EARLYdrain - Outcome After Early Lumbar CSF-drainage in Aneurysmal SAH
EARLYdrain - Outcome After Early Lumbar CSF-drainage in Aneurysmal SAH
The intention of the study is to investigate whether drainage of cerebral spinal fluid via a
 lumbar route ("Tuohy-drain") will improve outcome after intracranial aneurysmal subarachnoid
 hemorrhage (SAH).
1. Introduction

 Patients suffering from aneurysmal subarachnoid hemorrhage (SAH) are predominantly
 threatened by two distinct medical problems. Firstly, they may experience a second - and
 often more severe - hemorrhage, and secondly, they may suffer a constringence reaction
 of the vessels supplying the brain with blood, called vasospasm.

 The first problem is resolved by rapid cerebrovascular imaging and subsequent treatment
 of the ruptured aneurysm, thus preventing recurrent hemorrhage. Aneurysm treatment may
 be performed either via craniotomy and surgical clipping of the aneurysm or with
 endovascular techniques by occluding the aneurysm with small platinum coils.

 The vasospasm - the second problem - is more difficult to handle. A hypothesis is that
 the development of vasospasm is related to the amount of blood in the basal cisterns.
 Therefore, a possible strategy tries to remove this blood as much as possible. Excess
 removal of cerebral spinal fluid (CSF) via an external ventricular drain fails in
 preventing vasospasm and may lead to a higher incidence of posthemorrhagic shunt
 dependency. Reason is that after aneurysmal SAH, the blood is packed more densely in the
 basal cisterns and therefore only CSF, being more lightweight, is drained from the
 ventricles. As an alternative approach, application of a lumbar drain is proposed to
 address clotting of the blood in the basal cisterns. Three retrospective studies in
 patients after aneurysmal SAH, the newest being available only as abstract, were able to
 establish the safety of this approach (Klimo et al, Kwon et al, Tizi et al (abstract
 DGNC 2009)). One of the fully published studies addressed vasospasm prophylaxis after
 surgical clipping, while the other was performed in patients after endovascular coiling.
 All studies led to a markedly diminished incidence of angiographic vasospasm. Therefore,
 a prospective study addressing the efficacy of this novel therapeutic approach is
 warranted.

 The focus of the EARLYDRAIN study is to examine the efficacy of application of lumbar
 drainage in patients with acute subarachnoidal hemorrhage from a cerebral aneurysm.
 Hypothesis is that early application of lumbar drainage after aneurysmal SAH leads to a
 diminished incidence of cerebral vasospasm, as assessed by digital subtraction
 angiography, and an improved outcome, measured by the modified Rankin score, at six
 months.

 2. Study outline

 Patients suffering from aneurysmal SAH are treated according to international standards.
 Aneurysm treatment is at the discretion of the neurovascular team taking care for a
 patient and not specified by the study protocol. All medical treatment is performed
 according to local guidelines and standard operating procedures.

 Any patient meeting the inclusion criteria and not violating the exclusion criteria may
 participate in the EARLYDRAIN study and be randomized to either receive a lumbar drain
 or not, thus defining the two distinct groups LD and NoLD. To prevent premature rupture
 of the aneurysm due to accidental drainage, randomization to the study and eventual
 placement of a lumbar drain takes place after securing the aneurysm by the preferred
 method of choice. Any patient in the LD group receives a lumbar drain during anesthesia
 required for aneurysm treatment. This is to be performed before anticoagulation or
 anti-platelet therapy is initiated, which sometimes is warranted after endovascular
 coiling. A post-procedural CCT scan of the brain is performed within to 24 hours of
 aneurysm treatment. In case of any neurological worsening after the procedure it is
 strongly recommended to perform the follow-up CCT scan as soon as possible.

 In patients in the LD group, CSF drainage is started via LD slowly and steadily at a
 rate of approximately 5 ml per hour after the post-interventional CCT. This leads to a
 planned daily CSF drainage of about 120 ml per day via lumbar route. Patients in both
 groups may receive additional CSF drainage via a ventricular device as required. The
 amount of CSF drained via ventricular route is according to clinical requirement and not
 specified.

 To facilitate accuracy of drainage, regular drainage control every other hour and
 stopping in case of excess drainage is strongly recommended by the principal
 investigators. In case of neurological decline suspiciously related to the lumbar
 drainage, the drain is closed immediately and may be gradually restarted after 12 to 24
 hours, after performing a CCT scan.

 If the post-procedural CCT or any other follow-up CCT scan shows absent basal cisterns
 or any signs of threatening herniation, lumbar CSF diversion in the LD group shall not
 be performed. It may still be feasible to carefully drain CSF via the lumbar route may
 (Tuettenberg et al), but this is at the discretion of the local investigator and not
 recommended.

 In patients requiring sedation and mechanical ventilation, either due to neurological
 impairment or otherwise, intracranial pressure monitoring is mandatory. This may be
 performed according to local policy either with parenchymal or ventricular devices. If
 the intracranial pressure exceeds 20 mmHg, further CSF drainage via lumbar route shall
 be interrupted until the ICP is below 20 mmHg again. Careful CSF drainage via the lumbar
 route may be still feasible in case of high intracranial pressure (Tuettenberg et al),
 but is at the discretion of the local investigator.

