Is Ventricular Lavage a Novel Treatment of Neonatal Posthemorrhagic Hydrocephalus? A Meta analysis

doi:10.21203/rs.3.rs-2127688/v1

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Is Ventricular Lavage a Novel Treatment of Neonatal Posthemorrhagic Hydrocephalus? A Meta analysis

https://doi.org/10.21203/rs.3.rs-2127688/v1

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Introduction

Intraventricular hemorrhage (IVH) may produce obliterative arachnoiditis, which disrupts the flow and absorption of cerebrospinal fluid (CSF), resulting in posthemorrhagic hydrocephalus (PHH). PHH gives a high risk of neurofunctional impairment.

Ventricular lavage is the treatment of choice for PHH in neonates with IVH for decades. It’s developing with the combination of fibrinolytic therapy also called drainage, irrigation and fibrinolytic therapy (DRIFT), and with the using of neuroendoscopic apparatus also called neuroendoscopic lavage (NEL).

Methods

This review is a meta-analysis using the PRISMA method guideline, including the clinical studies comparing ventricular lavage (VL) with standard treatment of PHH between 2000 and 2021.

Results

VL group reduce the shunt dependency compared to standard treatment (OR = 0.22; 95CI 0.05 to 0.97; p = 0.05). VL group has less infection risk compared to the standard treatment group (RR = 0.20; 95CI 0.07 to 0.59; p < 0.05). The severe neurofunctional outcome is similar between the two groups (OR = 0.99; 95CI 0.13 to 7.23; p = 0.99). The early approach treatment group may give better neurofunctional outcome compared to the late approach (OR = 0.14; 95CI 0.06 to 0.35; p < 0.05).

Conclusion

VL reduce the shunt dependency on the PHH, decreasing the shunt’s related infection rate. The early ventricular lavage may give benefit for the neurocognitive outcome.

Posthemorrhagic hydrocephalus

intraventricular hemorrhage

neuroendoscopic lavage

cerebrospinal diversion

ventriculoperitoneal shunt

neonates

Intraventricular hemorrhage (IVH) is frequently found in premature babies, with incidence occurred up to 25–30% in this group.¹ Large IVHs (Grade III/IV) produce obliterative arachnoiditis, which disrupts the flow and absorption of cerebrospinal fluid (CSF), resulting in post-hemorrhagic hydrocephalus (PHH).²

The presence of a blood clot inside the CSF and the characteristics of the premature newborn prohibits the use of a permanent CSF shunting device. Thus, a temporary management of hydrocephalus is required.³

The standard management for temporary alleviate the increasing intracranial pressure (ICP) includes lumbar punctures, ventricular access device, ventriculosubgaleal shunt (VSgS) and external ventricular drain.^1–6 However, the optimal treatment strategy that is effective, had low complication rate, and provide better cognitive outcome has yet to be found.³

NEL is another treatment option for PHH. This procedure were developed following DRIFT method, aiming for removal of intraventricular hematoma in less invasive and more controlled setting.⁴ This method eliminates intraventricular blood clots to reduce brain damage and hydrocephalus. NEL reduces persistent shunting and increases shunt survival/ shunt malfunction.⁸

DRIFT is one of the methods developed to alleviate the rise of ICP. DRIFT is conducted by administering sub-systemic dosage of tissue plasminogen activator intraventricularly.^2,7 DRIFT were reported to have better neurodevelopmental outcome compared to standard management.⁴ Basically, DRIFT and NEL treatment’s goal is to eliminate the intraventricular blood clots.

PHH remains a critical illness with a high risk of cognitive, motor, and sensory impairment.⁷ The ventricular system's increased pressure, distortion, and neurotoxic and inflammatory consequences induce gradual brain damage and consequent neuro-disability, which is sometimes severe.⁹ In 48 percent of newborns with a grade 4 IVH and receiving shunt, severe cognitive disability (Mental Development Index [MDI] 50) was identified.⁷ It is also the leading risk factor for special educational needs in children of school age.²

Thus, the main goal of treatment for PHH in neonates with IVH management is to clear the intraventricular hematoma. This meta-analysis conducted to evaluate the benefits for reducing shunt dependency, reducing infection risk, neurofunctional outcome in clearing the intraventricular hematoma. The recommended treatment should not only be effective, but it should also be capable of reducing severe disability.

General information and literature search strategy

Selection of studies was carried out with PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol) method guideline. The data was collected from PubMed, ScienceDirect, Cochrane Library and Google Scholar.

