailed in Part 1 of the Guidelines.



studies documented the safety and efficacy of VADs, or Ommaya reservoirs, for the aspiration of CSF, ventricu-lar decompression, and lowering of intracranial pres-sure.3,8,11,25,26,29,31,39,78,80 The authors of 2 Class II studies reported that ventricular reservoirs may reduce the inci-dence of shunt infection as well as noninfectious shunt complications.8,26 In one Class II study and one class III study, repeated aspiration of CSF from a VAD did not sig-nificantly increase the risk of infection.26,39 Three Class III studies reported that ventricular reservoirs did not significantly reduce the need for permanent shunt place-ment.29,31,78 One Class III study reported that the use of VADs, compared with the use of continuous ventricular drainage, significantly reduced morbidity and mortality rates that were associated with the surgical treatment of PHH in LBW infants with reservoirs, instead of EVDs (Table 1).26

The placement of an EVD has also been used to treat hydrocephalus in preterm infants with PHH and is an op-tion for these children, as shown in 1 Class II and 7 Class III studies.9,17,28,36,40,59,60,69 Three Class III studies reported that an EVD obviated the need for VP shunt placement in fewer than one-third of infants treated.9,40,60 More than 50% of preterm infants with PHH did require permanent VP shunt placement following removal of an EVD (95 out of 132 survivors required a shunt).9,40,59,60,69

It has been reported that placement of a VSG shunt may reduce the need for permanent shunt placement. The authors of Class II and Class III studies reported trends toward shunt independence, but the studies only enrolled 32 and 95 patients, respectively, and the results were not statistically significant.41,43 In their report of a Class II, retrospective historical cohort study, Lam and Heilman demonstrated that VSG shunting significantly reduced the need for daily CSF aspiration, which may decrease the risk of introducing a de novo CSF infection.41 A chi-square test performed on their data indicated that a VSG shunt did significantly reduce the need for daily CSF as-piration when compared with a VAD (c2 = 19.2, df = 1, p = 0.000016, p < 0.05).41 This may reduce the risk of infection or other complications. A larger, prospective study reported a statistically significant decreased need for permanent CSF diversion in infants treated with VSG shunts.43 This study reported that 66% of infants (20 of 30) treated with VSG shunts required VP shunts and 33% (10 of 30) remained shunt free; this was compared with a group of infants treated with VADs in which 75% (49 of 65) required VP shunts and only 25% of infants (16 of 65) remained shunt free.43

In 2 studies, 1 intervention was compared to another with specific recommendations about the timing of the intervention for temporizing measures for the treatment of PHH in very LBW infants. In 1 Class III study, the au-thors compared early versus late intervention, as assessed by ventricular dilation in 5 collaborating neonatal cen-ters.18 Ninety-five patients were subdivided into early in-tervention or late intervention groups, depending on their ventricular index at the time of initial treatment. Early treatment was safe and effective regardless of whether LP and/or reservoir placement was used. Early interven-tion was associated with a reduced requirement for a VP

shunt (OR = 0.22) and reduced risk of moderate-to-severe disability.18 Additionally, there was a single Class III ob-servational study of outcomes in which LPs, EVD, VSG shunts, and reservoirs were used.57 All interventional studies were found to be safe and effective.57

Routine Use of Serial Lumbar PunctureRecommendAtion: The routine use of serial lumbar

puncture (LP) is not recommended to reduce the need for shunt placement or to avoid the progression of hydroceph-alus in premature infants. StRength of RecommendAtion: Level I, high degree of clinical certainty.

One Class I study was included, and it reported no statistical differences in outcomes of preterm infants with PHH treated with observation alone or infants treated with daily LP (Table 2).4 Lumbar puncture is often used early in the treatment of PHH, despite the fact that there is no statistically significant reduction in the need for a shunt or progression of PHH.4,54 In fact, LP neither pre-dicts nor prevents the need for a permanent VP shunt.36 A second study, a Class III study, also reported no dif-ference in adverse outcome regardless of whether infants were untreated or treated with serial LP.15 Without ag-gressive treatment of hydrocephalus and with persistent ventricular dilation, outcome was poor.15 Additionally, there was a single Class III study that concluded that re-peated LPs may cause or contribute to subsequent shunt infection.6 Although LP may be useful for drawing off CSF as an immediate treatment for elevated intracranial pressure in infants with PHH, or for sampling CSF, we do not recommend the routine use of LP to eliminate the need for a VP shunt.15

Nonsurgical Temporizing AgentsIntraventricular Thrombolytic Agents. Recommen-

dAtion: Intraventricular thrombolytic agents including tissue plasminogen activator (tPA), urokinase, or strepto-kinase are not recommended as methods to reduce the need for shunt placement in premature infants with PHH. StRength of RecommendAtion: Level I, high clinical cer-tainty.

Based on 1 high-quality Class I study, the DRIFT procedure—DRainage, Irrigation, and Fibrinolytic Ther -apy (intraventricular tPA)—is not recommended for PHH.71 DRIFT did not significantly reduce shunt surgery or death, but it was associated with an increased rate of secondary IVH (Table 3).71 Forty-four percent (15 of 34) of infants in the DRIFT group died or required a shunt, compared with 50% (19 of 36) of infants who received standard treatment. Thirty-five percent (12 of 34) of pre-term infants in the DRIFT study had secondary IVH, compared with 8% (3 of 34) who received standard treat-ment.71 These results differ from those of earlier Class II and Class III studies in which a decreased rate for the need for permanent shunt placement was reported when low-dose urokinase or fibrinolytic therapy with tPA was used for ventricular irrigation and clot reduction.32,61,75,77

Reviews conducted by Whitelaw and Odd74 have also revealed that intraventricular injection of streptokinase has not been shown to be beneficial.74 A single case re-



TABL

E 1:

Surg

ical

tem

poriz

ing

mea

sure

s: su

mm

ary o

f evid

ence

*

Auth

ors &

Yea

rSt

udy D

escr

iption

Data

Clas

s, Qu

ality,

& R

easo

nsRe

sults

& C

onclu

sions

Corn

ips et

al.,

1997

Retro

spec

tive r

eview

of 14

pts w

/ Gra

de II

I or G

rade

IV IV

H dia

gnos

ed on

HUS

stud

y & tr

eated

w/ E

VD.

14 pt

s wer

e com

pare

d w/ a

histo

rical

coho

rt of

15 in

fants

w/

simila

r Gra

de II

I/IV

IVH.

Clas

s II

Retro

spec

tive r

eview

of 2

coho

rts: p

rema

ture i

nfants

tre

ated w

/ EVD

vs th

ose t

reate

d med

ically

.

Ventr

icular

drain

age i

s a sa

fe op

tion f

or in

fants

w/ P

HH.

Gurtn

er et

al.,

1992

Retro

spec

tive c

onse

cutiv

ely en

rolle

d stu

dy of

736 L

BW in

fants

(<

1500

g).

After

exclu

sion o

f som

e infa

nts fo

r var

ious r

easo

ns, 5

47 in

fants

were

inclu

ded i

n the

retro

spec

tive c

onse

cutiv

e rev

iew.

