Intraventricular Lavage vs External Ventricular Drainage for Intraventricular Hemorrhage: A Randomized Clinical Trial

Mette Haldrup; Mads Rasmussen; Niwar Mohamad; Stig Dyrskog; Line Thorup; Nikola Mikic; Joakim Wismann; Mads Grønhøj; Frantz Rom Poulsen; Mojtaba Nazari; Naveed Ur Rehman; Claus Ziegler Simonsen; Anders Rosendal Korshøj

doi:10.1001/jamanetworkopen.2023.35247

. 2023 Oct 10;6(10):e2335247. doi: 10.1001/jamanetworkopen.2023.35247

Intraventricular Lavage vs External Ventricular Drainage for Intraventricular Hemorrhage

A Randomized Clinical Trial

Mette Haldrup ^1,^2,³, Mads Rasmussen ^2,⁴, Niwar Mohamad ^1,^2,^4,⁵, Stig Dyrskog ⁶, Line Thorup ⁶, Nikola Mikic ^1,², Joakim Wismann ^3,⁷, Mads Grønhøj ^3,⁷, Frantz Rom Poulsen ^3,⁷, Mojtaba Nazari ⁸, Naveed Ur Rehman ⁸, Claus Ziegler Simonsen ^2,⁹, Anders Rosendal Korshøj ^1,^2,^✉

¹Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark

²Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

³Department of Neurosurgery, Odense University Hospital, Odense, Denmark

⁴Department of Anesthesiology, Section of Neuroanesthesia, Aarhus University Hospital, Aarhus, Denmark

⁵Department of Anesthesiology, Regional Hospital Goedstrup, Herning, Denmark

⁶Department of Intensive Care, Aarhus University Hospital, Aarhus, Denmark

⁷Department of Clinical Research and BRIDGE, University of Southern Denmark, Odense, Denmark

⁸Department of Engineering, Electrical and Computer Engineering, Aarhus University, Aarhus, Denmark

⁹Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

Accepted for Publication: July 23, 2023.

Published: October 10, 2023. doi:10.1001/jamanetworkopen.2023.35247

^✉

Corresponding Author: Anders Rosendal Korshøj, MD, PhD, Department of Neurosurgery, Aarhus University Hospital, Palle Juul Jensens Boulevard 165, J604, DK8200 Aarhus N, Denmark (andekors@rm.dk).

Author Contributions: Drs Haldrup and Korshøj had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Haldrup, Dyrskog, Wismann, Grønhøj, Korshøj.

Acquisition, analysis, or interpretation of data: Haldrup, Rasmussen, Mohamad, Dyrskog, Thorup, Mikic, Poulsen, Nazari, Rehman, Simonsen, Korshøj.

Drafting of the manuscript: Haldrup, Rasmussen, Grønhøj, Korshøj.

Critical review of the manuscript for important intellectual content: Haldrup, Rasmussen, Mohamad, Dyrskog, Thorup, Mikic, Wismann, Poulsen, Nazari, Rehman, Simonsen, Korshøj.

Statistical analysis: Korshøj.

Obtained funding: Haldrup, Korshøj.

Administrative, technical, or material support: Haldrup, Mohamad, Dyrskog, Mikic, Wismann, Grønhøj, Poulsen, Nazari, Korshøj.

Supervision: Rasmussen, Mohamad, Dyrskog, Poulsen, Korshøj.

Conflict of Interest Disclosures: Dr Rasmussen reported receiving grants the Health Research Foundation Fund of Central Denmark Region outside the submitted work. Dr Simonsen reported receiving grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region outside the submitted work. Dr Korshøj reported receiving personal fees from IRRAS during the conduct of the study; grants from IRRAS (paid to Aarhus University Hospital), the Danish Cancer Society, the Lundbeck Foundation, and the Independent Research Fund Denmark outside the submitted work; and having a patent for a neuromonitoring technology pending with relation to the IRRAflow technology. No other disclosures were reported.

Funding/Support: The study was supported by a grant from IRRAS to Aarhus University Hospital and a grant from Aarhus University. The study device and related utensils were purchased by Aarhus University Hospital by independent procurement for treatments conducted at Aarhus University Hospital. The study device and related utensils were provided by IRRAS to Odense University Hospital for treatments conducted at Odense University Hospital as a part of the study grant from IRRAS to Aarhus University Hospital.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; and decision to submit the manuscript for publication. IRRAS AB was permitted to review the study protocol prior to initiation and also review the manuscript prior to submission.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Fie Jappe, BSN, Camilla Basse Larsen, BSN, and Kirsten Loch, BSN (Department of Intensive Care, Aarhus University Hospital) and Maria Halle, BSN, and Helle Dixen Hansen, BSN (Department of Intensive Care, Odense University Hospital) assisted with implementation and handling of trial procedures. Ane Kirkegaard, BSN (Department of Neurosurgery, Aarhus University Hospital), assisted with trial implementation in the surgical facility. Hamed Zaer, MD, PhD; Ann Kathrine Sindby, MD; Ivona Nemeiko, MD; Laila Islamagic, MD; Bo Bergholt, MD, PhD; Mahmoud Albarazi, MD; and Boris Cehov, MD (Department of Neurosurgery, Aarhus University Hospital), assisted with patient enrollment and follow-up. Marianne Esbjerg, BSN (Good Clinical Practice Unit, Aarhus University), coordinated trial monitoring.

^✉

Corresponding author.

PMCID: PMC10565600 PMID: 37815832

Key Points

Question

Is ventricular lavage a safe and effective treatment of intraventricular hemorrhage compared with passive drainage?

