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com
ADC-FNN Online First, published on February 10, 2018 as 10.1136/archdischild-2017-314206
Original article

Treatment thresholds for intervention in

posthaemorrhagic ventricular dilation: a randomised
controlled trial
Linda S de Vries,1 Floris Groenendaal,1 Kian D Liem,2 Axel Heep,3
Annemieke J Brouwer,1,4 Ellen van ’t Verlaat,4,5 Isabel Benavente-Fernández,6
Henrica LM van Straaten,7 Gerda van Wezel-Meijler,7,8 Bert J Smit,9 Paul Govaert,5
Peter A Woerdeman,10 Andrew Whitelaw,3 the ELVIS study group

►► Additional material is Abstract

published online only. To view, Objective  To compare a low versus a higher What is already known on this topic?
please visit the journal online
(http://d​ x.​doi.o​ rg/​10.​1136/​ threshold for intervention in preterm infants with
►► Posthaemorrhagic ventricular dilatation (PHVD)
archdischild-​2017-​314206). posthaemorrhagic ventricular dilatation.
most likely to occur in infants with a grade III or
Design  Multicentre randomised controlled trial
For numbered affiliations see IV haemorrhage.
(ISRCTN43171322).
end of article. ►► A ventriculoperitoneal (VP) shunt rate has been
Setting  14 neonatal intensive care units in six
reported to be 35%–60% in infants who need
countries.
Correspondence to intervention for PHVD.
Dr Linda S de Vries, Department Patients  126 preterm infants ≤34 weeks gestation
of Neonatology and Brain with ventricular dilatation after grade III–IV haemorrhage
Center Rudolf Magnus, were randomised to low threshold (LT) (ventricular
Wilhelmina Children’s Hospital, index (VI) >p97 and anterior horn width (AHW) >6 mm) What this study adds?
University Medical Center
or higher threshold (HT) (VI>p97+4 mm and AHW
Utrecht, 3508 AB Utrecht,
The Netherlands; ​l.​s.d​ evries@​ >10 mm). ►► Intervention using lumbar punctures and/or
umcutrecht.​nl Intervention  Cerebrospinal fluid tapping by lumbar taps from a ventricular reservoir just after the
punctures (LPs) (max 3), followed by taps from a ventricular index crossed the p97+4 mm line
Received 2 October 2017 ventricular reservoir, to reduce VI, and eventually a results in the lowest VP shunt rate reported
Revised 13 January 2018
Accepted 15 January 2018 ventriculoperitoneal (VP) shunt if stabilisation of the VI so far and was associated with fewer invasive
below the p97+4 mm did not occur. procedures than earlier intervention.
Composite main outcome measure  VP shunt or ►► Risk of infection following taps from a
death. ventricular reservoir in this multicentre study
Results  19 of 64 (30%) LT infants and 23 of 62 (37%) was not increased compared with our single-
HT infants were shunted or died (P=0.45). A VP shunt centre study.
was inserted in 12/64 (19%) in the LT and 14/62 (23%)
infants in the HT group. 7/12 (58%) LT infants and 1/14
(7%) HT infants required shunt revision (P<0.01). 62 ventricular dilatation (PHVD), are at increased
of 64 (97%) LT infants and 36 of 62 (58%) HT infants risk of developing neurological sequelae. PHVD
had LPs (P<0.001). Reservoirs were inserted in 40 of occurs in about 30%–50% of infants with a severe
64 (62%) LT infants and 27 of 62 (43%) HT infants GMH-IVH and there is an ongoing discussion
(P<0.05). about the best time to intervene.2–4 Due to the high
Conclusions  There was no significant difference in water content of the immature white matter and
the primary composite outcome of VP shunt placement the large extracerebral space in extremely preterm
or death in infants with posthaemorrhagic ventricular infants,  symptoms and signs of raised intracranial
dilatation who were treated at a lower versus a higher pressure develop several weeks following the onset
threshold for intervention. Infants treated at the lower of PHVD. This allows a considerable increase in
threshold received more invasive procedures. Assessment ventricular size without affecting fontanelle pres-
of neurodevelopmental outcomes will provide further sure or head circumference.5
important information in assessing the risks and benefits In infants with progressive PHVD, deteriora-
of the two treatment approaches. tion of electroencephalography  (EEG) background
activity, increased latency of evoked potentials,
increasing Doppler Resistance Index and decreasing
cerebral oxygenation have been reported,6–11 all
Introduction showing improvement within a week following
To cite: de Vries LS, Although the incidence of germinal matrix-intra- neurosurgical intervention.
Groenendaal F, Liem KD, et al.
ventricular haemorrhage (GMH-IVH) in very low Cranial ultrasound (cUS) is used to follow the