Shun

ts we

re pl

aced

for p

rogr

essiv

e hyd

roce

phalu

s & O

FC >

95

perc

entile

.3 y

rs of

data

exam

ined b

y yr, b

y ana

lyses

of va

rianc

e, &

Dunc

an’s

mean

comp

ariso

n tes

ts.Ch

i-squ

are a

nalys

es on

disc

rete

varia

bles s

uch a

s rate

s of

comp

licati

on &

mor

tality

. Stu

dent

t-tes

t w/ B

onfer

roni

cor-

recti

ons.

Spea

rman

corre

lation

coef

ficien

ts we

re co

mpute

d wh

en ap

prop

riate.

Qua

ntita

tive d

ata a

re pr

esen

ted.

Clas

s II

Cons

ecut

ive, b

ut no

t a ra

ndom

ized c

ontro

lled s

tudy

.A

nonr

ando

mize

d hist

orica

l coh

ort, c

ompa

red b

y yr o

f tre

atmen

t & tr

eatm

ent t

ype.

1st y

r: EV

D.2n

d & 3

rd yr

: sub

cuta

neou

s res

ervo

ir was

used

.Ou

tcome

s eva

luated

: mor

bidity

, mor

tality

, & ne

ed fo

r sh

unt r

evisi

on.

Freq

uenc

y & m

orta

lity of

Gra

des I

II & IV

hemo

rrhag

e in

infan

ts we

ighing

btwn

500

& 70

0 g re

maine

d re

lative

ly co

nsta

nt ov

er th

e 3-y

r per

iod.

Auth

ors c

onclu

ded t

hat th

ere w

as a

signifi

cant

redu

c-tio

n in m

orbid

ity &

mor

tality

asso

ciated

w/ L

BW

infan

ts wh

en th

ey be

gan u

sing r

eser

voirs

inste

ad of

EV

Ds.

Hudg

ins et

al.,

1997

Use o

f uro

kinas

e via

rese

rvoir

to tr

eat P

HH in

18 pt

s. 4 d

iffer-

ent d

oses

of ur

okina

se; u

ltimate

ly gr

oupe

d into

“high

” (n =

9)

& “l

ow” d

ose (

ever

yone

else

, n =

9).

Both

grou

ps co

mpar

ed to

histo

rical

contr

ol gr

oup w

/ res

pect

to ou

tcome

& ne

ed fo

r shu

nt. P

rosp

ectiv

e, ca

se co

ntrol.

Clas

s II

Pros

pecti

ve, n

onra

ndom

ized,

case

-con

trol s

eries

.Di

vision

of 9

pts in

to “lo

w” do

se gr

oup w

ould

appe

ar to

dil

ute st

atisti

cal p

ower

desp

ite st

atisti

cal s

ignific

ance

ob

taine

d.

“Low

dose

” uro

kinas

e red

uced

shun

t rate

(71%

vs 92

%)

comp

ared

to hi

storic

al co

ntrols

. Few

er sh

unt r

evi-

sions

in bo

th gr

oups

comp

ared

to co

ntrol

grou

p.

Lam

& He

il-ma

n, 20

09Si

ngle-

institu

tion,

retro

spec

tive h

istor

ical c

ohor

t stu

dy of

32

prete

rm in

fants

w/ P

HH. T

his st

udy c

ompa

red 2

coho

rts of

inf

ants:

thos

e tre

ated w

/ VAD

/Omm

aya p

lacem

ent v

s tho

se

treate

d w/ V

SG sh

unts.

Ther

e wer

e no s

tatis

tical

differ

ence

s in a

ge or

birth

weig

ht of

the i

nfants

in th

e 2 gr

oups

. The

grou

ps w

ere s

tudie

d for

IVH

grad

e, ne

ed fo

r dail

y CSF

with

draw

al, C

SF le

ak fr

om th

e sc

alp, C

SF in

fectio

n, &

need

for a

VP

shun

t.

Clas

s II

A ch

i-squ

are t

est w

as pe

rform

ed (c

2 = 19

.2, d

f = 1,

p =

0.000

016,

p < 0.

05),

which

show

ed th

at VS

G sh

unts

signifi

cantl

y red

uced

the n

eed f

or da

ily C

SF as

pira-

tion c

ompa

red t

o VAD

s.Th

e high

er ra

te of

comp

licati

ons o

f VSG

shun

ts wa

s not

statis

ticall

y sign

ifican

t com

pare

d w/ th

e VAD

grou

p (p

= 0.

17).

93.75

% (1

5 of 1

6 pts)

in th

e VAD

grou

p req

uired

VP

shun

ts wh

ile 71

.42%

(10 o

f 14 p

ts) in

the V

SG sh

unt

grou

p nee

ded V

P sh

unts.

Ther

e was

a tre

nd to

ward

VP

shun

t inde

pend

ence

in

the V

SG sh

unt g

roup

, as c

ompa

red t

o the

VAD

gr

oup,

but it

did n

ot re

ach s

ignific

ance

.VS

G sh

unts

decr

ease

d the

need

for d

aily t

aps.

Ther

e wa

s a sl

ightly

high

er ra

te of

comp

licati

ons i

n the

VS

G sh

unt g

roup

, but

it was

not s

ignific

ant.

Anwa

r et a

l., 19

86Co

nsec

utive

, non

rand

omize

d stu

dy of

19 pr

eterm

infa

nts w

/ PH

H wh

o und

erwe

nt pla

ceme

nt of

rese

rvoir

s for

symp

tom-

atic h

ydro

ceph

alus.

Symp

tomati

c hyd

roce

phalu

s was

defin

ed as

infa

nts w

/ rap

idly

incre

asing

OFC

, ven

tricu

lomeg

aly, &

sign

s of in

crea

sed I

CP

pres

ent, s

uch a

s ten

se fo

ntan

elle,

splay

ed su

tures

, apn

ea,

brad

ycar

dia, s

eizur

e, fe

eding

diffic

ulties

, or le

thar

gy.

Clas

s III

Stud

y was

a ca

se se

ries o

f infa

nts w

eighin

g <20

00 g,

w/

clea

r CSF

& tr

eated

w/ r

eser

voirs

.Th

ere w

as on

ly lim

ited p

rese

ntati

on of

quali

tativ

e &

quan

titativ

e dat

a. Da

ta in

clude

d: mo

rbidi

ty, m

orta

lity,

& ne

ed fo

r shu

nt pla

ceme

nt in

thes

e infa

nts.

Ther

e was

no co

mpar

ison w

/ a co

hort

of no

ntrea

ted

infan

ts or

infa

nts tr

eated

w/ v

entri

cular

drain

s.

The a

utho

rs co

nclud

ed th

at re

serv

oirs p

rovid

e safe

&

effec

tive t

reatm

ent fo

r infa

nts w

/ PHH

& sy

mptom

-ati

c hyd

roce

phalu

s.

(cont

inued

)



TABL

E 1:

Surg

ical

tem

poriz

ing

mea

sure

s: su

mm

ary o

f evid

ence

* (co

ntin

ued)

Auth

ors &

Yea

rSt

udy D

escr

iption

Data

Clas

s, Qu

ality,

& R

easo

nsRe

sults

& C

onclu

sions

Benz

el et

al.,

1993

41 pt

s req

uiring

ventr

icular

drain

age f

or hy

droc

epha

lus/P

HH

were

evalu

ated r

etros

pecti

vely.

