Diagnosis and Treatment of Late Neurological Ischemic Deficit in Patients Suffering From Subarachnoid Hemorrhage. (DINTESA-France)

Diagnosis and Treatment of Late Neurological Ischemic Deficit in Patients Suffering From Subarachnoid Hemorrhage

Recent studies state that patients affected by aneurysmal subarachnoid hemorrhage (aSAH) today survive longer because they are treated early. Unfortunately, patients often develop chronic disabling neurological deficits at a rate that is still unacceptable given the progress in the specific treatment of this pathology and the volume of systems of neurological monitoring available to date in Italy.

The main cause of unfavorable neurological outcome is delayed cerebral ischemia (DCI), often resulting from symptomatic vasospasm defined as delayed neurological ischemic deficit (DIND). The incidence of DIND is not defined and is difficult to diagnose early as there is no gold standard for identifying it, nor guidelines regarding the most effective treatment.

Given these gaps, the primary objective of this study is to describe the incidence of DIND in patients affected by aSAH, collecting information regarding the diagnostic imaging (neurological symptom on clinical examination or alteration on instrumental monitoring). Secondary objectives will be to evaluate the different therapeutic strategies adopted in the different participating centers and compare these strategies to mortality and short- and long-term functional neurological outcome. Furthermore, as there are no data in the literature, the Investigators want to describe the indications, usefulness and intensity of treatment in the aSAH patient in case of monitoring of parenchymal intracranial pressure.

Same as italian study, with their consent. For France addition of medical imaging

Study Overview

• Status: Not yet recruiting
• Conditions: Delayed Ischemic Neurological Deficit; Aneurysmal Subarachnoid Haemorrhage

Detailed Description

Aneurysmal subarachnoid hemorrhage (aSAH) is a particular form of hemorrhagic stroke characterized by blood spillage into the intracranial subarachnoid spaces due to the rupture of an aneurysm of a large cerebral arterial vessel of the circle of Willis. It can cause sudden and intense symptoms, such as violent headache, nausea, vomiting, neck stiffness and sensitivity to light, but also loss of consciousness, cardiac arrest and death.

The pre-hospital mortality rate in the literature remains high (22-26%), even if it is lower than in previous decades. However, the number of patients discharged from hospital with permanent disabilities is increasing, especially those of working age (the average age at onset of symptoms is 55 years), contributing significantly to public health costs.

The incidence of aSAH worldwide is approximately 6.1 cases per 100,000 people per year, but there are national differences. In Italy, for example, it is 11.2 (10.5-12.4) cases per 100,000 inhabitants per year.

At the onset of symptoms, once the aneurysmal origin of the cerebral hemorrhage has been confirmed through radiological examinations, it is essential to promptly ensure treatment of the ruptured aneurysm. Early repair of the ruptured aneurysm is recommended within 24 to 72 hours, via endovascular coiling or neurosurgical clipping. This allows to prevent any rebleeding and reduce the risk of cerebral vasospasm, as it reduces the amount of blood distributed in the subarachnoid space. The latter, in fact, represents the main inflammatory stimulus on large cerebral arteries, favoring the vasoconstriction reaction which manifests itself angiographically and/or ultrasonographically in 70% of cases. Cerebral vasospasm is very often clinically silent, since the reduction of the vascular lumen is not sufficient to generate the conditions of discrepancy between the arterial flow of the perfused brain parenchyma and its metabolic demand.

However, in 20-30% of cases a neurological deterioration also occurs, called delayed ischemic neurological deficit or DIND (Delayed Ischemic Neurological Deficit), defined as a focal neurological deterioration (appearance of at least one of the symptoms including hemiparesis, aphasia, hemianopsia or neglect) or global (sudden neurological worsening leading to at least a two-point decrease in the Glasgow Scale or the appearance of anisocoria or pupillary reactivity). DIND is not always immediately evident after securing the aneurysm, and it is necessary to exclude other causes of neurological deterioration, such as hydrocephalus, convulsions, rebleeding and hyponatremia in order to confirm it.