Eligibility Criteria

Articles included in this review were clinical study comparing ventricular lavage (VL) with standard treatment for neonatal posthemorrhagic hydrocephalus or intraventricular hemorrhage induced ventricular dilatation, published in English or Bahasa between 2000 and 2021, information regarding the safety and efficacy of ventricular lavage as the first-line therapy for posthemorrhagic hydrocephalus.

Proceeding articles, editorials, commentaries or publications without peer-review process were excluded. Congenital, infection, tumor and spinal dysraphism related hydrocephalus were excluded.

Information Source and Search Strategy

We conducted a systematic searched for the literature to identify relevant articles using PubMed, ScienceDirect, Cochrane Library and Google Scholar for articles published from January 2000 to December 2021 using keywords our search strategy below (Table 1). We also performed a hand-search of references listed in relevant articles to identify additional primary studies and minimalize bias.

Table 1

Keywords Search Strategy
1	(Posthemorrhagic ventricular dilatation)
2	(Intraventricular hemorrhage) OR (Germinal matrix hemorrhage)
3	#1 OR #2
4	(Ventricular Lavage)
5	(Neuroendoscopic lavage) OR (endoscopic irrigation)
6	#4 OR #5
7	(Cerebrospinal fluid diversion) OR (Cerebrospinal fluid shunt)
8	(Ventriculoperitoneal shunt) OR (Ventriculosubgaleal shunt) OR (Lumboperitoneal shunt) OR (Lumbar drainage) OR (Ventriculoatrial shunt) OR (CSF tapping) OR (Ommaya reservoir) OR (Temporary CSF diversion) OR (External ventricular drainage)
9	#7 OR #8
10	(Treatment timing)
11	(Treatment strategy)
12	#10 AND #11
13	(Outcome) OR (Neurodevelopmental outcome) OR (morbidity) OR (Mortality) OR (Shunt dependency) OR (Shunt conversion) OR (Shunt requiring)
14	#3 AND #6 AND #9 AND #12 AND #13
15	(Infants) OR (Pediatrics)
16	#14 AND #15

Statistical Analysis

This meta-analysis utilized Revman version 5.4 from the Cochrane Review was used for the meta-analysis. Count data were presented as odds ratio (OR) and risk ratio (RR), the presented data were based on a 95% confidence interval (CI). Fixed-effects model (FEM) and Random-effects model (REM) were adopted in the meta-analysis.

Data Collection

The extracted data included bibliographic data, safety and efficacy results (shunt dependency, infection rate and neurofunctional outcome). The data extraction was conducted independently by 3 investigators, any disputes were resolved by the senior author. The systematic search is represented in PRISMA flow diagram (Fig. 1).

Risk of Bias Analysis

The result of bias risk assessment of the included studies was measured using risk of bias tool developed by the member of the Cochrane Methods Bias Group. For non-randomized studies we used the risk of bias in non-randomized studies of intervention (ROBINS-I) and version 2 of the Cochrane risk of bias tool for randomized trial (RoB-2) for the randomized studies. We have data (not shown) to show normal distribution results, with some acceptable deviations. Thus, the eligibility of the literature is high.

Quantitative Analysis

The authors conducted the meta-analysis into several group of analysis for the specific outcome which were carried out on homogenous studies for each group of analysis (shunt dependency after VL, infection rate after VL, severe neurofunctional outcome after VL, neurofunctional outcome in the early treatment group versus the late treatment group).

VL treatment group seems to have less need for permanent CSF diversion compared to standard treatment group (ventriculoperitoneal shunt, ventriculosubgaleal shunt, extra-ventricular drainage, lumbar drainage, lumbo-peritoneal shunt) during the follow up and statistically significant (OR = 0.22; 95CI 0.05 to 0.97; p = 0.05; Fig. 2).

In terms of infection rate, the VL treatment group has less risk of infection compared to the standard treatment group (RR = 0.20; 95CI 0.07 to 0.59; p < 0.05; Fig. 3).

The VL treatment group seems to have no significant difference compared to the standard treatment group for severe neurofunctional outcome events (OR = 0.99; 95CI 0.13 to 7.23; p = 0.99; Fig. 5).

The early approach treatment group is better compared to late approach treatment group for mitigating severe neurofunctional outcome events (OR = 0.14; 95CI 0.06 to 0.35; p < 0.05; Fig. 6).