All d

raina

ge pr

oced

ures

wer

e per

form

ed on

pts w

/ IVH

& hy

-dr

ocep

halus

(Gra

de II

I [25 p

ts]) &

pts w

/ IVH

& IP

H (G

rade

IV

[16 p

ts]) in

who

m me

dical

mana

geme

nt ha

d fail

ed.

Clas

s III

Retro

spec

tive c

ase s

eries

of 41

cons

ecut

ive pr

ematu

re

infan

ts.26

ventr

icular

rese

rvoir

s (Ri

ckha

m or

McC

omb r

eser

-vo

irs) w

ere p

laced

in ne

onate

s weig

hing <

1500

g,

allow

ing fo

r safe

but in

termi

ttent

ventr

icular

acce

ss.

18 of

thes

e res

ervo

irs w

ere s

ubse

quen

tly co

nver

ted

to VP

shun

ts. 32

% of

pts d

evelo

ped a

VP

shun

t &/or

re

serv

oir in

fectio

n & 59

% re

quire

d a sh

unt r

evisi

on

durin

g the

1st y

r of li

fe.No

Gra

de IV

pts a

chiev

ed no

rmal

func

tiona

l leve

l, whil

e 10

Gra

de III

pts d

id. T

he in

ciden

ce of

seve

re de

vel-

opme

ntal

delay

(44%

vs 28

%) &

death

(38%

vs 12

%)

was g

reate

r in G

rade

IV th

an in

Gra

de II

I pts.

Auth

ors s

tate,

“The

plac

emen

t of v

entri

cular

rese

rvoir

s is

acce

ptab

le as

an al

terna

tive t

o ear

ly pla

ceme

nt of

ventr

iculo-

perit

onea

l shu

nts. T

his ap

proa

ch m

ay

redu

ce th

e inc

idenc

e of s

hunt

infec

tion a

s well

as

nonin

fectio

us sh

unt c

ompli

catio

ns.”

Berg

er et

al.,

2000

Retro

spec

tive r

eview

of ou

tcome

s afte

r plac

emen

t of E

VDs

in 37

prem

ature

infa

nts (5

1 dra

ins).

PHH

diagn

osed

by

ultra

soun

d.

Clas

s III

Sing

le-ins

titutio

n retr

ospe

ctive

revie

w.Ne

urod

evelo

pmen

tal o

utcom

e dep

ende

nt on

exten

t of

pare

nchy

mal in

jury.

Infec

tion r

ates:

5.4%

pts,

3.9%

drain

. 11 o

f 37 p

ts did

no

t req

uire s

hunt

place

ment.

Brou

wer e

t al.,

2007

Sing

le-ce

nter r

etros

pecti

ve re

view

of 76

prete

rm in

fants

tre

ated f

or P

HVD

w/ ve

ntricu

lar re

serv

oirs.

Infec

tion r

ates w

ere m

easu

red i

n 2 su

cces

sive 6

-yr in

terva

ls.

No. o

f res

ervo

ir pun

cture

s also

exam

ined.

Clas

s III

Sing

le-ce

nter r

etros

pecti

ve re

view.

Whil

e the

no. o

f res

ervo

ir pun

cture

s did

not c

hang

e, th

e infe

ction

rate

was l

ower

in th

e 2nd

, mor

e rec

ent

inter

val (2

of 5

0 pts

[4%] v

s 5 of

26 pt

s [19

.2%

]).Co

nclus

ion: R

isks a

ssoc

iated

w/ v

entri

cular

rese

rvoir

s ar

e w/in

acce

ptab

le lim

its.

de V

ries e

t al.,

2002

Retro

spec

tive r

eview

of co

nsec

utive

prete

rm in

fants

(EGA

≤3

4 wks

) w/ G

rade

III I

VH tr

eated

for p

osth

emor

rhag

ic ve

ntricu

lar di

latati

on in

5 co

llabo

ratin

g NIC

Us (n

= 9

5). P

ts we

re su

bdivi

ded i

nto ea

rly in

terve

ntion

or la

te int

erve

ntion

gr

oups

, dep

endin

g on t

heir v

entri

cular

inde

x at th

e tim

e of

initia

l trea

tmen

t.

Clas

s III

Mult

icente

r stu

dy, r

etros

pecti

ve ca

se se

ries.

Trea

tmen

ts we

re no

t sta

ndar

dized

trea

tmen

ts.LP

s, re

serv

oir, &

shun

t.

Early

trea

tmen

t was

asso

ciated

w/ a

redu

ced r

equir

e-me

nt fo

r VP

shun

t (OR

= 0.

22) &

redu

ced r

isk of

mo

dera

te-to

-sev

ere d

isabil

ity.

Gask

ill et

al.,

1988

The u

se of

a su

bcut

aneo

us re

serv

oir w

as st

udied

in a

con-

secu

tive,

nonr

ando

mize

d ser

ies of

38 i

nfants

w/ p

reter

m IV

H &

PHH.

In al

l infa

nts LP

& m

edica

l trea

tmen

t had

faile

d.

Clas

s III

Retro

spec

tive s

tudy

of a

serie

s of p

rema

ture i

nfants

wh

o req

uired

temp

orizi

ng m

easu

res (

rese

rvoir

plac

e-me

nt) af

ter m

edica

l trea

tmen

t/LP

for P

HH ha

d fail

ed.

Ther

e wer

e 28 s

urviv

ors o

vera

ll (8 d

ied be

fore

a sh

unt

could

be pl

aced

, 2 di

ed af

ter sh

unt p

lacem

ent).

4 su

rvivo

rs (1

5%) d

id no

t req

uire a

shun

t.

The a

utho

rs co

nclud

ed th

at ea

rly re

serv

oir pl

acem

ent

is a f

easib

le, sa

fe, &

effe

ctive

trea

tmen

t for P

HH

asso

ciated

w/ p

reter

m IV

H.

Harb

augh

et

al., 1

981

Retro

spec

tive r

eview

of 11

prem

ature

infa

nts w

/ IVH

& P

HH

who w

ere t

reate

d w/ tu

nnele

d EVD

. The

mea

n dur

ation

of

drain

age f

or th

is gr

oup w

as 20

.7 da

ys.

No m

orbid

ity or

mor

tality

occu

rred a

s a re

sult.

7 of 1

1 pts

requ

ired a

shun

t. 2 of

11 di

d not

requ

ire a

VP sh

unt.

Clas

s III

Small

retro

spec

tive c

ase r

eview

.EV

D via

a su

bcut

aneo

usly

tunne

led ca

thete

r was

fo

und t

o be a

safe

& re

liable

initia

l meth

od of

trea

t-ing

PHH

in pr

ematu

re in

fants

.

(cont

inued

)



TABL

E 1:

Surg

ical

tem

poriz

ing

mea

sure

s: su

mm

ary o

f evid

ence

* (co

ntin

ued)

Auth

ors &

Yea

rSt

udy D

escr

iption

Data

Clas

s, Qu

ality,

& R

easo

nsRe

sults

& C

onclu

sions

Heep

et al

., 20

01Sa

fety/e

fficac

y of R

ickha

m re

serv

oir pl

acem

ent fo

r pts

w/

PHH.

Clas

s III

Retro

spec

tive r

eview

. Bro

ad in

clusio

n crit

eria

for

rese

rvoir

plac

emen

t.No

comp

ariso

n w/ p

ts ma

nage

d w/ o

ther

meth

ods.