Identifying DIND early is essential to prevent the formation of a true ischemic core in the area affected by vasospasm, i.e. late cerebral ischemia, DCI (Delayed Cerebral Ischemia), defined by radiological criteria: evidence of cerebral infarction on brain computed tomography (CT) scan or brain magnetic resonance imaging (MRI) within 6 weeks of onset of aSAH complicated by vasospasm.

DIND, in fact, is the main preventable cause of unfavorable neurological-functional outcome and DCI in patients with SAH.

Regarding the identification of DIND, it is certainly crucial to carry out a systematic clinical neurological examination on the awake patient. In comatose patients, or in those in whom it is not possible to carry out a sedation window, multimodal instrumental monitoring is certainly helpful. In fact, if the patient is sedated or cannot be awakened, the information deriving from the inspection (pupillary reactivity and isocoria) should be integrated with continuous electroencephalographic monitoring (cEEG) and/or transcranial color Doppler ultrasound (TCD)ccc. Instrumental monitoring is, in fact, fundamental in those patients in whom a suspension of sedation generates an increase in intracranial pressure and consequent reduction in cerebral oxygenation, making clinical neurological evaluation impossible.

The alterations associated with DIND most commonly described during quantitative EEG (qEEG) are decreased alpha/delta ratio and reduced alpha variability. EEG changes may precede clinical deterioration by several hours, and allow for a differential diagnosis with nonconvulsive status epilepticus. Instrumental vasospasm is defined as an average blood flow velocity > 120 cm/sec detected ultrasonographically via TCD. Instead, clinical vasospasm, i.e. DIND that requires treatment, is diagnosed in case of speed of at least 200 cm/sec, or increased by 50 cm/sec in the last 24 hours, or even if the Lindeegard index is greater of 3 (defined as the ratio of flow velocities between the middle cerebral artery and the ipsilateral distal internal carotid artery, MCA/ICA).

Regarding second-level tests, in sedated or unconscious patients, it is also reasonable to perform screening through repeated imaging tests, such as computed perfusion tomography (CTP), cerebral angiotomography (CTA) and intracranial vessel angiography ( TSA). The use of CTP is increasingly widespread: it detects imminent ischemia by decreasing cerebral perfusion, thus identifying salvageable brain tissue (ischemic penumbra) before irreversible brain damage occurs. This approach, however, involves transporting the critically ill patient to radiology and administering a contrast medium, adding considerable risks. It should also be underlined that, in case of clinical or instrumental suspicion of DIND, in some centers second level tests are used less and less, intervening early with therapy to resolve it.

As with the diagnostic procedure, the therapeutic strategies implemented are also very different from each other, and none has been proven to be more effective than another. They can be more or less invasive, and the main ones are:

hemodynamic therapy, i.e. permissive hypertension, in which systemic blood pressure is increased to increase cerebral perfusion and ensure that an adequate quantity of blood supplies the brain parenchyma downstream of vasospasm; local intra-arterial pharmacological therapy, in bolus or continuous infusion, with a vasodilator drug (calcium antagonist/milrinone); mechanical therapy, whereby action is taken on the muscular wall of the vessel in question by carrying out angioplasty with a transluminal balloon.

Innovative techniques, such as stent retriever angioplasty, which also allows the application of intra-arterial calcium channel antagonists, can be an additional tool in selected patients with refractory vasospasm.

To date, there is no gold standard for diagnosing DIND, evidence on which patients are at greatest risk of developing it and recommendations regarding the most effective treatment to resolve it. Management is delegated to the multidisciplinary department team of each centre.

In conclusion, also in light of the recent guidelines on aSAH, it is urgent to establish how to prevent DCI, identifying the onset of DIND early, both clinically and instrumentally.

With this study the Investoigators aim to determine the incidence of DIND in patients with aSAH, to evaluate the effectiveness of different treatments and to compare the different diagnostic/therapeutic strategies in the participating centers, investigating the impact of DIND on short-term and long-term neurological-functional outcomes.