Arch Dis Child Fetal Neonatal
Ed Epub ahead of print: birthweight infants decreased in the 90s, there progress of PHVD and the ‘ventricular index’ (VI)
[please include Day Month has been no further decrease over the last decade. is most often used.12 Most intervention studies have
Year]. doi:10.1136/ Infants with grade III and IV haemorrhage,1 taken the 97th centile (p97)+4 mm as a starting
archdischild-2017-314206 especially those who develop posthaemorrhagic point for randomisation.13–15 Other useful measures
de Vries LS, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F6. doi:10.1136/archdischild-2017-314206    F1
Copyright Article author (or their employer) 2018. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence.
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Original article
are the anterior horn width (AHW) and thalamo-occipital and/or the TOD was >25 mm (figure 1). Intervention started
distance (TOD).16 17 with LPs (max 3), and if necessary, followed by insertion and
In previous retrospective studies, very early intervention, taps from a VR, aiming for VI<p97 over the next 7–10 days. Ten
prior to development of clinical symptoms and prior to severe mL/kg were removed once or twice a day, the volume adjusted
dilatation of the lateral ventricles, was associated with a reduced according to cUS. When taps from a VR were still needed 28
need for a ventriculoperitoneal (VP) shunt and better neurode- days after insertion to keep the VI well below the p97+4 mm,
velopmental outcome.2 3 18 one or two ‘challenges’ were performed with discontinuation of
Our aim was to test the hypothesis that very early interven- taps. Reservoir taps were resumed in case of expanding ventri-
tion, before crossing the p97+4 mm line, reduces death and/or cles, clinical symptoms and/or excessive head growth. Taps
the need for VP shunt when compared with later intervention. were continued until infant's weight reached 2000–2500 g and
according to unit protocol, the protein had decreased to <1.5 g/L
Patients and methods and erythrocytes <100/mm3, at which stage the infant became
Study infants eligible for a VP shunt.
Enrolled infants were born between July 2006 and July 2016
and admitted to eight neonatal intensive care units in the Neth- High threshold 
erlands, five centres in Europe and one in the USA. Inclusion Treatment was started once the VI had crossed the p97+4 mm
criteria: (1) preterm infants (gestational  age   (GA)≤34 weeks) line and the AHW was >10 mm. Further treatment was compa-
with a grade III or IV haemorrhage diagnosed with cUS; (2) <28 rable to the early treatment arm (figure 2).
days after birth; (3) progressive dilatation of both lateral ventri-
cles with ventricular width >p97 and AHW >6 mm. Exclusion Shunt surgery
criteria: (1) chromosomal disorders; (2) congenital malforma- Adequate weight, cerebrospinal fluid (CSF) protein and eryth-
tions; (3) cystic periventricular leukomalacia; (4) infection of the rocytes being achieved, reservoir punctures were discontinued
central nervous system prior to randomisation. and VI/AHW, head circumference measurements and clinical
symptoms reviewed daily. If the local team observed continued
Cranial ultrasound ventricular expansion and accelerated head enlargement, a
Serial cUS was performed at least twice a week following the VP shunt was indicated, with symptoms increasing the urgency.
diagnosis of a grade III/IV haemorrhage to diagnose PHVD and An external review was performed later for infants who under-
follow progression. Ventricular measurements, VI/AHW and went shunt surgery. PG and LSdV reviewed the VI and AHW
TOD were performed on all ultrasound scans and plotted on graphs, the head circumference graphs and the cUS images for
the Levene and Davies graphs.12 16 Measurements were recorded infants shunted but not born in their own centres to confirm
following informed consent, at randomisation, before each that shunt criteria were met. They were blind to the treatment
lumber puncture (LP), 1, 2 and 3 weeks after the first LP, before allocation. These external reviews agreed with the local shunt
ventricular reservoir (VR) insertion and weekly till stabilisation, decision in all cases.
discharge or VP shunt placement.
Outcomes
Treatment Primary outcome was a composite of VP shunt placement and/
Low threshold  or death. Diagnosis of VR dysfunction, infection and revi-
Treatment was started after the VI had crossed p97 but before sion or need for a second reservoir were recorded as well
crossing the p97+4 mm line, the AHW was >6 mm but <10 mm as VP shunt dysfunction, infection and need for revision.