Omma

ya/R

ickha

m re

serv

oir is

a sa

fe, ef

fectiv

e opti

on

for m

anag

ing P

HH un

til pt

is re

ady f

or a

shun

t. 5%

inf

ectio

n rate

, 85%

of pt

s nee

ded a

shun

t.

Hudg

ins et

al.,

1998

Use o

f VAD

in 14

9 pts

w/ P

HH. D

aily t

aps f

or 1s

t “se

vera

l” da

ys (1

0–15

cm3 /k

g).Cl

ass I

IISi

ngle-

institu

tion r

etros

pecti

ve ca

se se

ries.

Shun

ts pla

ced a

t 2 kg

if pt

was s

till sy

mptom

atic,

but

crite

ria no

t oth

erwi

se cl

ear o

n whe

n to s

top V

AD

aspir

ation

s.

8% in

fectio

n & 20

% re

vision

rates

. 88%

shun

t impla

nta-

tion r

ate.

Kaza

n et a

l., 20

05Re

trosp

ectiv

e rev

iew of

prete

rm &

LBW

infa

nts di

agno

sed w

/ IV

H by

ultra

soun

d (n =

42).

11 in

fants

who

requ

ired V

P sh

unts

were

comp

ared

w/ 3

1 who

did

not. A

ll pts

rece

ived a

ceta

zolam

ide &

furo

semi

de as

an

initia

l med

ical tr

eatm

ent.

Clas

s III

Small

, sing

le-ce

nter r

etros

pecti

ve ca

se se

ries w

/ gr

oupin

g of p

ts de

spite

varia

ble tr

eatm

ents.

Risk

facto

rs fo

r VP

shun

t inclu

ded I

VH gr

ade,

later

EG

A at

birth,

& ag

e (da

ys) a

t time

of IV

H, bu

t not

treatm

ent fo

r IVH

/PHH

(ace

tazo

lamide

, fur

osem

ide,

LP, &

exter

nal v

entri

cular

drain

age).

Korm

anik

et al.

, 201

0Re

trosp

ectiv

e rev

iew of

the o

utcom

e of in

fants

rece

iving

a ve

ntricu

lar re

serv

oir fo

r PHH

.Cl

ass I

IIRe

trosp

ectiv

e obs

erva

tiona

l stu

dy: a

revie

w of

medic

al re

cord

s of a

ll infa

nts w

ho re

ceive

d a ve

ntricu

lar

rese

rvoir

in 1

cente

r bet

ween

2000

& 20

07.

35 ve

ntricu

lar re

serv

oirs w

ere p

laced

. 6 pt

s (17

%) w

ere

exclu

ded.

29 pt

s had

a tot

al of

681 t

aps.

Ther

e was

no

incr

ease

d risk

of in

fecti

on fr

om re

peate

d or d

aily

aspir

ation

.On

ly 1 C

SF cu

lture

-pro

ven r

eser

voir i

nfecti

on: C

andid

a alb

icans

.Kr

euss

er et

al.,

1984

Stud

y of 1

9 con

secu

tive i

nfants

w/ P

HH do

cume

nted b

y CT

or cr

anial

ultra

soun

d, &

ICP

meas

urem

ent b

y an i

ndwe

lling

ICP

monit

or.5 o

f 19 p

ts we

re in

itially

trea

ted w

/ LP,

30–4

0 ml C

SF dr

ained

da

ily fo

r 5–7

days

.Su

rvivi

ng pt

s wer

e eva

luated

w/ th

e Bay

ley S

cale

of Inf

ant

Deve

lopme

nt, th

e Car

tell In

fant

Intell

igenc

e Sca

le, or

the

Stan

ford

-Bine

t Intel

ligen

ce Te

st, ba

sed o

n the

child

’s ag

e at

evalu

ation

. Dev

elopm

enta

l quo

tient

(DQ)

was

deter

mine

d us

ing th

e Den

ver D

evelo

pmen

tal S

cree

ning T

est.

Clas

s III

Case

serie

s of a

grou

p of 1

9 con

secu

tive i

nfants

tre

ated w

/ exte

rnal

ventr

icular

drain

age.

Ther

e wa

s no r

ando

miza

tion t

o tre

at or

not tr

eat, &

no

rand

omiza

tion o

f typ

e of tr

eatm

ent. T

here

was

no

case

-con

trolle

d com

para

tive c

ohor

t or g

roup

.

Exter

nal v

entri

cular

drain

age d

ecre

ased

ventr

icular

siz

e.3 i

nfants

did n

ot de

velop

recu

rrent

hydr

ocep

halus

& di

d no

t req

uire a

shun

t. 16 i

nfants

suffe

red r

ecur

rent

hy-

droc

epha

lus, w

/in 1

wk af

ter dr

ain re

mova

l. Ano

ther

EV

D wa

s plac

ed in

10 pt

s.Fo

llowi

ng re

peate

d EVD

s, 9 o

f the 1

0 infa

nts w

ere

stable

enou

gh fo

r a sh

unt. T

he au

thor

s con

clude

th

at EV

D is

a safe

& ef

fectiv

e tre

atmen

t for P

HH.

Limbr

ick et

al.,

2010

Larg

e sing

le-ce

nter r

etros

pecti

ve re

view

of 32

5 pre

term

infan

ts w/

Gra

de II

I or I

V IV

H. T

he de

velop

ment

of PH

H &

the n

eed f

or a

tempo

rizing

devic

e (VA

D or

VSG

shun

t) we

re

studie

d. Inf

ectio

ns, c

ompli

catio

ns, &

need

for V

P sh

unt

were

analy

zed,

as w

as th

e mor

tality

rate.

Clas

s III

Retro

spec

tive a

nalys

is sh

owed

75.4%

of th

e 65 i

nfants

tre

ated w

/ VAD

need

ed a

shun

t; 66.7

% of

the 3

0 tre

ated w

/ VSG

shun

ts re

quire

d a sh

unt.

Ther

e was

no si

gnific

ant d

iffere

nce i

n the

infe

ction

rate

betw

een V

AD &

VSG

shun

ts, re

vision

rate,

or V

P sh

unt in

fectio

n afte

rwar

ds.

Ther

e was

no si

gnific

ant d

iffere

nce i

n outc

ome b

e-tw

een i

nfants

trea

ted w

/ VAD

or V

SG sh

unts. (co

ntinu

ed)



TABL

E 1:

Surg

ical

tem

poriz

ing

mea

sure

s: su

mm

ary o

f evid

ence

* (co

ntin

ued)

Auth

ors &

Yea

rSt

udy D

escr

iption

Data

Clas

s, Qu

ality,

& R

easo

nsRe

sults

& C

onclu

sions

Rahm

an et

al.,

1993

Sing

le-ins

titutio

n, sm

all re

trosp

ectiv

e rev

iew of

37 pt

s w/ P

HH,

31 of

who

m re

quire

d VP

shun

t.Cl

ass I

IIOb

serv

ation

al stu

dy of

outco

mes.

LP, E

VD, V

SG

shun

ts, &

Omm

aya r

eser

voirs

wer

e use

d.No

stati

stica

l dat

a ava

ilable

.