Findings

This randomized clinical trial of 21 patients comparing intraventricular lavage with standard drainage treatment found significantly higher risks of SAEs and catheter occlusions in the intervention group. The trial was terminated early, as recommended by an independent data safety monitoring board, due to safety concerns at preplanned interim analysis of 20 patients.

Meaning

These findings suggest that caution should be taken when using intraventricular lavage for IVH treatment and technology adaptations should be implemented to mitigate future adverse events.

This randomized clinical trial evaluates the safety and potential efficacy of intraventricular lavage treatment for intraventricular hemorrhage.

Abstract

Importance

Intraventricular lavage has been proposed as a minimally invasive method to evacuate intraventricular hemorrhage. There is little evidence to support its use.

Objective

To evaluate the safety and potential efficacy of intraventricular lavage treatment of intraventricular hemorrhage.

Design, Setting, and Participants

This single-blinded, controlled, investigator-initiated 1:1 randomized clinical trial was conducted at Aarhus University Hospital and Odense University Hospital in Denmark from January 13, 2022, to November 24, 2022. Follow-up duration was 90 days. The trial was set to include 58 patients with intraventricular hemorrhage. Prespecified interim analysis was performed for the first 20 participants. Data were analyzed from February to April 2023.

Interventions

Participants were randomized to receive either intraventricular lavage or standard drainage.

Main Outcomes and Measures

The main outcome was risk of catheter occlusions. Additional safety outcomes were catheter-related infections and procedure time, length of stay at the intensive care unit, duration of treatment, and 30-day mortality. The main outcome of the prespecified interim analysis was risk of severe adverse events. Efficacy outcomes were hematoma clearance, functional outcome, overall survival, and shunt dependency.

Results

A total of 21 participants (median [IQR] age, 67 [59-82] years; 14 [66%] male) were enrolled, with 11 participants randomized to intraventricular lavage and 10 participants randomized to standard drainage; 20 participants (95%) had secondary intraventricular hemorrhage. The median (IQR) Graeb score was 9 (5-11), and the median (IQR) Glasgow Coma Scale score was 6.5 (4-8). The study was terminated early due to a significantly increased risk of severe adverse events associated with intraventricular lavage at interim analysis (risk difference for control vs intervention, 0.43; 95% CI, 0.06-0.81; P = .04; incidence rate ratio for control vs intervention, 6.0; 95% CI, 1.38-26.1; P = .01). The rate of catheter occlusion was higher for intraventricular lavage compared with drainage (6 of 16 patients [38%] vs 2 of 13 patients [7%]; hazard ratio, 4.4 [95% CI, 0.6-31.2]; P = .14), which met the prespecified α = .20 level. Median (IQR) procedure time for catheter placement was 53.5 (33-75) minutes for intraventricular lavage vs 12 (4-20) minutes for control (P < .001).

Conclusions and Relevance

This randomized clinical trial of intraventricular lavage vs standard drainage found that intraventricular lavage was encumbered with a significantly increased number of severe adverse events. Caution is recommended when using the device to ensure patient safety.

Trial Registration

ClinicalTrials.gov Identifier: NCT05204849

Introduction

Intraventricular hemorrhage (IVH) is a serious hemorrhagic stroke characterized by bleeding within the brain’s ventricles.¹ Current treatment relies on supportive care and cerebrospinal fluid (CSF) drainage to decompress the intracranial space and facilitate passive hematoma evacuation using an external ventricular drain (EVD). Recent studies² have shown that intraventricular fibrinolysis (IVF) can accelerate clot removal, increase overall survival, and improve functional outcomes. It has been suggested that further acceleration of clot removal is required to substantially improve patient outcomes.^3,4 However, major treatment advances to this end are lacking.

Recently, a new technology, called IRRAflow (IRRAS AB), was introduced to address the unmet clinical needs in IVH treatment. It uses a dual lumen catheter to actively and precisely perfuse the ventricular system with physiological saline, while simultaneously monitoring intracranial pressure. This continuous irrigation and aspiration is hypothesized to enable accelerated washout of IVH and continuous intrathecal drug perfusion and to further prevent complications, such as catheter obstruction and bacterial infection, which is commonly associated with passive drainage. IRRAflow received Conformité Européene marking in 2019 and US Food and Drug Administration approval in 2018 and has been used to treat more than 600 patients with IVH, brain abscess, and chronic subdural hematoma worldwide (postmarket surveillance data; J. Unser, MBA, IRRAS AB, written communication, January 2023). Currently, however, there is no evidence to support the safety or efficacy of the treatment. Only 1 published case report has evaluated this intraventricular lavage technology for IVH treatment.⁵ Additionally, a registered randomized clinical trial⁶ is currently evaluating intraventricular lavage in combination with IVF for patients with IVH. Moreover, there are 5 unregistered trials presently under way to test intraventricular lavage in different settings.

In this study, we investigated the safety and preliminary efficacy of intraventricular lavage compared with standard EVD treatment of IVH. The study aimed to evaluate the occurrence of adverse events (AEs) and investigate the value propositions of the technology, particularly reduced rates of drain occlusion and central nervous system infection, as well as accelerated hematoma clearance. To our knowledge, the study represents the first class 1 evidence on the IRRAflow intraventricular lavage performance and operation under basic recommended treatment conditions, observed harms, and an important basis for future studies and developments in the area.