Same as italian study, with their consent. For France addition of medical imaging

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

• Study Contact: Name: Edoardo Di Paolo, MD; Phone Number: 0145658902; Email: edoardo.di_paolo@ghu-paris.fr
• Study Contact Backup: Name: Aurélien Mazeraud, MD; Phone Number: 0145658902; Email: a.mazeraud@ghu-paris.fr

Study Locations

• France
  • Paris, France, 75014
    • GHU Paris
    • Contact: Edoardo Di Paolo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Patients with primary diagnosis of subarachnoid hemorrhage due to rupture of a cerebral artery aneurysm confirmed by cerebral angiotomography or angiography of the intracranial vessels, with the need for admission to the Intensive Care Unit in France

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Primary diagnosis of subarachnoid hemorrhage due to rupture of a cerebral artery aneurysm, confirmed by cerebral CT angiography or intracranial angiography, requiring admission to an intensive care unit (ICU)
3. No objection to the use of data in accordance with regulations.

Exclusion Criteria:

• Age < 18 years
• Primary diagnosis of subarachnoid hemorrhage sine materia, i.e. post-traumatic or caused by arteriovenous malformation or bleeding from a brain tumor.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Aneurysmal subarachnoid hemorrhage group; Patients diagnosed with aneurysmal subarachnoid hemorrhage.
Delayed Ischemic Neurologic Deficit Group; Patients diagnosed with aneurysmal subarachnoid hemorrhage who develop delayed ischemic neurologic deficit

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DIND incidence	Calculation of the incidence of DIND in patients affected by aSAH. The presence of a suspicious alteration for DIND at the neurological clinical examination (if the patient is awake or if a sedation window is possible) or instrumental (if the clinical examination is not possible), confirmed or not by radiological examinations, will be recorded. Conditions that are considered diagnostic are discribed in the protocole for : patient who is awake or can be awakened to undergo a clinical neurological examination; in comatose or unresponsive patients	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imaging application	Describe and analyze the variability of the diagnostic methods (clinical and instrumental examination) applied by each center to identify DIND in patients with aSAH and how this is treated.	12 months
Neurological-functional outcome assessment	Evaluate the impact of DIND and its treatment on short-term and long-term neurological-functional outcomes by neurological-functional outcome (GOSE, Glasgow Outcome Scale Extended) at 6 months and 12 months after the acute event. From GOSE=1 (death) to GOSE=8 (good recovery).	12 months
Neurological-functional outcome assessment	Evaluate the impact of DIND and its treatment on short-term and long-term neurological-functional outcomes by neurological-functional outcome (mRS, modified Rankin Scale) at 6 months and 12 months after the acute event. From mRS=0 (no symptoms) to mRS=5 (severe disability).	12 months
Neurological-functional outcome assessment	Evaluate the impact of DIND and its treatment on short-term and long-term neurological-functional outcomes by mortality at 6 months and 12 months after the acute event. Assess mortality and neurological-functional outcomes (GOSE - Glasgow Outcome Scale Extended, and mRS - modified Rankin Scale) at 6 and 12 months after the acute event	12 months
Invasive monitoring of intracranial pressure	To evaluate the usefulness of invasive monitoring of intracranial pressure (ICP) in guiding the treatment of patients with SAH by comparing the variation of intracranial pressure in patients who have ICP monitoring with the intensity of the treatment applied (TIL, Therapy Intensity Level). Compare changes in intracranial pressure (ICP) in patients undergoing ICP monitoring with the intensity of the treatment received (TIL - Therapy Intensity Level)	12 months

Collaborators and Investigators

• Sponsor: Société Française d'Anesthésie et de Réanimation
• Collaborators: Fondazione IRCCS San Gerardo dei Tintori
• Investigators: Study Chair: Aurélien Mazeraud, MD, Société Française d'Anesthésie et de Réanimation

Study record dates

Study Major Dates

• Study Start (Estimated): June 15, 2026
• Primary Completion (Estimated): June 15, 2028
• Study Completion (Estimated): June 15, 2028

Study Registration Dates

• First Submitted: May 28, 2026
• First Submitted That Met QC Criteria: June 3, 2026
• First Posted (Actual): June 8, 2026

Study Record Updates

• Last Update Posted (Actual): June 8, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: 2026-01 (Hitit University Non-Interventional Research Ethics Committee)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No