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

Primary Purpose

Cerebral Ischemia, Subarachnoid Hemorrhage

Status

Terminated

Phase

Phase 3

Locations

Netherlands

Study Type

Interventional

Intervention

Induced hypertension

About this trial

This is an interventional treatment trial for Cerebral Ischemia focused on measuring subarachnoid hemorrhage, ischemia, vasospasm, CT, perfusion, induced hypertension, delayed cerebral ischemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria for eligibility

Admission to one of the participating study centres.
Age 18 years or over.
SAH with an aneurysmatic bleeding pattern.

Exclusion criteria for eligibility

Evidence of DCI after the SAH, defined as any decrease in the level of consciousness or the development of new focal neurological deficits after the onset of the SAH that is not due to increasing hydrocephalus, rebleeding of the aneurysm, epileptic seizure, septic- or metabolic encephalopathy, unless symptoms of DCI started within 3 hours.
Co-existing severe head injury.
Perimesencephalic haemorrhage (perimesencephalic bleeding pattern and no aneurysm on CT-angiography).
A history of a ventricular cardiac rhythm disorder, necessitating medical treatment.
A history of a left ventricular heart failure, necessitating medical treatment.
Likely transfer to another hospital, not participating in the trial, soon after treatment for the aneurysm.
Moribund.
Pregnancy.
And furthermore, in selected centres where the sub study with CT perfusion will be performed:
Known allergy for CT-contrast agents.
Renal failure, defined as a serum creatinine > 150 µmol/l, because of the risk of contrast nephropathy.
Diabetes mellitus.

Inclusion criteria for trial participation

Informed consent to participate in the proposed trial when DCI will develop.
DCI based on a decrease of at least one point on the Glasgow Coma Scale sum score unless the decrease doesn't reflect DCI as evaluated by the treating physician, and/or the development of new focal neurological deficits, diagnosed by a neurologist, neurosurgeon or intensivist.

Exclusion criteria for trial participation:

Another cause for neurological deterioration including.
A symptomatic aneurysm not yet treated by coiling or clipping.
Severe hypertension, defined as a spontaneous MAP of 120 mmHg or more at the moment of evaluation for trial participation.
Any contraindication for induced hypertension (such as a cardiac complication necessitating medical treatment) as evaluated by the treating physician.
And furthermore, in selected centres where the sub study with CT perfusion will be performed:
No CTP scan at time of neurological deterioration.
More than 3 CTP scans since admission.

Sites / Locations

Academic Medical Centre Amsterdam
Universitair Medisch Centrum Utrecht

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

No intervention

Induced hypertension

Arm Description

No induced hypertension (reference group)

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Related to the functional condition: Case fatality 30 days after SAH

Related to the functional condition, activities of daily living (ADL), three months after the SAH assessed with the Barthel Index.

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).

Related to the functional condition: anxiety and depression, three months after the SAH, assessed with the Hospital Anxiety and Depression Scale (HADS).

Related to the functional condition: cognitive functioning, three months after the SAH, evaluated by the Cognitive Failures Questionnaire (CFQ).

Related to adverse effects: complications related to insertion of a central venous catheter or intra-arterial catheter (including local haemorrhage and pneumothorax).

Related to adverse effects: intracranial complications related to induced hypertension (such as exacerbation of cerebral oedema, hemorrhagic infarction and bleeding of an asymptomatic aneurysm).

Related to adverse effects± • Systemic complications related to induced hypertension (including cardiac rhythm disorders, low cardiac output state and cardiac ischemia).

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)

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.

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.

Full Information

NCT ID

NCT01613235

First Posted

June 1, 2012

Last Updated

November 2, 2017

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

1. Study Identification

Unique Protocol Identification Number

NCT01613235

Brief Title

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

Acronym

HIMALAIA

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2017

Overall Recruitment Status

Terminated

Why Stopped

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

Study Start Date

August 2010 (undefined)

Primary Completion Date

January 2015 (Actual)

Study Completion Date

December 10, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cerebral Ischemia, Subarachnoid Hemorrhage

Keywords

subarachnoid hemorrhage, ischemia, vasospasm, CT, perfusion, induced hypertension, delayed cerebral ischemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

26 (Actual)

8. Arms, Groups, and Interventions

Arm Title

No intervention

Arm Type

No Intervention

Arm Description

No induced hypertension (reference group)

Arm Title

Induced hypertension

Arm Type

Active Comparator

Arm Description

Intervention Type

Other

Intervention Name(s)

Induced hypertension

Other Intervention Name(s)

Hypertension., Raised blood pressure.

Intervention Description

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.

Primary Outcome Measure Information:

Title

Time Frame

assessed three months after the SAH

Secondary Outcome Measure Information:

Title

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

Time Frame

24 hours after start of induced hypertension

Title

Related to the functional condition: Case fatality 30 days after SAH

Time Frame

30 days per patient

Title

Related to the functional condition, activities of daily living (ADL), three months after the SAH assessed with the Barthel Index.

Time Frame

assessed 3 months after the SAH

Title

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).

Time Frame

assessed 3 months after the SAH

Title

Related to the functional condition: anxiety and depression, three months after the SAH, assessed with the Hospital Anxiety and Depression Scale (HADS).

Time Frame

assessed 3 months after the SAH

Title

Related to the functional condition: cognitive functioning, three months after the SAH, evaluated by the Cognitive Failures Questionnaire (CFQ).