Methods

Trial Design and Oversight

This is a single-blinded, phase 2 randomized clinical trial evaluating the safety and efficacy of intraventricular lavage vs passive EVDs for treating IVH. It is a prospective, investigator-initiated, multicenter, comparative trial conducted at 2 sites in Denmark (Aarhus University Hospital and Odense University Hospital). The study was performed according to the ethical principles of the Declaration of Helsinki,⁷ Good Clinical Practice Guidelines, and ISO-14155 standards, with approval from the Danish Central Region Committee on Health Research Ethics. Written informed consent was obtained from all participants or a legal authorized representative in accordance with ethical requirements. An independent data safety monitoring committee (DMC) and contract research organization monitored the trial. The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline, with harms reported following the CONSORT Extension reporting guideline for harm reporting. Details of the trial design, conduct, oversight, and analysis can be found in the trial protocol and statistical analysis plan in Supplement 1 and published elsewhere.⁸ A prespecified interim analysis was planned after 3 months of follow-up for the first 20 participants.

Randomization and Blinding

Baseline data were recorded on inclusion and prior to randomization. Participants were then randomly assigned in a 1:1 ratio to either intraventricular lavage (intervention) or standard EVD (control). Randomization was implemented automatically by the REDCap system randomization module (Vanderbilt University) on participant enrollment. The allocation sequence for randomization was created prior to study initiation by an independent administrator at Aarhus University.

The study was single-blinded, since participants were blinded to the randomization and treatment. The independent study statistician was blinded for end point assessment. Blinding of treating physicians and investigators was not feasible due to the nature of the surgery and the intraventricular lavage operational features. End points and AEs were registered prospectively and predefined using objective parameters to minimize bias.

Participants

Patients aged at least 18 years with a primary or secondary IVH and indication for CSF drainage were assessed for eligibility. An IVH Graeb score of 3 or greater was required for inclusion (head computed tomography [CT] required <24 hours before inclusion). Patients with fixed and dilated pupils were excluded, as were pregnant or nursing patients. A full list of inclusion and exclusion criteria is given in the trial protocol in Supplement 1.

Interventions

Participants in the intervention group were treated with IRRAflow (9F dual lumen catheter, version 2.0 ICGS020, and control unit, version 3.0) (eAppendix 1 and eAppendix 2 in Supplement 2), whereas participants in the control group were treated with a standard EVD (Silverline, size 10F; Spiegelberg). Catheters were placed using neuronavigation guidance (AxiEM; Medtronic) and positioned in the lateral ventricle with the least amount of blood, preferably outside the hematoma, to avoid catheter obstruction. In case of obstruction of the foramen Monro, a standard EVD was placed contralaterally to ensure bilateral drainage. All study personnel received thorough training and certification in the use of the intraventricular lavage device from the manufacturer prior to patient enrollment.

Safety Outcomes

The primary outcome was the rate of catheter occlusion, defined as complete drainage stop. Secondary safety outcomes were procedure time for primary catheter placement, length of intensive care unit stay, duration of catheter treatment, 30-day mortality, and number of catheter interventions.

The main outcome of the interim analysis was the risk of severe AEs (SAEs). If the risk of SAEs associated with intraventricular lavage was increased compared with EVD at the α = .20 significance level, early stopping was considered. AEs were defined and their severity was graded according to the Common Terminology Criteria of Adverse Events version 5.0, with AEs grade 3 to 5 categorized as SAEs. Predefined SAEs of interest with possible causal relationships to IVH or catheter treatment were death, culture-positive central nervous system infections, intracranial hemorrhage occurring after inclusion, catheter displacements evaluated using head CT where irrigation or drug administration was applied, catheter misplacement evaluated with head CT directly after catheter placement, and catheter occlusion leading to surgical replacement or administration of alteplase (eAppendix 3 in Supplement 2).

All AEs and SAEs were recorded, and their causality was evaluated using the standardized World Health Organization–Uppsala Monitoring Centre system.⁹ All AEs were thoroughly evaluated in a root cause analysis, which was reviewed and validated by the DMC. AEs with a certain, probable, or possible relationship to the intervention or to catheter treatment were included in the analyses of AEs (eAppendix 3 in Supplement 2). The independent neurosurgical DMC member determined the causal relationship of all SAEs with EVD treatment in general and the specific feature differences between intraventricular lavage and EVD (Figure 1; eAppendix 1 and eAppendix 2 in Supplement 2).

Efficacy Outcomes

Shunt dependency was evaluated as the proportion of participants with an implanted CSF shunting device at 90 days. IVH clearance rate was based on CT volumetrics at days 0, 2, 4, 6, and 8 after inclusion. Functional outcome was assessed using modified Rankin Scale (mRS; range, 0-6; higher score indicates worse outcome) score at inclusion, discharge, and 90 days after inclusion, and extended Glasgow Outcome Scale (eGOS; range, 1-8; higher score indicates better outcome) at discharge and 90 days.

Sample Size Calculation

The study was designed to enroll 58 participants to achieve a power of 80%, based on an assumption of a superiority effect in the primary outcome. We used a 2-sided log-rank test to compare the time-to-catheter occlusion between treatment groups, assuming an equal length of follow-up and an occlusion risk of 10% in the intervention group and 35% in the control group. We set a more conservative estimate of occlusion rates than reported in the literature for the control group and a higher risk of occlusion than the 0% reported in postmarket surveillance.^2,10,11 Patient mortality was assumed to be independent of time to catheter occlusion and to correspond to a 30% dropout rate.

Statistical Analysis

The null hypothesis was that intraventricular lavage has no effect on the occlusion rate compared with standard passive EVD. All end points were analyzed as intention-to-treat. Statistical tests were performed at the 2-sided significance level of α = .05, except for the primary outcomes of the interim and final analyses, which were set to α = .20 due to the exploratory nature of the study and to ensure patient safety. Absolute numbers and percentages were used to report binary and categorical variables. Effect measures on binary and categorical variables were analyzed using a generalized linear model with log-link function and reported using risk ratios and risk differences. Measures of functional outcome (mRS and eGOS) were dichotomized and analyzed using baseline-adjusted logistic regression.