Sugg

ested

LP, V

SG, O

mmay

a res

ervo

ir, &

VP sh

unts

are s

afe &

effec

tive.

Of 26

infa

nts w

/ PHH

trea

ted w

/ EV

D, 20

did r

equir

e shu

nts. 6

did n

ot re

quire

furth

er

treatm

ent.

Rhod

es et

al.,

1987

37 pr

ematu

re in

fants

w/ P

HH w

ere t

reate

d w/ a

n EVD

. Com

pli-

catio

ns, in

cludin

g mor

bidity

, are

pres

ented

.32

pts d

id no

t req

uire a

perm

anen

t shu

nt. N

euro

deve

lopme

n-ta

l & ne

urom

uscu

lar ou

tcome

s are

pres

ented

.

Clas

s III

Retro

spec

tive,

cons

ecut

ive ca

se se

ries.

Leve

l III

Ventr

icular

drain

age i

s a sa

fe &

effec

tive m

echa

nism

for t

reati

ng in

fants

w/ P

HH &

may

obvia

te th

e nee

d fo

r a sh

unt.

Wen

inger

et

al., 1

992

Stud

y of 2

7 con

secu

tive i

nfants

w/ a

n ave

rage

gesta

tiona

l age

of

31 w

ks, w

ho ha

d PHH

& in

crea

sed I

CP &

wer

e tre

ated w

/ a t

unne

led E

VD.

PHH

was d

efine

d as v

entri

cular

dilat

ion, p

rogr

essiv

ely in

cr

eas in

g OFC

, bulg

ing fo

ntan

elle,

wide

ning o

f the s

uture

s, ap

nea,

or br

adyc

ardia

.

Clas

s III

The s

tudy

is a

case

serie

s rep

ort.

PHH

was s

ucce

ssfu

lly tr

eated

in al

l pts;

the E

VD w

as

left in

situ

for a

n ave

rage

of 23

± 9

days

. 4 pt

s died

of

unre

lated

caus

es, &

23 pt

s sur

vived

. 16 r

equir

ed

shun

ts.Ne

urolo

gical

outco

me co

rrelat

ed w

/ sev

erity

of th

e Gr

ade o

f IVH

. Gra

de IV

IVH

infan

ts ha

d the

wor

st ne

urolo

gical

outco

mes,

desp

ite tr

eatm

ent.

The a

utho

rs co

nclud

e tha

t EVD

is a

safe

& ef

fectiv

e tre

atmen

t for P

HH in

prem

ature

infa

nts.

Willi

s et a

l., 20

0932

prem

ature

infa

nts w

/ PHH

wer

e tre

ated w

/ shu

nts or

re

serv

oirs.

Clas

s III

Retro

spec

tive,

cons

ecut

ive ca

se se

ries o

f 32 i

nfants

wh

o nee

ded t

reatm

ent fo

r PHH

. Mult

ivaria

te an

alysis

&

time s

eries

wer

e use

d to i

denti

fy fac

tors t

hat in

flu-

ence

the o

utcom

e in t

erms

of sh

unt r

evisi

ons.

Initia

lly re

serv

oirs w

ere p

laced

in 4

6.8%

of pt

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port of intravenous streptokinase, published in 1998, sug-gested that there may be some benefit.45 This report was followed by an early Class III study that found benefit in a nonrandomized cohort of preterm infants with PHH who were treated with intravenous low-dose streptokinase.76 However, data from a later Class II study led to the con-clusion that routine use of intraventricular streptokinase in PHH was not recommended.79 These studies were in-cluded in the 2007 Whitelaw and Odd Cochrane review,74 which argues against intravenous streptokinase for the treatment of PHH in preterm infants (Table 3).

Despite increased short-term morbidity and recurrent

IVH, some benefits were noted in the DRIFT survivors.72 In the most recent Whitelaw study,72 the reduction in the primary long-term outcome—death or severe disability—at 2 years in the DRIFT group reached statistical signifi-cance when adjusted for sex, birth weight, and grade of IVH. Severe cognitive disability also was reduced, and this improvement in cognitive function was statistically significant. There was also a reduction in severe senso-rimotor disability with DRIFT, but this clinical improve-ment did not reach statistical significance. The authors hypothesized that the greater effect on cognitive rather than sensorimotor function may be attributed to paren-

TABLE 2: Serial lumbar punctures: summary of evidence

Authors & Year Study Description Data Class, Quality, & Reasons Results & Conclusions

Anwar et al., 1986

Randomized controlled study of 47 consecutive preterm infants w/ PHH & Grade III or Grade IV IVH.

Infants enrolled in the study were random-ized to observation only or daily LP. Cohorts were studied for morbidity, mortality, & need for a shunt.

Class IConsecutively enrolled infants randomized to

treatment (daily LP) (n = 24) or observation only (n = 23).

10 of 24 infants treated w/ LP required shunts & 9 of 23 infants in the observation-only group required shunt placement for progres-sive PHH & hydrocephalus.

There were no statistical differences in outcomes studied in infants treated w/ observation alone & infants treated w/ daily LP.

Although LP was safe, there was no statistically significant reduction in the need for shunt or progression of PHH.

Behjati et al., 2011

Case series study that investigated risk factors for VP shunts in infants w/ hydro-cephalus following IVH in 97 consecu-tive preterm infants w/ IVH.

Class IIICase series of 97 infants w/ IVH associated

w/ prematurity. Risks factors associated w/ need for a shunt were investigated. Infants were followed for 1 yr.

Morbidities & mortalities were reported in a quantitative fashion. Pts treated medically w/ acetazolamide showed no benefit; however, infants treated w/ repeated CSF drainage through LP did have a higher shunt infection rate once the shunts were placed.

Infants w/ Grade III or IV IVH are at the highest risk of PHH & hydro-cephalus.

11 of 31 pts who required a shunt developed shunt infection, which was significantly associated w/ repeated LPs.

Chaplin et al., 1980

Retrospective review of 22 consecutive LBW infants w/ PHH.

All pts developed hydrocephalus after 2 wks of age. The first 12 required VP shunts. In 10 infants born after Septem-ber 1974, an attempt was first made to control the hydrocephalus w/ repeated LPs & diuretics prior to placing a shunt.

In 7 of 10 pts hydrocephalus was success-fully arrested by medical therapy alone.

Class IIIRetrospective review of 22 infants w/ PHH.

There were 2 cohorts: 12 pts treated w/ VP shunt, & 10 pts treated w/ LP & diuretics.

Follow-up when pt was 1–8 yrs of age in 18 infants.

2 of 12 pts treated w/ permanent shunts & 3 of 6 pts treated medi-cally had IQ scores ≥85. These results indicate a poor long-term outlook for the LBW infant who de-velops clinically overt hydrocepha-lus after intracranial bleeding.

Kazan et al., 2005

Single-center retrospective review of pre-term & LBW infants w/ IVH diagnosed by ultrasonography (n = 42).

11 infants who required VP shunts were compared w/ 31 who did not. All pts received acetazolamide & furosemide as an initial medical treatment.

Class IIISmall, retrospective case series w/ grouping of

pts despite variable treatments.

Risk factors for VP shunt included IVH grade, later EGA at birth, & age (days) at time of IVH, but not treatment for IVH/PHH (acetazol-amide, furosemide, LP, or external ventricular drainage).

