Strategies for prevention and treatment of delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage

Abstract

In this thesis, risk factors and treatment strategies for delayed cerebral ischaemia (DCI) are discussed. In Chapter 2 we showed in 333 aSAH patients that total haemorrhage volume, quantified with an automatic quantification method, was associated with DCI. This method might attribute to improvement of prediction of DCI. In Chapter 3, we showed in 1167 aSAH patients admitted to the intensive care unit (ICU) that a mean arterial pressure (MAP) of 60 mmHg or lower in the 24 hours preceding DCI was statistically significantly associated with occurrence of DCI. Whether preventing a MAP of 60 mmHg or lower would actually prevent DCI should be further investigated in randomised trials. As inflammation and infection are both associated with the development of DCI, we investigated in Chapter 4 whether preventive antibiotics could lead to a decreased risk of DCI. In our cohort of 459 aSAH patients admitted to the ICU, 274 patients (60%) received preventive antibiotics, and 185 (40%) did not. We found no association between the use of preventive antibiotics and DCI or poor outcome. Induced hypertension is widely used to treat DCI but its presumed effectiveness was based on uncontrolled case series only. We set up a multicenter randomised clinical (the HIMALAIA study) in which we investigated the efficacy and safety of induced hypertension versus no induced hypertension as treatment for DCI (Chapter 5). In Chapter 6, the results of the substudy on the effect of induced hypertension on cerebral perfusion as measured by CT perfusion are shown. This substudy involved 25 DCI patients: 12 received induced hypertension and 13 did not. There was no difference between the groups in the change of overall CBF or change of CBF in the lowest perfused region. Only in the hypertension group, there was a trend towards improved CBF after induced hypertension in the lowest perfused region. Chapter 7 describes the effects of induced hypertension on functional outcome. The trial aiming to include 240 patients was ended prematurely after inclusion of 41 patients (21 received induced hypertension; 20 did not) due to lack of effect on cerebral perfusion and slow recruitment. Induced hypertension did not result in improved functional outcome (adjusted risk ratio for poor outcome 1.0, 95% confidence interval 0.6-1.8) but showed a trend towards more serious complications (risk ratio 2.1, 95% confidence interval 0.9 – 5.0). Due to the underpowered sample size, the results of our trial do not add evidence to support induced hypertension but do show that this treatment can lead to serious complications. In Chapter 8, we discuss the reasons for slow patient inclusion in our trial. The most important reasons were the large proportion of ineligible patients and the small proportion of eligible patients providing informed consent which was probably due to our rather complex informed consent procedure. Our findings can be used for the design and for sample size calculations for future randomised trials. Multicenter and multinational collaborations are essential to find better treatment options for patients with DCI.