Since standard management of using lumbar punctures or ventricular drainage had poor result in functional outcome, other methods are proposed. Ventricular lavage was introduced, with aim to decompress early and clearing blood clots. The commonly known techniques for ventricular lavage were DRIFT and NEL.⁸ The outcomes that were evaluated in this study were shunt dependency, infection rate and neurofunctional outcome.

Shunt Dependency

Schulz reported that the period of eventually needing a permanent shunt is longer in VL group compared to the standard group (temporary CSF diversion: lumbar punctures, a ventricular access device, or an external ventricular drain).⁵ Our data showed that VL group is significant less shunt dependent than standard treatment group (11 of 19 patients vs. 10 of 10 patients). However, in the standard group, repeated CSF removal is required immediately after surgery and on a regular basis.⁵

Etus also reported a significant lower rate of shunt dependency in VL group compared to those who receiving standard treatment.¹ The discrepancy of the population size between these two groups due to the ventriculosubgaleal shunt is included into the standard treatment together (23 patients vs. 51 patients, respectively)¹ might give a significant impact for the overall quantitative analysis.

Park utilizes ventricular lavage (with fibrinolytic therapeutic strategy using urokinase) in attempt to manage PHH. Eighteen out of 21 patients (86%) receiving VL did not require permanent shunt placement, which was considered as a great success.⁶ Although, this result might cause this group’s sample population heterogenous (I² = 78%).

On the contrary, Whitelaw and Frassanito reported that ventricular lavage treatment did not reduce the shunt dependency rate. Whitelaw reported that VL did not reduce the need of permanent shunt with comparable number between VL and standard treatment group (16 of 39 patient vs. 15 of 38 patients, respectively).¹ Frassanito reported that shunt dependency is similar in group receiving ventriculosubgaleal shunt (VSgS) compared to those receiving VSgS and VL.³ Although this results may be caused by the small number of patients, timing of surgery and other factors.³

Infection rate and multiloculated hydrocephalus

Schulz reported a lower infection rate in VL group. This might be caused by smaller number of serial CSF punctures in VL group. Rate of multiloculated hydrocephalus were also lower, since this condition is usually precipitated by previous infection. In study by Etus et al., VL group had significant lower rate of infection and multiloculated hydrocephalus compared to group with standard treatment or VSgS.¹

In line with Schulz, Frassanito reported that group receiving VSgS and VL had lower infection rate (4.2%) compared to group with VSgS only (10.3%). In this study multiloculated hydrocephalus were also lower in VSgS and VL group (20.8%) compared to those only receiving VSgS (23.1%). VL were able to lower the rate of multiloculated hydrocephalus, since it was able to decrease blood clot and protein load.⁴

Neurofunctional Outcome

In PHH, multiple blood clots initially restrict CSF reabsorption but eventually progress to chronic arachnoiditis of the basal cisterns with extracellular matrix protein deposition.¹⁰ Approximately half of all infants with PHH have an early hemorrhagic infarction of periventricular white matter, but over the next few weeks, pressure, distortion, free radical generation facilitated by free iron, and inflammation may cause progressive injury to the immature cerebral hemispheres globally.² This mechanism leads to high probability of serious cognitive, motor, and sensory disability in children with PHH.

Since decompressing early and clearing the blood clots in ventricle may lead to a better neurofunctional outcome. This study reported that in 2 years, with adjusted gender, birth weight, and IVH grade; the reduction in the primary long-term outcome, death or severe impairment in the VL group attained statistical significance compared to the standard treatment. Furthermore, severe cognitive impairment was substantially halved and was statistically significant while the sensorimotor outcome was unremarkable statistically. This may be explained by the presence of periventricular white matter infarction, and VL cannot undo this condition.⁷

Luyt also conducted a long-term follow-up of 10 years in patients who underwent VL management. It shows that VL in preterm children with PHH after severe IVH enhances cognitive function at a 10-year follow-up when birth weight, IVH grade, and sex are considered. This finding is especially important since it follows the patient until middle school age, thus further proving the benefit of VL in long-term neurocognitive outcome.²

Leijser and Park conducted study for the neurocognitive outcome based on the treatment’s timing.^6,11

Park used a ventricular lavage method with urokinase injections and compared group with early ventricular lavage (within 3 weeks of IVH) and those who had late ventricular lavage (after 3 weeks of IVH onset). Good functional outcome was in patients who underwent early ventricular lavage. The functional outcome evaluated were lower limb function and walking ability; upper limb function and feeding ability; and cognitive function and speaking capacity. All domains were statistically significant better in early treatment group (p < 0,05).⁶