Müller et al., 1998

Effect of aggressive LP schedule on PHH.LPs started at 0–4 days; on average 11

LPs performed per pt, 15 ml/kg or end of CSF flow per LP.

Used protein, red blood cell count, glu-cose, & ventricle size to determine end point.

Class IIISingle-institution nonrandomized prospective

study.16% complete resolution, 65% ventriculomega-

ly but no shunts, 19% w/ shunts.

Serial LP should be started early for treatment of hydrocephalus.



TABLE 3: Intraventricular thrombolytic agents: summary of evidence


Whitelaw et al., 2007

Randomized multicenter clinical trial com-paring standard treatment to DRIFT.

70 infants enrolled (34: DRIFT; 36: stan-dard treatment).

Outcomes: pts at 6 mos of age or at hospital discharge: death or VP shunt surgery, secondary IVH, & infection.

Class IMulticenter randomized controlled trial.

15 of 34 pts (44%) in the DRIFT group died or required a shunt, compared w/ 19 of 36 pts (50%) who received standard treatment.

12 of 34 pts (35%) in DRIFT group had secondary IVH compared w/ 8% of pts who received standard treatment.

Conclusion: DRIFT did not reduce shunt surgery or death but was associated w/ an increased rate of secondary IVH.

Hudgins et al., 1997

Use of urokinase via reservoir to treat PHH in 18 pts. 4 different doses of urokinase; pts ultimately grouped into “high” (n = 9) & “low” dose (everyone else, n = 9).

Both groups compared to historical control group w/ respect to outcome & need for shunt. Prospective, case control.

Class IIProspective nonrandomized case-

control series.Division of 9 pts into “low” dose group

would appear to dilute statistical power, despite statistical significance obtained.

“Low dose” urokinase reduced shunt rate (71% vs 92%) compared to historical controls.

Fewer shunt revisions in both groups compared to control group.

Whitelaw & Odd, 2007

Review & meta-analysis of 2 prospective case-control studies (Luciano et al., 1997 & Yapicioğlu et al., 2003).

Both source studies included total of 12 pts: 6 cases, 6 controls.

Meta-analysis.

Class IIBoth sources’ studies were Class II

(both were small randomized, pro-spective case-control studies).

No difference in mortality or VP shunt rate was observed w/ intraventricular streptokinase.

Intraventricular fibrinolytic therapy cannot be recommended for infants following IVH.

Yapicioğlu et al., 2003

Single-blind prospective study.12 preterm infants who developed PHH

were randomly assigned to the control group (no treatment) or to receive intraventricular streptokinase (×3 days). Note: the streptokinase group also had an LP (10–15 ml) prior to treatment & then daily LPs (5–10 ml). They also received intraventricular vancomycin.

Primary outcome: VP shunt placement.

Class IISmall randomized, prospective study

5 of 6 infants in the streptokinase group & 3 of 6 in the control group required VP shunts.

No complications were noted.Routine use of intraventricular streptoki-

nase in PHH was not recommended.

Richard et al., 2001

Single-institution experience w/ Ommaya reservoir in 64 pts.

17 pts received fibrinolytic therapy through Ommaya reservoir.

Class IIIRetrospective case series.Statistics performed on fibrinolytic

therapy subgroup, which consisted of 2 different agents w/ multiple doses. Fibrinolytic subgroup then mixed back into overall outcome analysis.

Fibrinolytic therapy led to statistically sig-nificant lower rate of shunt placement (31% vs 87%).


Prospective Phase I trial of new treatment methodology (DRIFT) for prevention of PHH of prematurity.

Data from 24 pts compared w/ historical controls. Outcome measures: death, need for shunt, secondary IVH, infec-tion, & neurodevelopmental outcome.

Class IIIProspective Phase I trial in 24 pts &

compared w/ historical controls.

1 pt died. 17 of 23 (74%) did not require a shunt. 2 pts experienced secondary IVH, & 2 experienced infections. 19 pts >12 mos had neurodevelopmental test-ing: 8 (42%) were normal; 7 (37%) had a single disability; 4 (21%) had multiple disabilities.

Conclusion: Compared w/ historical controls, DRIFT reduced the need for shunts & showed a trend toward lower rates of mortality & disability.

(continued)



chymal infarction in the periventricular white matter, which was seen in about half of the infants enrolled in the trial.72

Acetazolamide and Furosemide. RecommendAtion: Acetazolamide and furosemide are not recommended as methods to reduce the need for shunt placement in pre-mature infants with PHH. StRength of RecommendAtion: Level I, high clinical certainty.

After our review of the literature, we found two Class I studies that reported that preterm infants with a diagnosis of PHH who were treated with acetazolamide

and furosemide demonstrated higher risks of neurologi-cal complications, morbidity, and mortality (Table 4).34,37 The International Posthemorrhagic Ventricular Dilation (PHVD) Drug Trial Group reported that administration of acetazolamide plus furosemide leads to higher rates of shunt placement (relative risk 1.42) and morbidity (84% vs 60%) compared with standard therapy.34 Kennedy et al.37 reported that treatment of PHVD with acetazolamide and furosemide did not decrease the rate of shunt place-ment (64% in the acetazolamide/furosemide group vs 52% in the control group, not treated with acetazolamide/ furosemide).37 However, treatment was associated with an

TABLE 3: Intraventricular thrombolytic agents: summary of evidence (continued)



Prospective study of 9 preterm infants w/ progressive posthemorrhagic ventricular dilation who underwent a 48- to 72-hr continuous intraventricular infusion of streptokinase.

Outcomes: death, need for shunt, second-ary IVH, & infection.

Class IIISmall, prospective, nonrandomized

cohort study (Phase I trial).

All pts survived; only 1 of 9 required a shunt prior to discharge (later reports indicated that a total of 4 of 9 ultimately required shunts).

No infections, 1 repeat hemorrhage.


Phase I study to evaluate safety of tPA in 22 preterm infants w/ posthemorrhagic ventricular dilation.

Dosefinding data reported.Outcome measures: death & need for

shunt prior to discharge & secondary IVH.

Class IIISmall, prospective, nonrandomized

cohort study (Phase I trial).

Dosefinding & pharmacokinetic data reported ([tPA], half-life tPA).

21 (95%) of 22 pts survived. 9 (43%) of 21 pts required shunts. 1 pt experienced secondary IVH.

Conclusion: tPA resulted in survival w/o shunt in most pts.

TABLE 4: Acetazolamide/furosemide: summary of evidence*


International PHVD Drug Trial Group, 1998

Use of acetazolamide & furosemide in pts w/ PHH.

Comparison w/ standard therapy for shunt placement & neurological outcome.

Class IRandomized controlled multicenter, well

designed.

Acetazolamide & furosemide led to higher rates of shunt placement (RR 1.42) & higher morbidity (84% vs 60%) com-pared w/ standard therapy

Kennedy et al., 2001

Multicenter randomized controlled trial designed to test the hypothesis that treatment of PHVD w/ acetazolamide & furosemide (vs standard therapy) would reduce: 1) risk of shunt placement or death before 1 yr; & 2) death or dis-ability at 1 yr.

177 pts recruited from 55 centers world-wide.

Class IMulticenter randomized controlled trial.Positive: Excellent subject retention.

Therapeutic CSF removal in 56% of pts (equivalent in both groups).