Time Frame

assessed 3 months after the SAH

Title

Related to adverse effects: complications related to insertion of a central venous catheter or intra-arterial catheter (including local haemorrhage and pneumothorax).

Time Frame

during hospital admission, an average of 3 weeks

Title

Related to adverse effects: intracranial complications related to induced hypertension (such as exacerbation of cerebral oedema, hemorrhagic infarction and bleeding of an asymptomatic aneurysm).

Time Frame

during admission, an average of 3 weeks

Title

Related to adverse effects± • Systemic complications related to induced hypertension (including cardiac rhythm disorders, low cardiac output state and cardiac ischemia).

Time Frame

during admission, an average of 3 weeks

Title

Time Frame

compared between scans made during admission at time of deterioration and 36 hours later.

Title

Time Frame

compared between scans made during admission at time of deterioration and 36 hours later.

Title

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.

Time Frame

assessed at 12 months after the SAH

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria for eligibility Admission to one of the participating study centres. Age 18 years or over. SAH with an aneurysmatic bleeding pattern. Exclusion criteria for eligibility Evidence of DCI after the SAH, defined as any decrease in the level of consciousness or the development of new focal neurological deficits after the onset of the SAH that is not due to increasing hydrocephalus, rebleeding of the aneurysm, epileptic seizure, septic- or metabolic encephalopathy, unless symptoms of DCI started within 3 hours. Co-existing severe head injury. Perimesencephalic haemorrhage (perimesencephalic bleeding pattern and no aneurysm on CT-angiography). A history of a ventricular cardiac rhythm disorder, necessitating medical treatment. A history of a left ventricular heart failure, necessitating medical treatment. Likely transfer to another hospital, not participating in the trial, soon after treatment for the aneurysm. Moribund. Pregnancy. And furthermore, in selected centres where the sub study with CT perfusion will be performed: Known allergy for CT-contrast agents. Renal failure, defined as a serum creatinine > 150 µmol/l, because of the risk of contrast nephropathy. Diabetes mellitus. Inclusion criteria for trial participation Informed consent to participate in the proposed trial when DCI will develop. DCI based on a decrease of at least one point on the Glasgow Coma Scale sum score unless the decrease doesn't reflect DCI as evaluated by the treating physician, and/or the development of new focal neurological deficits, diagnosed by a neurologist, neurosurgeon or intensivist. Exclusion criteria for trial participation: Another cause for neurological deterioration including. A symptomatic aneurysm not yet treated by coiling or clipping. Severe hypertension, defined as a spontaneous MAP of 120 mmHg or more at the moment of evaluation for trial participation. Any contraindication for induced hypertension (such as a cardiac complication necessitating medical treatment) as evaluated by the treating physician. And furthermore, in selected centres where the sub study with CT perfusion will be performed: No CTP scan at time of neurological deterioration. More than 3 CTP scans since admission.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Arjen Slooter, MD, PhD

Organizational Affiliation

AMC Amsterdam and UMC Utrecht

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Walter van den Bergh, MD, PhD

Organizational Affiliation

AMC Amsterdam and UMC Groningen

Official's Role

Principal Investigator

Facility Information:

Facility Name

Academic Medical Centre Amsterdam

City

Amsterdam

State/Province

Noord Holland

ZIP/Postal Code

1105AZ

Country

Netherlands

Facility Name

Universitair Medisch Centrum Utrecht

City

Utrecht

ZIP/Postal Code

3584 CX

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

36042527

Citation

Gathier CS, van der Jagt M, van den Bergh WM, Dankbaar JW, Rinkel GJE, Slooter AJC; HIMALAIA Study Group. Slow recruitment in the HIMALAIA study: lessons for future clinical trials in patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage based on feasibility data. Pilot Feasibility Stud. 2022 Aug 30;8(1):193. doi: 10.1186/s40814-022-01155-4. Erratum In: Pilot Feasibility Stud. 2022 Sep 22;8(1):214.

Results Reference

derived

PubMed Identifier

29158449

Citation

Gathier CS, van den Bergh WM, van der Jagt M, Verweij BH, Dankbaar JW, Muller MC, Oldenbeuving AW, Rinkel GJE, Slooter AJC; HIMALAIA Study Group. Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial. Stroke. 2018 Jan;49(1):76-83. doi: 10.1161/STROKEAHA.117.017956. Epub 2017 Nov 20.

Results Reference

derived

PubMed Identifier

26443829

Citation

Gathier CS, Dankbaar JW, van der Jagt M, Verweij BH, Oldenbeuving AW, Rinkel GJ, van den Bergh WM, Slooter AJ; HIMALAIA Study Group. Effects of Induced Hypertension on Cerebral Perfusion in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial. Stroke. 2015 Nov;46(11):3277-81. doi: 10.1161/STROKEAHA.115.010537. Epub 2015 Oct 6.

Results Reference

derived

PubMed Identifier

23692645

Citation

Gathier CS, van den Bergh WM, Slooter AJ; HIMALAIA-Study Group. HIMALAIA (Hypertension Induction in the Management of AneurysmaL subArachnoid haemorrhage with secondary IschaemiA): a randomized single-blind controlled trial of induced hypertension vs. no induced hypertension in the treatment of delayed cerebral ischemia after subarachnoid hemorrhage. Int J Stroke. 2014 Apr;9(3):375-80. doi: 10.1111/ijs.12055. Epub 2013 May 22.

Results Reference

derived

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

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