EARLYDRAIN
Effectiveness of Lumbar Cerebrospinal Fluid Drain Among Patients With Aneurysmal Subarachnoid Hemorrhage
Year of Publication: 2023
Authors: Stefan Wolf, Dorothee Mielke, Christoph Barner, ..., for the EARLYDRAIN Study Group
Journal: JAMA Neurology
Citation: JAMA Neurol. 2023;80(8):833-842
PDF: https://jamanetwork.com/journals/jamaneu...article/2806583
PDF: Clinical Question
Does prophylactic lumbar cerebrospinal fluid drainage improve clinical outcomes measured by the modified Rankin Scale score among patients with aneurysmal subarachnoid hemorrhage?
Study Overview
Objective
To determine the effectiveness of early lumbar cerebrospinal fluid drainage added to standard of care in patients after aneurysmal subarachnoid hemorrhage
Study Summary
- Lumbar drainage reduced unfavorable neurological outcome at 6 months from 44.8% (standard of care) to 32.6% (RR 0.73, P=0.04)
- Patients treated with lumbar drain had fewer secondary infarctions at discharge (28.5% vs 39.9%, P=0.04)
- Number needed to treat was 8.3 to prevent one unfavorable outcome
Intervention
Lumbar cerebrospinal fluid drainage at 5 mL per hour started within 72 hours of SAH and continued for up to 8 days, in addition to standard of care
Patients per Arm
Lumbar drain n=144, Standard of care n=143
Bottom Line
In this pragmatic multicenter randomized trial of 287 patients with aneurysmal subarachnoid hemorrhage of all clinical grades, prophylactic lumbar drainage at 5 mL per hour for up to 8 days lessened the burden of secondary infarction and decreased the rate of unfavorable outcome at 6 months (32.6% vs 44.8%, RR 0.73, P=0.04). The number needed to treat was 8.3.
Major Points
- Pragmatic, multicenter, open-label RCT with blinded endpoint evaluation at 19 centers in Germany, Switzerland, and Canada
- Included 287 patients with aneurysmal SAH of all clinical grades (Hunt-Hess 1-5, WFNS 1-5)
- Lumbar drainage started at median day 2 after SAH at 5 mL/hour for up to 8 days
- Primary outcome (mRS 3-6 at 6 months) significantly reduced: 32.6% lumbar drain vs 44.8% standard care (RR 0.73, 95% CI 0.51-0.98, P=0.04)
- Secondary infarctions at discharge significantly reduced: 28.5% vs 39.9% (RR 0.71, 95% CI 0.49-0.99, P=0.04)
- No significant difference in vasospasm rates by clinical assessment, TCD, or angiography
- Patients in lumbar drain group had significantly lower intracranial pressure
- No difference in mortality at 6 months (13.2% vs 17.5%, NS)
- Consistent benefit across prespecified subgroups
- Per-protocol and as-treated sensitivity analyses confirmed findings
- Lumbar drainage more efficient at removing blood from basal cisterns due to gravity effect
Design
Study Type: Pragmatic, multicenter, parallel-group, open-label randomized clinical trial with blinded end point evaluation
Randomization: 1
Blinding: Open-label for acute care providers, but blinded outcome assessment at 6 months by masked assessors; radiologists evaluating scans for secondary infarctions also blinded to treatment groups
Enrollment Period: January 31, 2011 to January 24, 2016
Follow-up Duration: 6 months after hemorrhage
Centers: 19
Countries: Germany, Switzerland, Canada
Sample Size: 287
Analysis: Intention-to-treat analysis as primary. Logistic regression for primary and secondary endpoints with transformation of odds ratios to risk ratios. Mixed models for repeated measurements. Per-protocol and as-treated sensitivity analyses performed. Statistical analysis with R version 4.1.0
Inclusion Criteria
- Age ≥18 years
- Acute aneurysmal subarachnoid hemorrhage diagnosed by computed tomography