Negative: Acetazolamide & furosemide administration was stopped in many pts due to adverse effects. Also, furosemide was given in the standard therapy group in some cases.

Treatment of PHVD w/ acetazolamide & furosemide did not decrease the rate of shunt placement (64% in acetazol-amide/furosemide group vs 52% in standard therapy group; RR = 1.23, 95% CI = 0.95–1.59) & was associated w/ increased neurological morbidity (81% vs 66%).

Authors concluded: “Treatment of PHVD w/ acetazolamide & furosemide cannot be recommended.”

Kazan et al., 2005

Single-center retrospective review of preterm & LBW infants diagnosed w/ IVH by ultrasonography (n = 42).

11 infants who required VP shunts were compared w/ 31 infants who did not. All pts received acetazolamide & furose-mide as an initial medical treatment.

Class IIISmall retrospective case series w/ group-

ing of pts despite variable treatments.

Risk factors for VP shunt included IVH grade, later EGA at birth, & age (days) at time of IVH, but not treatment for IVH/PHH (acetazolamide, furosemide, LP, or external ventricular drainage).

* RR = relative risk.



increased rate of neurological morbidity (81% vs 66%).37 Treatment of PHVD with acetazolamide and furosemide was not recommended.37 One Class III study reported this treatment was not associated with VP shunt place-ment, but the severity of IVH (based on IVH grade) and the patient age at the time of IVH were significantly asso-ciated with the need for permanent CSF diversion.36 Ken-nedy et al. also noted that the ventricular index at time of entry into trial was the only factor significantly predictive of death or need for shunt, after multiple logistic regres-sion analysis.37

Timing of Shunt Placement StRength of RecommendAtion: There is insufficient

evidence to recommend a specific infant weight or CSF parameter to direct the timing of shunt placement in pre-mature infants with PHH. StRength of RecommendAtion: Level III, unclear degree of clinical certainty.

There were two Class III studies which evaluated the lower limits of infant weight at time of initial shunt inser-tion (Table 5).4,8 A weight of 1500 g was safely used as a criterion for VP shunt placement in the Benzel study.8 A single Class III study showed that CSF cell count, protein, and glucose levels were not statistically related to the oc-currence of shunt failure or infection in the study popula-tion.24 The authors recommended that placement of the shunt be timed when the infant’s age, weight, and overall stability allow.24

Endoscopic Third Ventriculostomy RecommendAtion: There is insufficient evidence to

recommend the use of endoscopic third ventriculostomy (ETV) in premature infants with PHH. StRength of Rec-ommendAtion: Level III, unclear degree of clinical cer-tainty.

Although ETV was discussed in several full-text ar-

TABLE 5: Timing of shunt placement—specific weight or CSF parameter: summary of evidence


Anwar et al., 1986

Consecutive, nonrandomized study of 19 preterm infants w/ PHH who underwent placement of reservoirs for symptom-atic hydrocephalus.

Symptomatic hydrocephalus was defined as presence of rapidly increasing OFC, ventriculomegaly, & signs of increased ICP, such as tense fontanelle, splayed sutures, apnea, bradycardia, seizure, feeding difficulties, or lethargy.

Class IIICase series study of infants who

weighed <2000 g & were treated w/ reservoirs. Data include morbidity, mortality, & need for shunt place-ment in these infants.

There was no comparison w/ a cohort of nontreated infants or infants treated w/ ventricular drains.

Authors concluded that reservoirs provide safe & effective treatment for infants w/ PHH & symptomatic hydrocephalus.

Benzel et al., 1992

41 pts requiring ventricular drainage for hydrocephalus/PHH were evaluated retrospectively. All drainage proce-dures were performed in pts w/ IVH & hydrocephalus (Grade III [25 pts]) & in pts w/ IVH & IPH (Grade IV [16 pts]) in whom medical management failed.

26 ventricular reservoirs were placed in neonates weighing <1500 g; 18 of these reservoirs were subsequently converted to VP shunts.

Class IIIRetrospective case series of 41 con-

secutive premature infants.

Authors endorse reservoirs as an alternative to early shunts & report that this strategy may “reduce the incidence of shunt infection as well as noninfectious shunt complications.”

There was a VP shunt &/or reservoir infection in 32% of pts.

59% of pts required a shunt revision during the 1st yr of life.

No Grade IV pts achieved normal functional level, while 10 Grade III pts did. The inci-dence of severe developmental delay (44% vs 28%) & death (38% vs 12%) was greater in the Grade IV than in Grade III pts.

Fulkerson et al., 2011

Premature infants w/ PHH have a high risk of shunt obstruction & infection. Risk factors for complications include grade of IVH & age at shunt insertion.

There is anecdotal evidence that the amount of red blood cells or protein levels in the CSF may also increase shunt complications.

This study examined whether any rela-tionship exists between CSF constitu-ents & shunt malfunction or infection.

Class IIIRetrospective cohort study evaluating

the risk factors for shunt failure in preterm infants w/ IVH & PHH.

Inclusion criteria & preintervention data points (baselines) were well documented. Outcomes reported included early shunt failure or infec-tion w/in 3 mos of shunt.

“Each CSF parameter was modeled as a possible predictor of the presence or absence of shunt malfunction or infection. Statistical significance was set at a probability level < 0.05.”

Authors concluded that neither CSF cell count nor protein or glucose levels were statisti-cally related to the occurrence of shunt failure or infection in the study population. The authors recommend that placement of the shunt be timed when age, weight, & the overall stability of the infant allow.



ticles that we reviewed, there was insufficient evidence available for us to make a recommendation for or against its use for the treatment of PHH in premature infants (Table 6). Endoscopic third ventriculostomy for the treat-ment of hydrocephalus in infants and children will be discussed more thoroughly in subsequent chapters (in particular, Part 4).42

Excluded StudiesWe excluded 1 Class III study for low “preterm” pa-

tient representation (7 patients); in the review of 52 con-secutive ETV procedures in 49 infants with hydrocepha-lus, most infants (31 patients) had aqueductal stenosis.20 Of the 7 infants with preterm PHH, 6 required a shunt even after ETV. Infants with PHH from premature birth did not benefit from ETV.20 We excluded another Class III study including patients with different etiologies for hydrocephalus.44 Although ETV was successful in 57% of patients (8 of 14), the majority of those infants had

congenital aqueductal stenosis without PHH. In the re-maining 6 patients, a VP shunt was needed. In 1 Class III single-institution retrospective case series, 18 preterm in-fants with PHH were treated initially with Ommaya res-ervoir placement: 1 patient died, 5 patients received a VP shunt, and 9 patients underwent ETV.56 Three patients did not require any further intervention. While overall, 59% were shunt free at the last follow-up, 5 of the 9 patients who were treated with ETV had to undergo repeated sur-gery for VP shunt placement. The authors recommended combining placement of an Ommaya reservoir with ETV to reduce shunt dependency for preterm infants with PHH.56 There was a large (101 patients) Class III multi-center, retrospective study evaluating the success rate of ETV in patients with hydrocephalus from subarachnoid hemorrhage, IVH, and/or CSF infection; a minority of the patients (25% [25 of 101]) had PHH of prematurity.65 Overall, ETV was successful in 52% of the infants with PHH of prematurity. Endoscopic third ventriculostomy was successful in 100% (13 of 13) of children with a his-

TABLE 6: Endoscopic third ventriculostomy for PHH in premature infants: summary of evidence*


Elgamal et al., 2011

Review of 52 consecutive ETV procedures in 49 infants w/ hydrocephalus not nec-essarily associated w/ preterm IVH.