Figure 1  Example of early intervention, gestational age 26 weeks/birth weight 925 g; three lumbar punctures (LPs) were performed when the
ventricular index had crossed the p97 (2SD) and was heading towards the p97+4 mm line. No further intervention was required. The first MRI (A,
coronal T2-weighted sequence) was performed after the three LPs at 30 weeks postmenstrual age and the second MRI (B) at term equivalent age,
showing remnants of the intraventricular haemorrhage and nearly normal size and shape of the lateral ventricles. VP, ventriculoperitoneal.
F2 de Vries LS, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F6. doi:10.1136/archdischild-2017-314206
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Original article

Figure 2  Example of later intervention, gestational age 33+6 weeks/birth weight 1790 g; three lumbar punctures (LPs) were performed once the
ventricular index had crossed the p97+4 mm line and a ventricular reservoir was subsequently inserted. The ventricular index came down to below
the p97 line with daily taps from the -ventricular reservoir, which could be stopped after 19 days. No further intervention was required. The coronal
ultrasound (A) performed before the first LP shows intraventricular clots and ballooning shape of the lateral ventricles. The coronal MRI (T1-weighted
image) at term equivalent age (B) shows mild ventricular dilatation. VP,  ventriculoperitoneal.

Neurodevelopmental outcome at 2 years corrected age will be decrease in the adverse outcome with 45%–22% with a power
reported separately. of 80%.
Written informed consent was obtained from both parents of
Randomisation and statistical analysis each infant.
Computer-generated randomisation was used online to allocate
infants to treatment groups in a 1:1 ratio. Randomisation was
stratified by centre and in blocks of 5. Analysis was by intention Results
to treat. Recruitment started in the Netherlands in July 2006 and ended
Based on previous trials, inclusion criteria predicted that 60% in July 2016. Due to slow enrolment, additional centres were
of the infants would die or need a VP shunt. Our initial power invited to participate, Bristol 2007, St Louis 2009, Lund 2010,
calculation (using a 5% level of significance) indicated that 50 Cadiz, Barcelona and Lisbon 2013. A total of 126 infants were
infants in each group would give 87% power of detecting a recruited. Most infants were recruited in Bristol (29), Utrecht
reduction from 60% in primary outcome to 30%. During the (23), Nijmegen (23), Zwolle (12), Cadiz (12), while between 2
trial, the incidence of an adverse outcome was found to be much and 6 infants were enrolled in the other nine centres.
lower (around 45%) than the expected adverse outcome of The two treatment groups were comparable for sex, gesta-
60%. Therefore, a new power calculation was done, indicating tional age and birth weight as well as having a grade III or IV
a sample size of 63 patients per study arm, to demonstrate a haemorrhage and day of randomisation (table 1).