Continuous data were reported using means and SDs for normally distributed data or medians and IQRs for data that were not normally distributed. Time-to-event end points were analyzed using the Kaplan-Meier method and Cox regression. The time to catheter occlusion was reported using plots of cumulative incidence ratios. Participants were censored at the time of death. SAEs were reported as absolute risk differences and incidence rates. Incidence rate ratios were estimated using the Poisson regression model. Analyses were conducted in Stata statistical software version 17 (StataCorp). Data were analyzed from February to April 2023.

Results

Early Stopping

The study was terminated early due to safety concerns identified on interim analysis of the first 20 participants. The decision was made by the trial steering committee based on recommendation by the independent DMC.

Baseline Characteristics

Among 24 participants assessed for eligibility, 21 participants (median [IQR] age, 67 [59-82] years; 14 [66%] male; 20 participants [95%] with secondary IVH) were included in analysis, with 11 participants randomized to the intervention and 10 participants randomized to the control (Figure 1). Baseline characteristics were balanced between the groups (Table 1). The median (IQR) Glasgow Coma Scale score 6.5 (4-8). In 9 of 17 patients (53%) with a Graeb score of 5 or above (median [IQR] Graeb score, 9 [5-11]), bilateral ventricular catheter treatment was administered due to Monro block. The number of patients with severe IVH was equally distributed in the 2 groups (median [SD] Graeb, score 8.7 [6] vs 9.5 [2]). The study period was January 13, 2022, to November 24, 2022, and the final end point data were collected on February 14, 2023. No loss to follow-up was experienced.

Table 1. Baseline Characteristics of Included Participants .

Characteristic	Participants, No. (%) (N = 21)
Characteristic	Intervention (n = 11)	Control (n = 10)
Age, median (IQR), y	66 (22)	69 (19)
Sex
Female	3 (27)	4 (40)
Male	8 (73)	6 (60)
Antihypertensive medicine adherent	3 (27)	6 (60)
Anticoagulation medication at enrollment	1 (9)	2 (20)
Antiplatelet treatment at enrollment	3 (27)	1 (10)
IVH type
SAH with intraventricular extension	6 (55)	4 (40)
ICH with intraventricular extension	4 (36)	6 (60)
Primary IVH	1 (9)	0 (0)
GCS score at inclusion, median (IQR)^a	6 (4)	7 (6)
Graeb score, median (IQR)^b	8 (6)	9.5 (2)

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Abbreviations: GCS, Glasgow coma scale; ICH, intracerebral hemorrhage; IVH, intraventricular hemorrhage; SAH, subarachnoid hemorrhage.

^{^a}

Range, 3 to 15; higher score indicates better outcome.

^{^b}

Range, 1 to 12; higher score indicates increasing amount of blood.

Safety Outcomes

The intervention group had a significantly higher rate of catheter occlusions (primary outcome) than the EVD group (6 of 16 participants [38%] vs 2 of 13 participants [7%]; hazard ratio [HR], 4.4 [95% CI, 0.6-31.2]; P = .14; meeting the prespecified α = .20) (Figure 2; eAppendix 4 in Supplement 2). In the intervention group, 4 of 6 participants with occlusions (67%) received a contralateral EVD and 2 participants (33%) were treated with tissue-type plasminogen activator (tPA) for clot resolution or had the catheter replaced. In the control group, the 2 patients (20%) experiencing occlusions had the catheters replaced. The procedure time for catheter placement was significantly longer for the intervention group compared with the control group (median [IQR] time, 53.5 [33-75] minutes vs 12 [4-20] minutes; P < .001).

On the basis of an interim analysis of the first 20 participants (10 treated with intraventricular lavage and 10 treated with EVD), 7 patients in the intervention group (70%) experienced at least 1 SAE, compared with 2 participants in the control group (20%) (P = .02). As a result of these findings, the study was terminated early. Root cause analysis, complete DMC safety report, frequencies, causality assessments, and gradings of all AEs are provided in eAppendices 5 to 8 in Supplement 2. Table 2 presents the safety outcomes for the final intention-to-treat population. The risk of experiencing at least 1 SAE was significantly higher in the intervention group (7 participants [64%]) compared with the control group (2 participants [20%]), with an absolute risk difference of 0.43 (95% CI, 0.06-0.81; P = .04). Similarly, the incidence of SAEs was significantly higher with intraventricular lavage (incidence rate ratio, 6.0 [95% CI, 1.4-26.1]; P = .01).

Table 2. Safety and Efficacy Outcomes.

Outcome	Intervention (n = 11)	Control (n = 10)	Estimate (95%CI)	P value
Safety
Risk of >1 SAE, No. (%)	7 (64)	2 (20)	0.43 (0.059 to 0.813)^a	.04
Grade 3-5 SAEs	17	2	6.0 (1.4 to 26.1)^b	.01
Grade 1-2 AEs	8	2	2.9 (0.6 to 12.9)^b	.20
Any catheter occlusion, No./total No. (%)	6/16 (38)^c	2/13 (6.5)^c	4.4 (0.6 to 31.2)^d	.14
Primary catheter occlusion, No. (%)	4 (36)	1 (10)	3.2 (0.4 to 28.7)^d	.30
Catheter-related infections, No. (%)	2 (18)	1 (10)	1.82 (0.19 to 7.10)^e	.60
30-d mortality, No. (%)	3 (27)	4 (40)	12.7% (−52.9% to 27.5%)^a	.54
Procedure time, median (IQR), min	55.3 (33-75)	12 (4-20)	4.5 (2.6 to 10.4)^f	<.001
ICU LOS, mean (SD), d	18 (9.4)	10.9 (15.5)	6.6 d (5.6 to 18.6)^g	.27
Duration of catheter treatment, mean (SD), d	12 (6.6)	11 (8.6)	0.5 (−6.5 to 7.6)^g	.87
Physician intervention with catheters, No.^a	13	4	2.9 (0.9 to 12.4)^b	.05
Efficacy
Clearance of blood, clot half-life, mean (SD), d	4 (1.35)	5 (2.2)	1.5 (−4.69 to 7.6)^g	.64
Shunt dependency, No. (%)	2 (18.2)	1 (10)	1.82 (0.19 to 17.1)^e	.60
90 d mRS score <3, No. (%)	10 (90.9)	9 (90.0)	1.01 (0.76 to 1.33)^e	.94

