Induced Hypertension for Treatment of Delayed Cerebral Ischaemia After Aneurysmal Subarachnoid Haemorrhage "HIMALAIA"

Terminated

Phase 3 Results N/A

Trial Description

The objective of this multi-centre, randomized controlled trial is to investigate the outcome after induced hypertension versus no induced hypertension in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH), and to assess whether induced hypertension results in improved cerebral blood flow (CBF) as measured by means of perfusion-CT.

Detailed Description

Background
Subarachnoid haemorrhage (SAH) from a ruptured cerebral aneurysm is a subset of stroke with a poor prognosis. Delayed cerebral ischemia (DCI) is a major complication after SAH in around 30% of SAH patients and increases case fatality 1.5 - 3 fold. One option to treat DCI is to use induced hypertension, alone or in combination with haemodilution and hypervolemia, so called Triple-H, but the efficacy of induced hypertension in reducing DCI is based on case series only, and not on a randomised clinical trial.
Objective
To investigate the outcome after induced hypertension versus no induced hypertension in patients with DCI after aneurysmal SAH.
Study design
A multi-centre, single blinded, randomized controlled trial.
Study population
Patients admitted to one of the participating centres after recent SAH with a treated aneurysm and DCI based on the onset of a new focal deficit and/or a decrease of the level of consciousness of at least 1 point of the Glasgow Coma Scale with exclusion of other causes of deterioration, will be randomized to either hypertension (n=120) or no hypertension (n=120).
Interventions
Patients in arm 1 will have their blood pressure raised in order to improve cerebral blood flow (CBF). In case of a low cardiac output, inotropics will be added. Induced hypertension will be continued for at least 48 hours when patients show some improvement within the first 24 hours. After 48 hours, the dose of vasopressor will be tapered daily, and resumed in case of clinical deterioration. In patients who do not show any improvement within 24 hours, induced hypertension will not be continued. In patients in arm 2 of the trial, hypertension will not be induced. Patients in both arms of the trial will be treated with oral nimodipine and normovolaemia without haemodilution. In some selected centres, an extra perfusion CT scan is performed 24-36 hours after instalment of the treatment. Measurement of CBF is performed in all participants with perfusion CT-scanning of the brain at the beginning of the study (as part of regular patient care), and after 24-36 hours.
Main outcome measurement
The modified Rankin scale at 3 months after the SAH, will be compared between patients who were randomized to induced hypertension and patients who were randomized to no induced hypertension.

Trial Stopped: As advised by the DSMB the study was stopped due to slow recruitment.

Conditions

Interventions

  • Induced hypertension Other
    Other Names: Hypertension.; Raised blood pressure.
    Intervention Desc: Blood pressure will be raised in order to improve cerebral blood flow (CBF). In case of a low cardiac output, inotropics will be added. Induced hypertension will be continued for at least 48 hours when patients show some improvement within the first 24 hours. After 48 hours, the dose of vasopressor will be tapered daily, and resumed in case of clinical deterioration. In patients who do not show any improvement within 24 hours, induced hypertension will not be continued.
    ARM 1: Kind: Experimental
    Label: Induced hypertension
    Description: Patients who are randomised to this arm will have their blood pressure raised with vasopressors and fluids. Blood pressure will be raised in order to improve cerebral blood flow (CBF). In case of a low cardiac output, inotropics will be added. Induced hypertension will be continued for at least 48 hours when patients show some improvement within the first 24 hours. After 48 hours, the dose of vasopressor will be tapered daily, and resumed in case of clinical deterioration. In patients who do not show any improvement within 24 hours, induced hypertension will not be continued.

Trial Design

  • Allocation: Randomized
  • Masking: Single Blind (Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary The main outcome measurement will be the modified Rankin scale at 3 months after the SAH, compared between patients who were randomized to induced hypertension and patients who were randomized to no induced hypertension. assessed three months after the SAH Yes
Secondary Related to treatment failure: proportion of patients in the induced hypertension group in which induced hypertension did not give clinical improvement of symptoms of DCI within 24 hours 24 hours after start of induced hypertension No
Secondary Related to the functional condition: Case fatality 30 days after SAH 30 days per patient Yes
Secondary Related to the functional condition, activities of daily living (ADL), three months after the SAH assessed with the Barthel Index. assessed 3 months after the SAH No
Secondary Related to the functional condition: quality of life, three months after the SAH, estimated with the Stroke Specific Quality of Life Scale (SSQoL-12-NL). assessed 3 months after the SAH No
Secondary Related to the functional condition: anxiety and depression, three months after the SAH, assessed with the Hospital Anxiety and Depression Scale (HADS). assessed 3 months after the SAH No
Secondary Related to the functional condition: cognitive functioning, three months after the SAH, evaluated by the Cognitive Failures Questionnaire (CFQ). assessed 3 months after the SAH No
Secondary Related to adverse effects: complications related to insertion of a central venous catheter or intra-arterial catheter (including local haemorrhage and pneumothorax). during hospital admission, an average of 3 weeks Yes
Secondary Related to adverse effects: intracranial complications related to induced hypertension (such as exacerbation of cerebral oedema, hemorrhagic infarction and bleeding of an asymptomatic aneurysm). during admission, an average of 3 weeks Yes
Secondary Related to adverse effects± • Systemic complications related to induced hypertension (including cardiac rhythm disorders, low cardiac output state and cardiac ischemia). during admission, an average of 3 weeks Yes
Secondary In selected centres: Related to the influence on cerebral haemodynamics: the difference in CBF, CBV, TTP and MTT between the intervention and the control groups 24-36 hours after the start of the study (i.e. CTP-2) compared between scans made during admission at time of deterioration and 36 hours later. No
Secondary Related to the influence on cerebral haemodynamics: the difference in CBF, CBV, TTP and MTT between the perfusion CT-scan (at baseline, the moment of deterioration, i.e. CTP-1) and the second perfusion CT-scan (CTP-2) within the same patients. compared between scans made during admission at time of deterioration and 36 hours later. No
Secondary Direct medical costs of used health care resources and indirect, non-medical costs of lost productivity, will be compared between the two arms of the trial, twelve months after the SAH. assessed at 12 months after the SAH No

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