Most infants (n = 31) had aqueductal stenosis. The remaining infants w/ hydrocephalus had other causes for it including Chiari II, Dandy-Walker cysts, quadrigeminal lipoma, & cerebellopon-tine angle arachnoid cyst. Only 6 pts had PHH caused by preterm IVH.

Class IIICase series of infants treated w/ an ETV.

Infants were followed up for 68 mos on average.

6 of the 7 infants w/ PHH from premature birth required a shunt.

Authors concluded that the success rate of 69.4% indicates that ETV is safe & effective in infants w/ hydrocephalus not associated w/ PHH & prematurity.

Infants w/ PHH from premature birth did not benefit from ETV.

Lipina et al., 2008

Retrospective consecutive case series of 14 infants <6 mo of age presenting w/ obstructive hydrocephalus.

8 of 14 pts had PHH.ETV was considered successful when a

VP shunt was not necessary.

Class IIIThis study included a small number of

pts w/ very different etiologies for hydrocephalus.

ETV was successful in 57% of pts—the majority of them w/ primary aqueductal stenosis. In the remaining 6 pts, a VP shunt was needed.

Peretta et al., 2007

Single-institution retrospective review of 18 consecutive preterm infants w/ PHH.

Pts were treated w/ placement of an Om-maya reservoir for temporizing ventricu-lar decompression. When necessary, pts later underwent VP shunt placement (n = 5) or ETV (n = 9).

Class IIISmall single-institution retrospective case

series w/ variable treatment patterns. 3 of the surviving 17 infants (17.6%) treated w/ Ommayas did not require additional surgery. 14 of 17 required VP shunt (n = 5) or ETV (n = 9).

While additional surgeries were required in the majority of cases, 59% of pts were shunt free at the last follow-up.

Recommended combining Ommaya placement w/ ETV. It reduces shunt dependency in this condition.

Siomin et al., 2002

Multicenter retrospective case series of 101 pts who underwent ETV for hemor-rhage or infection. Both pediatric & adult pts included.

Of the 101 pts, 25 were treated for PHH of prematurity, & specific data were reported for this cohort.

Successful ETV was defined as no further hydrocephalus operations required.

Class IIIMulticenter study w/ a minority of pts

(25%) w/ PHH of prematurity.

ETV was successful in 52% of pts w/ PHH of prematurity.

Note: ETV was successful in 13 of 13 of pts w/ PHH who were previously treated w/ a shunt, whereas it was unsuccessful in 12 of 12 pts treated w/ ETV as the firstline treatment.

ETV was not successful in pts w/ both hemorrhage & infection.



tory of preterm PHH, even though these patients were initially treated with a shunt. Endoscopic third ventricu-lostomy was unsuccessful in 12 of 12 infants treated with ETV as the first-line treatment, following preterm PHH. In patients with both hemorrhage and infection, ETV was not successful.65

ConclusionsSurgical Temporizing Measures

RecommendAtion: Ventricular access devices (VADs), external ventricular drains (EVDs), ventriculosubgaleal (VSG) shunts, or lumbar punctures (LPs) are treatment options in the management of posthemorrhagic hydro-cephalus (PHH). Clinical judgment is required. StRength of RecommendAtion: Level II, moderate degree of clini-cal certainty.

RecommendAtion: The evidence demonstrates that VSG shunts reduce the need for daily CSF aspiration com-pared with VADs. StRength of RecommendAtion: Level II, moderate degree of clinical certainty.

The evidence demonstrates that VADs reduce mor-bidity and mortality compared with EVDs.

Routine Use of Serial Lumbar PuncturesRecommendAtion: The routine use of serial lumbar

puncture (LP) is not recommended to reduce the need for shunt placement or to avoid the progression of hydroceph-alus in premature infants. StRength of RecommendAtion: Level I, high clinical certainty.

Nonsurgical Temporizing MeasuresRecommendAtion: Intraventricular thrombolytic agents

including tissue plasminogen activator (tPA), urokinase, or streptokinase are not recommended as methods to re-duce the need for shunt placement in premature infants with PHH. StRength of RecommendAtion: Level I, high clinical certainty.

RecommendAtion: Acetazolamide and furosemide are not recommended as methods to reduce the need for shunt placement in premature infants with PHH. StRength of RecommendAtion: Level I, high clinical certainty.

Timing of Shunt PlacementRecommendAtion: There is insufficient evidence to

recommend a specific weight or CSF parameter to direct the timing of shunt placement in premature infants with PHH. Clinical judgment is required. StRength of Recom-mendAtion: Level III, unclear clinical certainty.

Endoscopic Third Ventriculostomy RecommendAtion: There is insufficient evidence to

recommend the use of endoscopic third ventriculostomy (ETV) in premature infants with PHH. StRength of Rec-ommendAtion: Level III, unclear clinical certainty.

Acknowledgments

We acknowledge the American Association of Neurologi-cal Surgeons (AANS)/Congress of Neurological Surgeons (CNS)

Joint Guidelines Committee for the members’ reviews, comments, and suggestions; the Hydrocephalus Association and Debby Buffa, patient advocate representative, for participation and input through-out the guidelines development; Pamela Shaw, research librarian, for her assistance with the literature searches; Kevin Boyer for his assistance with data analysis; and Sue Ann Kawecki for her assis-tance with editing.

We acknowledge the following individuals for their contribu-tions throughout the review process: Timothy Ryken, M.D.; Kevin Cockroft, M.D.; Sepideh Amin-Hanjani, M.D.; Steven N. Kalkanis, M.D.; David P. Adelson, M.D.; Brian L. Hoh, M.D.; Mark D. Krieg-er, M.D.; Mark E. Linskey, M.D.; Jeffrey J. Olson, M.D.; Patricia Raskin, M.D.; Krystal L. Tomei, M.D.; and Monica Wehby, M.D.

Disclosure

Dr. Limbrick receives research funding from the National Institute of Neurological Disorders and Stroke. The systematic review and evidence-based guidelines were funded exclusively by the CNS and AANS Pediatric Section, which received no funding from outside commercial sources to support the development of this document.

Conflict(s) of Interest: None. All Pediatric Hydrocephalus Systematic Review and Evidence-Based Guidelines Task Force members declared any potential conflicts of interest prior to begin-ning work on this systematic review and evidence-based guidelines.

Author contributions to the study and manuscript preparation include the following. Conception and design: AANS/CNS Joint Section on Pediatrics. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Mazzola. Crit-ically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Flannery. Administrative/technical/material support: all authors. Study supervision: Flannery.

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Manuscript submitted June 25, 2014.Accepted July 7, 2014.Please include this information when citing this paper: DOI:

10.3171/2014.7.PEDS14322.Address correspondence to: Ann Marie Flannery, M.D., Depart-

ment of Neurological Surgery, Saint Louis University, 3565 Vista Ave., St. Louis, MO 63110. email: [email protected].

pediatric hydrocephalus: systematic literature review and ......a history of intraventricular...

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