Table 1  Clinical and intervention characteristics and primary outcomes

Early intervention n=64 Later intervention n=62 P value
Patient characteristics
 GA (weeks), median (SD) 27.4 (3.3) 27.4 (3.2) NS
 BW (g), median (SD) 1110 (494) 1160 (548) NS
 Male 36 37 NS
 PVHI 24 (37.5%) 19 (30.6%) NS
 Death 7 (11%) 9 (14%) NS
Intervention details
 Day of randomisation (median, range) 9 (2–22) 9 (3–21) NS
 Day of first intervention (LP) following randomisation (median, range) 1 (1–11) 6 (2–19) <0.001
 LPs 62 (97%) 36 (58%) <0.001
 VR 40 (62%) 27 (43%) <0.05
 Day of VR placement following randomisation (median, range) 6 (2–15) 10 (5–28) <0.001
 VP shunt 12 (19%) 14 (23%) NS
 CSF protein before VP shunt (g/L, median—IQR) 1.5 (1.4) (available in 8 infants) 1.0 (1.1)(available in 11 infants) NS
 CSF erythrocytes before VP shunt (median, IQR) 3 (32) (available in 8 infants) 10 (33) (available in 11 infants) NS
BW, birth weight; CSF, cerebrospinal fluid; GA, gestational age; LP, lumbar puncture; NS, not significant; PVHI, periventricular haemorrhagic infarction; VP, ventriculoperitoneal; VR,
ventricular reservoir.

de Vries LS, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F6. doi:10.1136/archdischild-2017-314206 F3
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Original article
aureus and Klebsiella pneumoniae occurred in two other infants,
both were treated with antibiotics without removal of the VR.
Nine infants died (14%), four without any intervention (two
sepsis, one NEC, one acute respiratory failure), three following
LPs (one sepsis, one BPD, one meningitis following discharge
home) and two following insertion of a VR (one candida sepsis,
one NEC). Fourteen infants required a VP shunt (23%), seven
following a grade III and seven following a grade IV haemor-
rhage. One infant needed a revision following an infection, one
had a disconnection but the VP shunt was not revised and in one
infant a second fenestration was performed.

