Induced Hypertension in Preventing Cerebral Infarction in Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Background and Purpose- Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage. If clinical signs of DCI occur, induced hypertension is a plausible but unproven therapeutic intervention. There is clinical equipoise if the use of hypertension induction is useful or not with the consequence that this strategy is irregularly used. We explored the effect of blood pressure augmentation in preventing cerebral infarction in patients with clinical signs of DCI. Methods- We performed a retrospective observational study, totaling 1647 patients with aneurysmal subarachnoid hemorrhage admitted at 3 academic hospitals in the Netherlands between 2006 and 2015. To study the primary outcome DCI related cerebral infarcts, we only included patients with no cerebral infarct at the time of onset of clinical signs of DCI. Cox regression was used to test the association between induced hypertension after onset of clinical signs of DCI and the occurrence of DCI related cerebral infarcts. Logistic regression was used to relate hypertension induction with poor outcome after 3 months, defined as a modified Rankin score >3. Results were adjusted for treatment center and baseline characteristics. Results- Clinical signs of DCI occurred in 479 (29%) patients of whom 300 without cerebral infarction on computed tomography scan at that time. Of these 300 patients, 201 (67%) were treated with hypertension induction and 99 were not. Of the patients treated with hypertension induction, 41 (20%) developed a DCI related cerebral infarct compared with 33 (33%) with no induced hypertension: adjusted hazard ratio, 0.59; 95% CI, 0.35 to 0.99. Hypertension induction also prevented poor outcome: adjusted odds ratio, 0.27; 95% CI, 0.14 to 0.55. Conclusions- Hypertension induction seems an effective strategy for preventing DCI related cerebral infarcts if not already present at the time of onset of clinical signs of DCI. This may lead to a reduction in poor clinical outcome

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

Background : Our randomized clinical trial on induced hypertension in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) was halted prematurely due to unexpected slow recruitment rates. This raised new questions regarding recruitment feasibility. As our trial can therefore be seen as a feasibility trial, we assessed the reasons for the slow recruitment, aiming to facilitate the design of future randomized trials in aSAH patients with DCI or other critically ill patient categories. Methods : Efficiency of recruitment and factors influencing recruitment were evaluated, based on the patient flow in the two centers that admitted most patients during the study period. We collected numbers of patients who were screened for eligibility, provided informed consent, and developed DCI and who eventually were randomized. Results : Of the 862 aSAH patients admitted in the two centers during the course of the trial, 479 (56%) were eligible for trial participation of whom 404 (84%) were asked for informed consent. Of these, 188 (47%) provided informed consent, of whom 50 (27%) developed DCI. Of these 50 patients, 12 (24%) could not be randomized due to a logistic problem or a contraindication for induced hypertension emerging at the time of randomization, and four (8%) were missed for randomization. Eventually, 34 patients were randomized and received intervention or control treatment. Conclusions : Enrolling patients in a randomized trial on a treatment strategy for DCI proved unfeasible: only 1 out of 25 admitted and 1 out of 14 eligible patients could eventually be randomized. These rates, caused by a large proportion of ineligible patients, a small proportion of patients providing informed consent, and a large proportion of patients with contraindications for treatment, can be used to make sample size calculations for future randomized trials in DCI or otherwise critically ill patients. Facilitating informed consent through improved provision of information on risks, possible benefits, and study procedures may result in improved enrolment

Induced hypertension for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage a randomized clinical trial

Background and Purpose-Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled caseseries only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. Methods-Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. Results-The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). Conclusions-Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events

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

Background: Our randomized clinical trial on induced hypertension in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) was halted prematurely due to unexpected slow recruitment rates. This raised new questions regarding recruitment feasibility. As our trial can therefore be seen as a feasibility trial, we assessed the reasons for the slow recruitment, aiming to facilitate the design of future randomized trials in aSAH patients with DCI or other critically ill patient categories. Methods: Efficiency of recruitment and factors influencing recruitment were evaluated, based on the patient flow in the two centers that admitted most patients during the study period. We collected numbers of patients who were screened for eligibility, provided informed consent, and developed DCI and who eventually were randomized. Results: Of the 862 aSAH patients admitted in the two centers during the course of the trial, 479 (56%) were eligible for trial participation of whom 404 (84%) were asked for informed consent. Of these, 188 (47%) provided informed consent, of whom 50 (27%) developed DCI. Of these 50 patients, 12 (24%) could not be randomized due to a logistic problem or a contraindication for induced hypertension emerging at the time of randomization, and four (8%) were missed for randomization. Eventually, 34 patients were randomized and received intervention or control treatment. Conclusions: Enrolling patients in a randomized trial on a treatment strategy for DCI proved unfeasible: only 1 out of 25 admitted and 1 out of 14 eligible patients could eventually be randomized. These rates, caused by a large proportion of ineligible patients, a small proportion of patients providing informed consent, and a large proportion of patients with contraindications for treatment, can be used to make sample size calculations for future randomized trials in DCI or otherwise critically ill patients. Facilitating informed consent through improved provision of information on risks, possible benefits, and study procedures may result in improved enrolment

Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage:A Randomized Clinical Trial

Background and Purpose-Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. Methods-Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. Results-The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). Conclusions-Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse event

Blood pressure and the risk of rebleeding and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Introduction and objective: Blood pressure is presumably related to rebleeding and delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (aSAH) and could serve as a target to improve outcome. We assessed the associations between blood pressure and rebleeding or DCI in aSAH-patients. Materials and methods: In this observational study in 1167 aSAH-patients admitted to the intensive care unit (ICU), adjusted hazard ratio's (aHR) were calculated for the time-dependent association of blood pressure and rebleeding or DCI. The aHRs were presented graphically, relative to a reference mean arterial pressure (MAP) of 100 mmHg and systolic blood pressure (sBP) of 150 mmHg. Results: A MAP below 100 mmHg in the 6, 3 and 1 h before each moment in time was associated with a decreased risk of rebleeding (e.g. within 6 h preceding rebleeding: MAP = 80 mmHg: aHR 0.30 (95% confidence interval (CI) 0.11–0.80)). A MAP below 60 mmHg in the 24 h before each moment in time was associated with an increased risk of DCI (e.g. MAP = 50 mmHg: aHR 2.59 (95% CI 1.12–5.96)). Conclusions: Our results suggest that a MAP below 100 mmHg is associated with decreased risk of rebleeding, and a MAP below 60 mmHg with increased risk of DCI

Induced Hypertension for Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage : A Randomized Clinical Trial

BACKGROUND AND PURPOSE: Induced hypertension is widely used to treat delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage, but a literature review shows that its presumed effectiveness is based on uncontrolled case-series only. We here report clinical outcome of aneurysmal subarachnoid hemorrhage patients with DCI included in a randomized trial on the effectiveness of induced hypertension. METHODS: Aneurysmal subarachnoid hemorrhage patients with clinical symptoms of DCI were randomized to induced hypertension or no induced hypertension. Risk ratios for poor outcome (modified Rankin Scale score >3) at 3 months, with 95% confidence intervals, were calculated and adjusted for age, clinical condition at admission and at time of DCI, and amount of blood on initial computed tomographic scan with Poisson regression analysis. RESULTS: The trial aiming to include 240 patients was ended, based on lack of effect on cerebral perfusion and slow recruitment, when 21 patients had been randomized to induced hypertension, and 20 patients to no hypertension. With induced hypertension, the adjusted risk ratio for poor outcome was 1.0 (95% confidence interval, 0.6-1.8) and the risk ratio for serious adverse events 2.1 (95% confidence interval, 0.9-5.0). CONCLUSIONS: Before this trial, the effectiveness of induced hypertension for DCI in aneurysmal subarachnoid hemorrhage patients was unknown because current literature consists only of uncontrolled case series. The results from our premature halted trial do not add any evidence to support induced hypertension and show that this treatment can lead to serious adverse events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01613235

Effects of Induced Hypertension on Cerebral Perfusion in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage : A Randomized Clinical Trial

BACKGROUND AND PURPOSE: The presumed effectiveness of induced hypertension for treating delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage is based on uncontrolled case-series only. We assessed the effect of induced hypertension on cerebral blood flow (CBF) in aneurysmal subarachnoid hemorrhage patients with delayed cerebral ischemia in a randomized clinical trial. METHODS: Aneurysmal subarachnoid hemorrhage patients were randomized to induced or no induced hypertension (control group) at delayed cerebral ischemia onset. CBF was assessed, blinded for treatment allocation, with computed tomographic perfusion in standardized predefined regions at delayed cerebral ischemia onset and after 24 to 36 hours of study treatment. Mean arterial blood pressure was compared between groups (linear mixed model). The primary outcome measure was the difference in change in overall CBF (Mann-Whitney U test). RESULTS: Mean arterial blood pressure was, on average, 12 mm Hg (95% confidence interval, 8.6-14.5) higher in the hypertension group (n=12) than in the control group (n=13). Change in overall CBF (mL/100g per s) was -8.5 (range, -42 to 30) in the control group and 0.1 (range, -31-43) in the hypertension group (P=0.25). CONCLUSIONS: Change in overall CBF did not differ to a statistically significant extent between the groups. Based on our results, 225 to 250 patients per group are needed to find a statistically significant difference in change in overall CBF between induced hypertension and no hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT0161323

Correction: 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 and Feasibility Studies, (2022), 8, 1, (193), 10.1186/s40814-022-01155-4)

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