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Abbreviations: AE, adverse event; ICU, intensive care unit; LOS, length of stay; mRS, modified Rankin Scale; SAE, serious adverse event.

^{^a}

Expressed as risk difference.

^{^b}

Expressed as incidence rate ratio.

^{^c}

Physician intervention with the catheter includes every time the physician had to intervene with the catheter except from placement and removal (eg, replacement or tissue-type plasminogen activator administration).

^{^d}

Expressed as hazard ratio.

^{^e}

Expressed as risk ratio.

^{^f}

Expressed as ratio.

^{^g}

Expressed as difference.

Of 21 SAEs in the intraventricular lavage group, 16 (76%) were related to the intervention, whereas 17 (81%) were related to catheter treatment in general. Specifically, 2 SAEs related to the intervention (13%) were rebleeding with probable relation to irrigation, 4 SAEs (25%) were catheter displacements with irrigation or tPA administration accidentally into parenchyma with probable relation to the unbolted fixation method, 3 SAEs (19%) were infections with possible relation to noncoating of the catheter, reverse tunneling, or repeated change of saline bags, and 7 SAEs (44%) were catheter occlusions resulting in replacement, contralateral catheter insertion, or tPA administration with probable relation to either the smaller inner diameter of the intraventricular lavage catheter compared with EVD (1.5 mm vs 1.9 mm), collapse of the ependyma around the catheter tip due to a negative aspiration gradient, or catheter displacement into the parenchyma due to insufficient fixation. No AEs or SAEs were related to differences in the neuronavigation procedure. All catheters were placed in the intended ventricle in 1 attempt with no additional surgical passes or replacements. One patient in the intervention group experienced a track hemorrhage categorized as an AE grade 2.

Efficacy Outcomes

Hematoma clearance rate did not differ significantly between the intervention and control groups (clot half-life, 3.9 [95% CI, 1.25 to 6.57] days vs 5.4 [95% CI, −0.17 to 10.9] days; P = .64). The mean (range) irrigation volume in the intervention group was 1093 (0-4166) mL per day. Additional secondary outcomes are provided in Table 2, Table 3, and Figure 2.

Table 3. eGOS and mRS Scores at 90 Days for the 2 Groups .

Measure	Participants, No./total No. (%)
Measure	Intervention	Control
eGOS score at 90 d
1 (Dead)	3/11 (27)	4/10 (40)
2 (Vegetative state)	0/11	1/10 (10)
3 (Lower severe disability)	2/11 (18)	3/10 (30)
4 (Upper severe disability)	2/11 (18)	0/10
5 (Lower moderate disability)	3/11 (27)	2/10 (20)
6 (Upper moderate disability)	0/11	0/10
7 (Lower good recovery)	0/11	0/10
8 (Upper good recovery)	1/11 (9)	0/10
mRS score at 90 d^a
0 (No symptoms)	1/11 (9)	0/10
1 (No significant disability despite symptoms)	0/11	0/10
2 (Slight disability)	1/11 (9)	1/10 (10)
3 (Moderate disability)	2/11 (18)	2/10 (20)
4 (Moderately severe disability)	1/11 (9)	1/10 (10)
5 (Severe disability)	3/11 (27)	2/10 (20)
6 (Dead)	3/11 (27)	4/10 (40)

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Abbreviations: eGOS, extended Glasgow Outcome Scale; mRS, modified Rankin Scale.

^{^a}

Risk ratio for good functional outcome mRS of less than 3, 1.01 (95% CI, 0.76-1.33; P = .94).

Discussion

We conducted a controlled randomized clinical trial of the safety and efficacy of the intraventricular lavage technology for active washout of IVH compared with standard practice passive EVD. Intraventricular lavage builds on the novel principle of controlled intraventricular perfusion, providing a potential leap forward in the treatment of hemorrhagic stroke. The method proposedly facilitates IVH clearance and reduces the risks of catheter clotting and catheter-related central nervous system infections, thereby addressing key issues of IVH treatment.

Despite the potential, the study was terminated early due to safety concerns with the intervention. Our findings revealed a significant 6-fold increase in SAE incidence with intraventricular lavage compared with EVD. Furthermore, there was a significant 4.4-fold increase in the risk of catheter occlusion with intraventricular lavage, which was contrary to the primary outcome hypothesis.

An extensive root cause analysis revealed that most SAEs were causally related to features of the intraventricular lavage device, such as small inner lumen of the drain line, lack of antibiotic catheter coating, repeated exchange of saline supply for irrigation, insufficient catheter fixation method, an excessively negative pressure gradient during the aspiration phase, and error-prone intracranial pressure measurements and supervisory control. Actions should be taken to mitigate these caveats and potential treatment hazards in future versions of the technology.^2,12,13,14

Except for the key safety outcomes, most end points in the study did not reach statistical significance, as expected, due to early termination and reduced statistical power. Mortality, functional outcomes, shunt dependency, and hematoma clearance did not show significant effects. However, there was a significant 4.5-fold increase in surgery time for intraventricular lavage despite proper training and certification of study personnel, underlining the need to simplify the surgical procedure and device setup, because CSF drainage is an acute and potentially life-saving treatment for IVH.