 Further neuromonitoring with TCD, EEG, brain tissue oxygenation, jugular bulb oxymetry,
 regional cerebral blood flow, microdialysis or other devices is at the discretion of the
 center and according to its local guidelines. As far as possible, this data should be
 saved electronically for post-hoc analysis.

 A CCT scan as well as conventional digital subtraction angiography, CT angiography or MR
 angiography for assessment of vasospasm in the larger vessels is routinely performed on
 day 7 to 10 after the initial hemorrhage, regardless of the patient condition. In case
 of clinical suspicion of vasospasm, angiography may be performed at any time. If it is
 performed earlier and the patient shows no clinical deterioration thereafter, the
 angiography on day 7 to 10 is omitted.

 After cerebrovascular imaging on day 7 to 10, or day 8 in case of an earlier
 angiography, the lumbar drainage of CSF is stopped in the LD group. It may be pursued on
 a clinical base, as required.

 Amount and duration of CSF drainage Patients randomized to the lumbar drainage group
 shall receive a daily drainage of 120 ml CSF, or 5 ml per hour for seven days. If higher
 amounts of CSF need to be drained on clinical grounds as in patients with hydrocephalus,
 this is preferably performed via external ventricular drain.

 The drain is planned to remain in place until the control angiography on day 7 to 10
 after the initial hemorrhage. The local investigator may decide to remove the drain
 earlier in patients fully mobilized without clinical necessity of CSF drainage. However,
 consecutive drainage should not be less than four days to achieve a valid study result.
 Lumbar CSF drainage may be prolonged beyond the control angiography on clinical
 requirement. The amount of CSF drainage may then be adjusted to clinical needs and bears
 no further restriction.

 Patients randomized to the control group should not receive a lumbar drain before the
 planned control angiography to be performed on day 7 to 10 after SAH. If the patient
 develops hydrocephalus, and no EVD was placed initially for CSF drainage, a lumbar drain
 may be installed at the discretion of the local investigator. These patients are
 analyzed in the intention-to-treat analysis, but are not suitable for per-protocol
 analysis.

 3. Consent to the study

 Consent for study inclusion is sought after explanation and agreement to a specific
 aneurysm treatment. Thus, patients capable of consenting to the aneurysm treatment get
 the study details explained themselves and may or may not agree to participate. If a
 patient is incapable for consenting to the proposed treatment, the legal representative
 should be informed on the conditions of treatment choices and afterwards, on the details
 of the EARLYDRAIN study. A patient may be randomized if the legal representative gives
 informed consent to the study, based on the presumed will of the patient. If neither the
 patient is capable of giving informed consent nor a legal representative is available in
 due time, an independent physician not involved in the patient's treatment nor in the
 trial may be asked for study approval. In these cases of deferred consent, a legal
 representative needs to be established as soon as possible, according to German law. As
 soon as a legal representative is available and/or the patient is capable again to
 consent to the study, he or she must be asked to give informed consent. If the patient
 or his/her legal representative refuses consent after inclusion by advice of an
 independent physician, no further study participation of the patient is possible. In
 this case, however, the patient or his/her legal representative are asked to give
 consent for evaluation of already acquired data.

 4. Safety of lumbar drains after aneurysmal SAH

 In all three retrospective studies, mortality was lower in the lumbar drainage group.
 None of the retrospective studies mentions procedural related complications for the
 lumbar drains (Klimo et al, Kwon et al, Tizi et al (abstract at the DGNC 2009)). In
 patients with increased intracranial pressure, careful lumbar drainage of CSF may be a
 possible treatment even in case of compressed basal cisterns (Tuettenberg et al). To
 date, there is no data available indicating an increased risk of lumbar drainage in a
 controlled neurointensive care environment.

 5. Insurance coverage

 As the EARLYDRAIN study compares two standard procedures of CSF drainage after subarachnoid
 hemorrhage used in clinical routine, no additional patient insurance is necessary to perform
 the study. German laws §§ 40 to 42 Arzneimittelgesetz or §§ 20 to 23 Medizinproduktegesetz
 are not applicable. Any hypothetical adverse events of either treatment are covered by the
 regular treatment contracts which do include clinical research.
Inclusion Criteria:

 -  Age of 18 years or older

 -  First aneurysmal SAH

 -  Pre-morbid modified Rankin Scale score 0 or 1

 -  Aneurysm treatment performed in the first 48 hours after the initial hemorrhage.

 -  Informed consent by the patient or his/her legal representative. In case neither the
 patient is capable of giving informed consent nor a legal representative is available,
 informed consent can be given by an independent physician neither involved in the
 patient´s treatment nor the trial (for specification see below)

 Exclusion Criteria:

 -  Subarachnoid hemorrhage of other than aneurysmal origin

 -  No hemorrhage visible on initial CCT scan (Fisher Grade I)

 -  Pregnancy

 -  Concurrent participation in another interventional trial (participation in an
 observational trial is allowed)

 -  Life expectancy less than 1 year for other reasons than the actual SAH

 -  Other concomitant severe disease that would confound with treatment

 -  Other clear contraindication for treatment