- Confirmation of intracranial aneurysm by CT angiography or digital subtraction angiography
- Aneurysm treatment with clipping or coiling performed within 48 hours after subarachnoid hemorrhage
- All clinical grades (Hunt-Hess 1-5, WFNS 1-5) were included
Exclusion Criteria
- Contraindications for placement of lumbar drain
- Absent or compressed basal cisterns on admission CT
- Presence of therapeutic anticoagulation
- Pregnancy
- Participation in another interventional trial
- Reduced life expectancy
- Hemorrhage of other than aneurysmal origin
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| n | 143 | 144 |
| Median age years | 56 (48-65) | 54 (48-63) |
| Female | 99 (69.2%) | 98 (68.1%) |
| Hunt-Hess grade 1 | 25 (17.5%) | 29 (20.1%) |
| Hunt-Hess grade 2 | 28 (19.6%) | 41 (28.5%) |
| Hunt-Hess grade 3 | 34 (23.8%) | 25 (17.4%) |
| Hunt-Hess grade 4 | 24 (16.8%) | 20 (13.9%) |
| Hunt-Hess grade 5 | 32 (22.4%) | 29 (20.1%) |
| WFNS grade 1 | 42 (29.4%) | 53 (36.8%) |
| WFNS grade 5 | 55 (38.5%) | 48 (33.3%) |
| Modified Fisher grade 4 | 79 (55.2%) | 85 (59%) |
| Intracerebral hemorrhage | 50 (35%) | 56 (38.9%) |
| Intraventricular hemorrhage | 85 (59.4%) | 90 (62.5%) |
| Anterior circulation aneurysm | 123 (86%) | 120 (83.3%) |
| Aneurysm coiling | 71 (treated patients) | 76 (treated patients) |
| External ventricular drain | 110 (76.9%) | 102 (70.8%) |
| Median daily lumbar drainage first 8 days | 108 (92-118) mL |
Arms
| Field | Control | Lumbar drain |
|---|---|---|
| Intervention | Standard acute neurosurgical and neurocritical care for aneurysmal SAH including aneurysm treatment (clipping or coiling), nimodipine, and fluid management. External ventricular drainage at discretion of local team. | Standard of care plus lumbar cerebrospinal fluid drain placed after aneurysm treatment. Lumbar CSF diversion started after postprocedural CT confirmed safety. Rate of 5 mL per hour recommended for first 8 days. Protocol-compliant treatment required at least 4 days, resulting in minimum 480 mL lumbar CSF drainage. ICP monitoring performed with zeroing of both ventricular and lumbar drains at level of external acoustic channel. |
| Duration | Acute care phase with 6-month follow-up | Drainage started within 72 hours of SAH (median day 2) and continued up to 8 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Rate of unfavorable neurological outcome at 6 months after subarachnoid hemorrhage measured with modified Rankin Scale (mRS). mRS dichotomized to 0-2 (good outcome) or 3-6 (unfavorable outcome including death). Score obtained by investigator not involved in acute care and blinded to clinical course via telephone interview or personal visit. | Primary | 64/143 (44.8%, 95% CI not specified) | 47/144 (32.6%, 95% CI not specified) | 12.12% | P=0.04 |
| Secondary infarctions at discharge - not present in postprocedural CT, diagnosed on last cerebral imaging before discharge (CT or MRI), radiologists blinded to treatment groups | Secondary | 57/143 (39.9%) | 41/144 (28.5%) | RR 0.71 (95% CI 0.49-0.99) | P=0.04 |
| Mortality at 6 months | Secondary | 25/143 (17.5%) | 19/144 (13.2%) | RR 0.75 (95% CI 0.42-1.28) | P=0.31 |
| Clinically suspected vasospasm | Secondary | 48/143 (33.6%) | 41/144 (28.5%) | RR 0.85 (95% CI 0.58-1.18) | P=0.35 |
| Transcranial Doppler vasospasm (threshold 160 cm/s) | Secondary | 31/125 (24.8%) | 36/134 (26.9%) | RR 1.08 (95% CI 0.70-1.58) | P=0.70 |
| Angiographic vasospasm | Secondary | 48/109 (44.0%) | 52/113 (46.0%) | RR 1.04 (95% CI 0.76-1.34) | P=0.77 |
| Glasgow Outcome Scale-Extended grade 1-4 at 6 months | Secondary | 54/143 (37.8%) | 38/144 (26.4%) | RR 0.70 (95% CI 0.47-0.98) | P=0.04 |