IVH is a severe condition causing substantial disability and death.¹⁵ Recent studies, including the current guidelines by the American Heart Association,¹⁶ indicate a potential benefit of accelerated clot evacuation and minimally invasive surgery for intracerebral hemorrhage and IVH. However, there is a need for novel technologies and treatments to achieve this goal. Although our findings do not support the use of intraventricular lavage for IVH under the given circumstances, the principle of intraventricular lavage shows promise for improving IVH clearance and patient outcomes. Combining IVF and intraventricular lavage may further accelerate blood clearance compared with either treatment alone, as evidenced by a 2021 case series⁵ of 4 patients treated with intraventricular lavage and IVF without any complications, demonstrating radiographic and clinical superiority compared with standard EVD. These results are being further investigated in an ongoing randomized clinical trial⁶ evaluating the safety, feasibility, and efficacy of combining intraventricular lavage and IVF infusion vs standard EVD and IVF combined. In addition, intraventricular lavage was recently tested in combinations with the Hummingflow bolt (IRRAS) in a series of 9 IVH cases and the combination was found to be safe and compatible.¹⁷ Further studies will provide a broader understanding of the safety, feasibility, and efficacy of the intraventricular lavage device under various conditions.

Limitations

This study has some limitations. First, the nature of the intraventricular lavage surgery and treatment made blinding of the treating physicians impossible. Second, the primary end point and the main end point of the interim analysis were assessed at the α = .20 level, increasing the risk of type I errors. However, this strategy was due to the exploratory nature of the study, but most importantly to ensure patient safety by minimizing the number of participants exposed to any potential hazard in the study. Third, 86% of the final analysis population had a Graeb score of 5 or above, corresponding to severe IVH, which is associated with a worse outcome compared with Graeb scores 1 to 4.¹⁸ This potentially compromises the generalizability of the results to less severe IVH conditions. Fourth, the study enrolled patients with primary and secondary IVH, including subarachnoid hemorrhage, collectively representing a relatively heterogeneous population. However, this was not a problem for assessing the general safety, feasibility, and surrogate markers of efficacy, such as IVH clearance and catheter obstruction. Fifth, this intraventricular lavage treatment was a new and nonroutine procedure at the study sites, although all staff were thoroughly trained before the study started and the treatment implemented in clinical practice at the sites prior to study initiation. This could have had a potential impact on the occurrence of AEs. Sixth, participants with Monro block were treated with standard EVD in the contralateral ventricle, regardless of randomization. This could potentially bias the intent-to-treat results, although most AEs in this study were found to be associated directly with intraventricular lavage features. We did not consider it feasible to use bilateral intraventricular lavage due to the complexity of the device, although such implementations could be investigated in future studies.

Conclusions

This randomized clinical trial found that the current intraventricular lavage technology had a significantly increased risk of SAEs under the investigated conditions. The principle of controlled intraventricular lavage may potentially hold promise for improvement of IVH treatment, but further evaluation is needed. Caution is recommended when using this treatment to ensure patient safety.

Supplement 1.

Trial Protocol and Statistical Analysis Plan

Click here for additional data file.^{(537.3KB, pdf)}

Supplement 2.

eAppendix 1. The IRRAflow System

eAppendix 2. Standard Operation Procedure (SOP), IRRAflow Treatment in the Active Study

eAppendix 3. SAEs With Possible Relation to Intervention and/or Catheter Treatment

eAppendix 4. Time-to-Catheter Occlusions

eAppendix 5. The Full DMC Safety Report and Interim Analysis

eAppendix 6. Root Cause Analysis of all SAEs in the Intervention and Control Group

eAppendix 7. Causality of Adverse Events

Click here for additional data file.^{(2MB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(13KB, pdf)}