Leijser compared two different timing approach for PHH, early approach by using temporary CSF drainage with lumbar punctures or ventricular reservoir followed by permanent shunt; and late approach by using clinical signs of increase intracranial pressure to start the placement of permanent shunt. The study shows that, regardless of intervention, infants receiving early approach have essentially normal early cognitive and motor outcomes, even when a permanent shunt is eventually required. Infants who receive LA, on the other hand, have poor cognitive and motor outcomes if intervention is eventually required. With the LA, the VP-shunt rate and shunt-related complications were also higher.¹¹

The poorer neurodevelopmental outcomes in infants who received late intervention suggest that progressive ventricular dilatation and prolonged pressure are harmful to immature white matter. Even if CSF pressure is restored to normal at a later point, the white may no longer be able to heal.¹²

Although not included in the meta-analysis, NEL were also may able to improve brain development and avoiding secondary damage by reducing triggered inflammation. NEL itself had similar principle with VL; but less invasive and more controlled settings.⁸

Since ventricular lavage is a feasible technique to remove intraventricular degraded blood residual in post-hemorrhage hydrocephalus, this procedure may able to reduce the shunt dependency risk caused by arachnoiditis-related hydrocephalus due to the high load of degraded blood products. Another important burden is the multiloculated hydrocephalus caused by the development from PHH and CSF infection. Our review show that a well-tolerated ventricular lavage has less risk of infection rate, that may mitigate multiloculated hydrocephalus, further may contribute in reducing shunt dependency rate.

White matter damage due to ventricular dilatation, neurotoxic, and inflammatory responses from blood products intraventricular may deteriorate the neuro-disability. On the contrary our meta data shows that ventricular lavage has no benefit in the neurofunctional outcome. To date, the main goal in the treatment of PHH has been to reduce mortality, shunt dependency, and infection risk. The further mission is to improve neurofunctional prognose which need further search for a novel treatment for PHH in the future.

Study Limitations

This review including both DRIFT and NEL as a single treatment group, thus the treatment’s main goal is similar, to decompress early and clearing blood clots of the IVH.

According to the treatment’s timing, Leijser and Park had different treatment’s strategy, but our meta data shows a promising result that the early treatment of the IVH may give benefit for the neurofunctional outcome.

Ventricular lavage may reduce the shunt dependency rate on the PHH in infant patients by mitigating multiloculated hydrocephalus caused by the inflammatory reaction of the IVH, furthermore, it may decrease the shunt’s related infection rate.

The early IVH treatment may give benefit for the neurocognitive outcome since the aim of this treatment is to eliminate the progressive inflammatory reaction caused by the free iron from the blood clot.

Acknowledgment

The authors would like to thank all the staff of Department of Neurosurgery, Faculty of Medicine, Universitas Airlangga. We would also like to give our gratitude toward all who have contributed to and are involved in the process of this reports

Ethical Approval

Not applicable.

Competing Interests

The authors declare that they have no competing interests.

Authors’ Contributions

I.G.M Aswin R. Ranuh contributed to the conceptualization, writing, and editing of the study. Muhammad Arifin Parenrengi and Wihasto Suryaningtyas contributed to conceptualization, reviewing, editing, and finalizing the manuscript of the study.

Funding

This study is not funded by any external institutions, nor does it have any sponsors.

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Luyt K, Jary SL, Lea CL, et al. Drainage, irrigation and fibrinolytic therapy (DRIFT) for posthaemorrhagic ventricular dilatation: 10-year follow-up of a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2020;105(5):466-473. doi:10.1136/archdischild-2019-318231
Frassanito P, Serrao F, Gallini F, et al. Ventriculosubgaleal shunt and neuroendoscopic lavage: refining the treatment algorithm of neonatal post-hemorrhagic hydrocephalus. Child’s Nerv Syst. 2021;37(11):3531-3540. doi:10.1007/s00381-021-05216-6
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No competing interests reported.

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Is Ventricular Lavage a Novel Treatment of Neonatal Posthemorrhagic Hydrocephalus? A Meta analysis

Archived Versions:

Version 1

Abstract

Figures

Introduction

Material And Methods

General information and literature search strategy

Eligibility Criteria

Information Source and Search Strategy

Statistical Analysis

Results

Data Collection

Risk of Bias Analysis

Quantitative Analysis

Discussion

Shunt Dependency

Infection rate and multiloculated hydrocephalus

Neurofunctional Outcome

Study Limitations

Conclusions

Declarations

References

Additional Declarations

Archived Versions:

Version 1