| Barthel Index ≤80 at 6 months (among survivors) | Secondary | 35/116 (30.2%) | 20/125 (16%) | RR 0.53 (95% CI 0.30-0.86) | P=0.01 |
| Permanent ventriculoperitoneal shunt at 6 months | Secondary | 42/143 (29.4%) | 41/144 (28.5%) | RR 0.97 (95% CI 0.66-1.36) | P=0.87 |
| mRS score 3-6 at discharge | Secondary | 101/143 (70.6%) | 88/144 (61.1%) | RR 0.87 (95% CI 0.69-1.02) | P=0.09 |
| Glasgow Outcome Scale-Extended grade 1-4 at discharge | Secondary | 90/143 (62.9%) | 81/144 (56.2%) | RR 0.89 (95% CI 0.71-1.07) | P=0.25 |
| Barthel Index ≤80 at discharge (among survivors) | Secondary | 71/121 (58.7%) | 73/129 (56.6%) | RR 0.96 (95% CI 0.75-1.16) | P=0.74 |
| Suspected infection of any cause | Adverse | 52/143 (36.4%) | 56/144 (38.9%) | RR 1.07 (95% CI 0.78-1.39) | P=0.66 |
| VP shunt during acute care | Adverse | 34/143 (23.8%) | 34/144 (23.6%) | RR 0.99 (95% CI 0.64-1.46) | P=0.97 |
| Increasing ICP gradient requiring drainage cessation | Adverse | 1 patient | |||
| Local skin infection at drain entrance | Adverse | 1 patient | |||
| Lumbar drain torn off requiring surgical removal | Adverse | 1 patient | |||
| Mortality at discharge | Adverse | 22/143 (15.4%) | 15/144 (10.4%) | RR 0.68 (95% CI 0.35-1.23) | P=0.21 |
Subgroup Analysis
Effect of lumbar drains on primary outcome was consistent across all prespecified subgroups including age (≤55 vs >55 years), Hunt-Hess grade (1-2 vs 3-5), sex, WFNS grade (1-3 vs 4-5), modified Fisher grade (1-3 vs 4), presence/absence of intracerebral or intraventricular hemorrhage, aneurysm location (anterior vs posterior circulation), treatment modality (clipping vs coiling), presence/absence of external ventricular drain, and center size. No significant interaction detected.
Criticisms
- Open-label design for acute care providers may introduce bias, though mitigated by blinded outcome assessment
- Significant crossover: 35 of 144 (24%) lumbar drain patients did not receive protocol-compliant treatment; 2 of 143 (1.4%) standard care patients received high-volume lumbar drainage
- Unable to secure sufficient funding for timely completion, prohibiting hiring of dedicated personnel
- No data collected on preexisting hypertension and other premorbid prognostic factors
- No detailed information on thickness of clots or amount of intraparenchymal/intraventricular blood on initial CT
- Did not record medical complications during clinical course
- Did not investigate additional application of clot thrombolysis or irrigation of subarachnoid space
- Unable to evaluate benefit of higher drainage rates than 5 mL/hour
- More than half of patients recruited from 2 centers, though investigators believe results are generalizable
- Baseline imbalances: higher proportion of WFNS grades 1-2 in lumbar drain group; less intracerebral and intraventricular hemorrhages in standard care group
- No adjustment for multiple testing on secondary endpoints - exploratory analyses only
- Secondary infarction detection mainly by CT, which is less sensitive than MRI
- Did not use current composite definition for delayed cerebral ischemia
Funding
Partially funded by the Center for Stroke Research (covering case report forms, ethics approval, randomization server, travel costs <€10,000). Additional costs covered by nonrestricted third-party funds to Charité University Medicine from Orsan Medical Systems (<€20,000). No case recruitment fee provided.
Based on: EARLYDRAIN (JAMA Neurology, 2023)
Authors: Stefan Wolf, Dorothee Mielke, Christoph Barner, ..., for the EARLYDRAIN Study Group
Citation: JAMA Neurol. 2023;80(8):833-842
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