References

1.Yamaguchi Y, Nakagawa K, Watanabe H, et al. Primary intraventricular hemorrhage. Article in Japanese. Jpn J Neurosurg. 2000;9(10):672-678. doi: 10.7887/jcns.9.672 [DOI] [Google Scholar]
2.Haldrup M, Miscov R, Mohamad N, et al. Treatment of intraventricular hemorrhage with external ventricular drainage and fibrinolysis: a comprehensive systematic review and meta-analysis of complications and outcome. World Neurosurg. 2023;174:183-196.e6. doi: 10.1016/j.wneu.2023.01.021 [DOI] [PubMed] [Google Scholar]
3.Hanley DF, Lane K, McBee N, et al. ; CLEAR III Investigators . Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017;389(10069):603-611. doi: 10.1016/S0140-6736(16)32410-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Carpenter AB, Lara-Reyna J, Hardigan T, Ladner T, Kellner C, Yaeger K. Use of emerging technologies to enhance the treatment paradigm for spontaneous intraventricular hemorrhage. Neurosurg Rev. 2022;45(1):317-328. doi: 10.1007/s10143-021-01616-z [DOI] [PubMed] [Google Scholar]
5.Rajjoub K, Hess RM, O’Connor TE, Khan A, Siddiqui AH, Levy EI. Drainage, irrigation, and fibrinolytic therapy (DRIFT) for adult intraventricular hemorrhage using IRRAflow self-irrigating catheter. Cureus. 2021;13(5):e15167. doi: 10.7759/cureus.15167 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.IRRAS . Active removal of intracerebral hematoma via active irrigation (ARCH). Accessed August 22, 2023. https://clinicaltrials.gov/study/NCT05118997
7.Association WM; World Medical Association . World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]
8.Haldrup M, Mohamad N, Rasmussen M, et al. Study protocol for ACTIVE study: safety and feasibility evaluation of external ventricular drainage with ACTIVE fluid exchange in intraventricular hemorrhage-a phase 2, multi-center, randomized controlled trial. Trials. 2022;23(1):1062. doi: 10.1186/s13063-022-07043-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Shukla AK, Jhaj R, Misra S, Ahmed SN, Nanda M, Chaudhary D. Agreement between WHO-UMC causality scale and the Naranjo algorithm for causality assessment of adverse drug reactions. J Family Med Prim Care. 2021;10(9):3303-3308. doi: 10.4103/jfmpc.jfmpc_831_21 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Kramer AH, Roberts DJ, Todd S, et al. Intraventricular thrombolysis in aneurysmal subarachnoid hemorrhage: a randomized controlled pilot trial. Neurocrit Care. 2013;19(1)(suppl 1):S9. doi: 10.1007/s12028-013-9895-1 [DOI] [PubMed] [Google Scholar]
11.Huttner HB, Kuramatsu JB. Current treatment concepts in intracerebral hemorrhage. Article in German. Med Klin Intensivmed Notfmed. 2017;112(8):695-702. doi: 10.1007/s00063-017-0361-2 [DOI] [PubMed] [Google Scholar]
12.Winkler KM, Woernle CM, Seule M, Held U, Bernays RL, Keller E. Antibiotic-impregnated versus silver-bearing external ventricular drainage catheters: preliminary results in a randomized controlled trial. Neurocrit Care. 2013;18(2):161-165. doi: 10.1007/s12028-013-9816-3 [DOI] [PubMed] [Google Scholar]
13.Park J, Choi YJ, Ohk B, Chang HH. Cerebrospinal fluid leak at percutaneous exit of ventricular catheter as a crucial risk factor for external ventricular drainage-related infection in adult neurosurgical patients. World Neurosurg. 2018;109:e398-e403. doi: 10.1016/j.wneu.2017.09.190 [DOI] [PubMed] [Google Scholar]
14.Nilsson A, Uvelius E, Cederberg D, Kronvall E. Silver-coated ventriculostomy catheters do not reduce rates of clinically diagnosed ventriculitis. World Neurosurg. 2018;117:e411-e416. doi: 10.1016/j.wneu.2018.06.045 [DOI] [PubMed] [Google Scholar]
15.Naff NJ. Intraventricular hemorrhage in adults. Curr Treat Options Neurol. 1999;1(3):173-178. doi: 10.1007/s11940-999-0001-0 [DOI] [PubMed] [Google Scholar]
16.Greenberg SM, Ziai WC, Cordonnier C, et al. ; American Heart Association/American Stroke Association . 2022 Guideline for the management of patients with spontaneous intracerebral hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke. 2022;53(7):e282-e361. doi: 10.1161/STR.0000000000000407 [DOI] [PubMed] [Google Scholar]
17.Carrera DA, Marsh LM, Roach JJ, et al. HummingFlow: novel single twist-drill access for ventricular drainage, irrigation, monitoring, and automated local drug delivery in subarachnoid hemorrhage. J Neurosurg. Published online March 31, 2023. doi: 10.3171/2023.2.JNS23295 [DOI] [PubMed] [Google Scholar]
18.Graeb DA, Robertson WD, Lapointe JS, Nugent RA, Harrison PB. Computed tomographic diagnosis of intraventricular hemorrhage: etiology and prognosis. Radiology. 1982;143(1):91-96. doi: 10.1148/radiology.143.1.6977795 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol and Statistical Analysis Plan

Click here for additional data file.^{(537.3KB, pdf)}

Supplement 2.

eAppendix 1. The IRRAflow System

eAppendix 2. Standard Operation Procedure (SOP), IRRAflow Treatment in the Active Study

eAppendix 3. SAEs With Possible Relation to Intervention and/or Catheter Treatment

eAppendix 4. Time-to-Catheter Occlusions

eAppendix 5. The Full DMC Safety Report and Interim Analysis

eAppendix 6. Root Cause Analysis of all SAEs in the Intervention and Control Group

eAppendix 7. Causality of Adverse Events

Click here for additional data file.^{(2MB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(13KB, pdf)}

[zoi231013r1] 1.Yamaguchi Y, Nakagawa K, Watanabe H, et al. Primary intraventricular hemorrhage. Article in Japanese. Jpn J Neurosurg. 2000;9(10):672-678. doi: 10.7887/jcns.9.672 [DOI] [Google Scholar]

[zoi231013r2] 2.Haldrup M, Miscov R, Mohamad N, et al. Treatment of intraventricular hemorrhage with external ventricular drainage and fibrinolysis: a comprehensive systematic review and meta-analysis of complications and outcome. World Neurosurg. 2023;174:183-196.e6. doi: 10.1016/j.wneu.2023.01.021 [DOI] [PubMed] [Google Scholar]

[zoi231013r3] 3.Hanley DF, Lane K, McBee N, et al. ; CLEAR III Investigators . Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017;389(10069):603-611. doi: 10.1016/S0140-6736(16)32410-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi231013r4] 4.Carpenter AB, Lara-Reyna J, Hardigan T, Ladner T, Kellner C, Yaeger K. Use of emerging technologies to enhance the treatment paradigm for spontaneous intraventricular hemorrhage. Neurosurg Rev. 2022;45(1):317-328. doi: 10.1007/s10143-021-01616-z [DOI] [PubMed] [Google Scholar]