Comparison of primary outcome between early and later

intervention
Outcomes at discharge are shown in table 1 and figure 3. Of 64
infants assigned to the LT group, 7 (11%) died and 12 (19%)
underwent VP shunt surgery (death or shunt 30%). Of 62 infants
assigned to HT group, 9 died (14%) and 14 (23%) required VP
Figure 3  Flow chart of patient allocation and subsequent treatment shunt placement (dead or VP shunt 37%). This difference was
of posthaemorrhagic ventricular dilatation. AHW, anterior horn width; not significant (P=0.45). Revision of the VP shunt was required
LP, lumbar puncture; VI, ventricular index; VP, ventriculoperitoneal. in 7/12 (58%) of the LT group vs 2/14 (14%) in the HT group
(P<0.01). This could not be explained by a difference in protein
levels or erythrocytes in the CSF prior to VP shunt placement.
Low threshold group
Randomisation was performed on median day 9 in both
All but two infants (97%) had their first LP on the day of rando-
study arms, followed by significantly more LPs in the LT group
misation. Two infants had no LPs, one was too unstable and
(P<0.001). The first intervention after randomisation was
the other due to violation of the protocol. Median number of
performed median day 1.0 in the LT compared with median day
LPs was 3 (range 0–6), and the number exceeded 3 in 12 (19%)
6 in the HT group (P<0.001). Subsequent insertion of a VR was
infants, due to unavailability of the neurosurgeon or a theatre
also more often performed in the LT group (62% early group;
slot. A VR was inserted in 40 infants (62%), median of 6 days
43% HT group; P<0.05). Insertion was performed at median
after the first LP. Reservoir dysfunction occurred in five infants
day 6 following randomisation in the LT group, compared with
(8%), due to dehiscence in one, obstruction in three, and malpo-
day 10 in the HT group (P<0.001). VR dysfunction occurred
sition in one, requiring a second VR in four. In the other infant,
in 5/40 (12.5%) of the LT group vs 6/27 (22%) in the HT
0.5 mg/kg of recombinant tissue plasminogen (rTPA) (Actilyse,
group. Median maximum VI measurements (mm over p97) were
Boehringer IngelheimInt, Ingelheim, Germany) was injected
2.7 mm in the LT group compared with 4.0 mm in the HT group
into the reservoir, which resolved the dysfunction. An infec-
(P<0.001). Median maximum measurements of the AHW (mm
tion occurred twice, once with Enterococcus faecalis, requiring
over 6 mm) were 3.0 mm in the LT and 5.0 mm in the HT group
removal of the VR and in the other infant Staphylococcus capitis
(P<0.001) (figure 4).
was cultured with CSF sterilisation with intraventricular antibi-
otics. However, subsequently multiloculated pocket formation
occurred, requiring endoscopic fenestration twice and subse- Violation of the protocol
quent VP shunt. Seven infants died (11%), two without any In the LT group, the first LP was performed too early in two
intervention (one due to Escherichia coli sepsis on the day of infants, when the VI was still on p97 but without upward progres-
randomisation and the other 3 days after randomisation due to sion. In another two infants, the VI was never reduced <p97 and
acute respiratory failure), two following LPs (one sepsis, one several measurements were over p97+4 mm (see online supple-
necrotising enterocolitis (NEC)) and three following insertion mentary figure).
of a VR (one bronchopulmonary dysplasia, two NEC). Twelve In the HT group, the first LP was performed before the
required a VP shunt (19%), including one following unsuccessful VI had crossed the p97+4 mm line in three infants. No LP
fenestration of the third ventricle twice. Seven had a grade III was performed >p97+4 mm in two infants as they were too
and five had a grade IV haemorrhage. Shunt revision (<1 month unstable and both subsequently died. Randomisation too early
after insertion) was needed in seven infants (58%) because of an occurred, when the VI was on, but had not yet crossed, the
infection in one (Streptococcus viridans) and dysfunction in the p97 line and without progression of the PHVD. In two infants,
other six. the VI was never reduced <p97  and several measurements
remained  >p97+4 mm.
Higher threshold group
Thirty-six of the 62 (58%) infants had LPs, performed at a Ventricular reservoirs
median of 5 days after randomisation. Median number of LPs No neurosurgeon was available on site in two Dutch centres
was three (range 0–4), and the number was more than three in and in one of the two hospitals in Bristol. Infants were referred
eight infants (22%), due to unavailability of the neurosurgeon or following randomisation, and when the need for neurosurgery
a theatre slot. VR was inserted in 27 infants (43%), median of was expected. Reservoir placement was performed in the oper-
10 days after the first LP. VR dysfunction occurred in six infants ating theatre in 10/14 centres. Taps from the reservoir were
(9%), due to obstruction in three, malposition in one and lack of performed by the neonatal staff in 12 and by neurosurgical
communication between the two ventricles requiring placement staff in the other 2 centres. There were more reservoir-related
of a second reservoir in two. An infection with Staphylococcus. complications in infants treated during the first half than in the
F4 de Vries LS, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F6. doi:10.1136/archdischild-2017-314206
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Original article

Figure 4  Median maximum ventricular measurements, including ventricular index in mm above the +2 SD line on the Y-axis on the left (panel A)
and anterior horn width (AHW) in mm above the 6 mm line on the Y-axis on the right (panel B), for the infants in the low (LT) and the high threshold
(HT) group depicted on the X-axis. Median maximum ventricular index measurements (mm >2SD) were 2.8 mm in the early group compared with
4.2 mm in the later intervention group (P<0.001). Median maximum measurements of the anterior horn width (mm >6 mm) were 3.0 mm in the early
and 5.0 mm in the later intervention group (P<0.001).

second half of the study period (10/19 and 5/33, respectively observational cohort study, as many as 92% of preterm infants
(P=0.01)). There was no significant difference in GA or birth required a shunt when treatment was started following onset
weight for infants with and without complications. of clinical symptoms.20
Enrolment in the present study was much slower than
Discussion expected, as fewer infants developed a severe GMH-IVH.
We were unable to show a further reduction in the need for Compliance with trial management was generally good, but
a VP shunt in the LT group, but the need for VP shunt place- interpretation of the protocol was inappropriate in about 10%
ment in both study groups is, to the best of our knowledge, of the cases but following intention to treat, these infants were
the lowest reported so far. In the HT group, the number of included in the analysis.
infants who had LPs and VRs was significantly lower than in The rate of infection for the different intervention methods
the LT group. Whether this increase in additional interven- was low. CNS infection did not occur following LPs and in
tions in the LT group will be associated with improved pres- only 6% of the infants following VR insertion, similar to a
ervation of brain volumes and improved neurodevelopmental previous single-centre study.21 A second VR was required in
outcome still needs to be determined. Intervention can be about 15% of the infants, mostly due to dysfunction. Both
considered early in both groups, when compared with timing types of complications may further increase the risk of an
of intervention in previous studies. In the first randomised adverse outcome. Infection is known to have an adverse
controlled trial (RCT) performed, the VentriculoMegaly effect on outcome, even when there is no evidence that the
trial, there was no upper limit on VI at entry and only LPs or CNS is involved.22 Complications were less common during
ventricular taps were performed. These methods were only the second half of the study period, suggestive of a learning
used to prevent further dilatation, but not to bring the VI curve. Recently, more attention has been given to the risk
down to within the normal range.13 There was no significant of anaesthesia in young children and this may be especially
difference between the number of infants VP shunted between important in extremely preterm infants.23 24 The proportion
the two groups (53% and 54%). The next RCT, using acet- of VR and VP shunts with dysfunction needing revision was
azolamide and furosemide, also had no upper limit on VI at higher in the LT group than the HT group. Even though, in
entry. Seven per cent had a VR inserted in the arm receiving most centres, insertion of a VP shunt was only performed
drugs and 14% in the standard arm.14 The number of infants when the infant had reached a weight of 2–2.5 kg and the
VP shunted was significantly higher in the treatment group protein and red cell count were low, the need for revision was
(51%) compared with the standard treatment group (38%) high (25%), which was due to disconnection or dysfunction
and the composite outcome (death and/or shunt) was signifi- in most cases. Each need for revision, involved a period of
cantly worse in the treatment arm as well. The DRIFT increased intracranial pressure and the need for anaesthesia.
(drainage, irrigation and fibrinolytic therapy) trial also had Every revision is associated with a small reduction in IQ
no upper limit on VI at entry. Thirty-eight per cent in the points.25
DRIFT arm had VR insertion and 75% in the standard group. In the DRIFT trial, there was no significant reduction in the
Once again, there was no significant difference between the need for a VP shunt, but a subsequent improvement in neuro-
number of infants VP shunted between the two groups (38% developmental outcome at 2 years corrected age was noted
and 39%). A recent prospective cohort study from the Hydro- in the DRIFT arm.26 In the current trial, we will determine
cephalus Clinical Research Network reported that 56% of whether the increased number of (neurosurgical) interventions
those treated when the frontal-occipital horn ratio exceeded needed in the early study arm influences neurodevelopmental
0.55 with clinical symptoms were VP shunted.19 In a recent outcome.
de Vries LS, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F6. doi:10.1136/archdischild-2017-314206 F5
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Original article
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F6 de Vries LS, et al. Arch Dis Child Fetal Neonatal Ed 2018;0:F1–F6. doi:10.1136/archdischild-2017-314206
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Treatment thresholds for intervention in

posthaemorrhagic ventricular dilation: a
randomised controlled trial
Linda S de Vries, Floris Groenendaal, Kian D Liem, Axel Heep,
Annemieke J Brouwer, Ellen van 't Verlaat, Isabel Benavente-Fernández,
Henrica LM van Straaten, Gerda van Wezel-Meijler, Bert J Smit, Paul
Govaert, Peter A Woerdeman and Andrew Whitelaw

Arch Dis Child Fetal Neonatal Ed published online February 10, 2018

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