[zoi231013r5] 5.Rajjoub K, Hess RM, O’Connor TE, Khan A, Siddiqui AH, Levy EI. Drainage, irrigation, and fibrinolytic therapy (DRIFT) for adult intraventricular hemorrhage using IRRAflow self-irrigating catheter. Cureus. 2021;13(5):e15167. doi: 10.7759/cureus.15167 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi231013r6] 6.IRRAS . Active removal of intracerebral hematoma via active irrigation (ARCH). Accessed August 22, 2023. https://clinicaltrials.gov/study/NCT05118997

[zoi231013r7] 7.Association WM; World Medical Association . World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]

[zoi231013r8] 8.Haldrup M, Mohamad N, Rasmussen M, et al. Study protocol for ACTIVE study: safety and feasibility evaluation of external ventricular drainage with ACTIVE fluid exchange in intraventricular hemorrhage-a phase 2, multi-center, randomized controlled trial. Trials. 2022;23(1):1062. doi: 10.1186/s13063-022-07043-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi231013r9] 9.Shukla AK, Jhaj R, Misra S, Ahmed SN, Nanda M, Chaudhary D. Agreement between WHO-UMC causality scale and the Naranjo algorithm for causality assessment of adverse drug reactions. J Family Med Prim Care. 2021;10(9):3303-3308. doi: 10.4103/jfmpc.jfmpc_831_21 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi231013r10] 10.Kramer AH, Roberts DJ, Todd S, et al. Intraventricular thrombolysis in aneurysmal subarachnoid hemorrhage: a randomized controlled pilot trial. Neurocrit Care. 2013;19(1)(suppl 1):S9. doi: 10.1007/s12028-013-9895-1 [DOI] [PubMed] [Google Scholar]

[zoi231013r11] 11.Huttner HB, Kuramatsu JB. Current treatment concepts in intracerebral hemorrhage. Article in German. Med Klin Intensivmed Notfmed. 2017;112(8):695-702. doi: 10.1007/s00063-017-0361-2 [DOI] [PubMed] [Google Scholar]

[zoi231013r12] 12.Winkler KM, Woernle CM, Seule M, Held U, Bernays RL, Keller E. Antibiotic-impregnated versus silver-bearing external ventricular drainage catheters: preliminary results in a randomized controlled trial. Neurocrit Care. 2013;18(2):161-165. doi: 10.1007/s12028-013-9816-3 [DOI] [PubMed] [Google Scholar]

[zoi231013r13] 13.Park J, Choi YJ, Ohk B, Chang HH. Cerebrospinal fluid leak at percutaneous exit of ventricular catheter as a crucial risk factor for external ventricular drainage-related infection in adult neurosurgical patients. World Neurosurg. 2018;109:e398-e403. doi: 10.1016/j.wneu.2017.09.190 [DOI] [PubMed] [Google Scholar]

[zoi231013r14] 14.Nilsson A, Uvelius E, Cederberg D, Kronvall E. Silver-coated ventriculostomy catheters do not reduce rates of clinically diagnosed ventriculitis. World Neurosurg. 2018;117:e411-e416. doi: 10.1016/j.wneu.2018.06.045 [DOI] [PubMed] [Google Scholar]

[zoi231013r15] 15.Naff NJ. Intraventricular hemorrhage in adults. Curr Treat Options Neurol. 1999;1(3):173-178. doi: 10.1007/s11940-999-0001-0 [DOI] [PubMed] [Google Scholar]

[zoi231013r16] 16.Greenberg SM, Ziai WC, Cordonnier C, et al. ; American Heart Association/American Stroke Association . 2022 Guideline for the management of patients with spontaneous intracerebral hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke. 2022;53(7):e282-e361. doi: 10.1161/STR.0000000000000407 [DOI] [PubMed] [Google Scholar]

[zoi231013r17] 17.Carrera DA, Marsh LM, Roach JJ, et al. HummingFlow: novel single twist-drill access for ventricular drainage, irrigation, monitoring, and automated local drug delivery in subarachnoid hemorrhage. J Neurosurg. Published online March 31, 2023. doi: 10.3171/2023.2.JNS23295 [DOI] [PubMed] [Google Scholar]

[zoi231013r18] 18.Graeb DA, Robertson WD, Lapointe JS, Nugent RA, Harrison PB. Computed tomographic diagnosis of intraventricular hemorrhage: etiology and prognosis. Radiology. 1982;143(1):91-96. doi: 10.1148/radiology.143.1.6977795 [DOI] [PubMed] [Google Scholar]

PERMALINK

Intraventricular Lavage vs External Ventricular Drainage for Intraventricular Hemorrhage

Mette Haldrup, MD

Mads Rasmussen, MD, PhD

Niwar Mohamad, MD

Stig Dyrskog, MD, PhD

Line Thorup, MD

Nikola Mikic, MD

Joakim Wismann, MD

Mads Grønhøj, MD, PhD

Frantz Rom Poulsen, MD, PhD

Mojtaba Nazari, MSc

Naveed Ur Rehman, MSc, PhD

Claus Ziegler Simonsen, MD, PhD

Anders Rosendal Korshøj, MD, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Trial Design and Oversight

Randomization and Blinding

Participants

Interventions

Safety Outcomes

Figure 1. Flowchart of Participant Enrollment, Allocation, Follow-Up, and Analysis.

Efficacy Outcomes

Sample Size Calculation

Statistical Analysis

Results

Early Stopping

Baseline Characteristics

Table 1. Baseline Characteristics of Included Participants .

Safety Outcomes

Figure 2. Kaplan-Meier Curves of Overall Survival in the 2 Groups.

Table 2. Safety and Efficacy Outcomes.

Efficacy Outcomes

Table 3. eGOS and mRS Scores at 90 Days for the 2 Groups .

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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