Increasing evidence supports etiologies of delayed cerebral ischemia (DCI) other than cerebral vasospasm (CV).
Delayed ischemic neurological deficit (DIND) due to symptomatic vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage complication (aSAH), most likely because of a decreased availability of nitric oxide (NO) in the cerebral microcirculation 1).
Intracerebral hematoma (ICH) was associated with an increased risk of DCI. Furthermore, adding the presence or absence of ICH to the modified Fisher Scale (mFS) improved the identification of patients at the highest risk for the development of DCI. Thus, a simple adjustment of the mFS might help to identify patients at high risk for DCI 3)
Early low CBF measurements and a high lactate and lactate to pyruvate ratio may be early warning signs of the risk of developing Delayed cerebral ischemia (DCI). The clinical value of these findings needs to be confirmed in larger studies 4).
Transcranial Doppler (TCD) and transcranial color-coded duplex sonography (TCCS) are noninvasive modalities that can be used to assess vasospasm. However, high flow velocity does not always reflect DCI.
In recent years, significant literature shows that computed tomography perfusion (CTP) can provide sufficient information on cerebral hemodynamics and effectively indicate delayed cerebral ischemia (DCI) before the development of infarction. Sun et al. aimed at performing a meta-analysis to provide a more full and accurate evaluation of CTP and CTP parameters in detecting DCI in patients with aneurysmal subarachnoid hemorrhage.
In the PubMed, MedLine, Embase and Cochrane databases analysis published from February 2005 to February 2013. The extraction of CTP parameters, including cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), time to peak (TTP), interhemispheric ratios for CBV and CBF and interhemispheric differences for MTT and TTP. Pooled estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and the summary receiver-operating characteristic curve were determined.
Four research studies are met the inclusion criteria for the analysis. The pooled sensitivity, specificity, PLR, NLR and DOR of CTP for detecting the DCI were 82%, 82%, 4.56, 0.22 and 20.96, respectively. Through the evaluation of absolute CTP parameters, CBF and MTT showed diagnostic value for DCI, but CBF and TTP did not. Moreover, CBF ratio, MTT difference and TTP difference showed more diagnostic value than CBV ratio in DCI detection by the assessment of relative CTP parameters.
As a non-invasive and short time consuming screening method, CTP own a high diagnostic value for the detection of DCI after aneurysm rupture 5).
CTP maps were calculated with tracer delay-sensitive and tracer delay-insensitive algorithms and were visually assessed for the presence of perfusion deficits by two independent observers with different levels of experience. The diagnostic value of both algorithms was calculated for both observers.
Seventy-one patients were included. For the experienced observer, the positive predictive values (PPVs) were 0.67 for the delay-sensitive and 0.66 for the delay-insensitive algorithm, and the negative predictive values (NPVs) were 0.73 and 0.74. For the less experienced observer, PPVs were 0.60 for both algorithms, and NPVs were 0.66 for the delay-sensitive and 0.63 for the delay-insensitive algorithm.
Test characteristics are comparable for tracer delay-sensitive and tracer delay-insensitive algorithms for the visual assessment of CTP in diagnosing DCI. This indicates that both algorithms can be used for this purpose 6).
Whole-brain CT Perfusion (CTP) on Day 3 after aneurysmal subarachnoid hemorrhage (aSAH) allows early and reliable identification of patients at risk for delayed ischemic neurological deficits (DIND) and tissue at risk for delayed cerebral infarction (DCI) 7).
Current treatment guidelines to prevent delayed cerebral ischemia is limited to oral nimodipine, maintenance of euvolemia, induction of hypertension if ischemic signs occur and endovascular therapy for patients with continued ischemia after induced hypertension. Future investigations will involve agents targeting vasodilation, anticoagulation, inhibition of apoptosis pathways, free radical neutralization, suppression of cortical spreading depolarization and attenuation of inflammation 8).
Metaanalysis indicated that the use of statins decreases the occurrence of cerebral vasospasm, whereas did not support a beneficial effect of statins on the occurrence of delayed ischemic neurological deficit (DIND), death or poor neurological outcomes in patients with aneurysmal SAH 9).
Volume expansion and hypertension are widely used for the hemodynamic management of patients with subarachnoid hemorrhage to prevent delayed cerebral ischemia.
For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during Vasopressor-induced hypertension (VIH) therapy is rare. Reynolds et al. do not recommend withholding VIH therapy from these patients 10).
A randomized pilot trial using a 2-way factorial design allocating patients within 72 hours of subarachnoid hemorrhage to either normovolemia (NV) or volume expansion (HV) and simultaneously to conventional (CBP) or augmented blood pressure (ABP) for 10 days. The study endpoints were protocol adherence and retention to follow-up. The quality of endpoints for a larger trial were 6-month modified Rankin Scale score, comprehensive neurobehavioral assessment, delayed cerebral ischemia, new stroke, and discharge disposition.
This pilot study showed adequate feasibility and excellent retention to follow-up. Given the suggestion of possible worse neurobehavioral outcome with ABP, a larger trial to determine the optimal blood pressure management in this patient population is warranted. (ClinTrials.gov NCT01414894.) 11).
Delayed cerebral ischemia (DCI) is a recognized complication of aneurysmal subarachnoid hemorrhage (aSAH) that contributes to poor outcome.
Imaging studies to test for the presence of angiographic vasospasm or perfusion deficits in patients with clinical DCI do not seem helpful in selecting which patients should undergo treatment and may not improve outcomes. Future directions include validating these results in prospective cohort studies 13).
The CONSCIOUS-1 trial revealed that clazosentan could not improve mortality or clinical outcome in spite of successful reduction of relative risk in angiographic vasospasm. This result indicates that the pathophysiology underlying DCI is multifactorial and that other pathophysiological factors, which are independent of angiographic vasospasm, can contribute to the outcome. Recent studies have focused on microcirculatory disturbance, such as microthrombosis and arteriolar constriction, as a factor affecting cerebral ischemia after SAH 14).
In one hundred fifty-three patients with aSAH. Delayed cerebral ischemia (DCI) was identified in 32 patients (20.9%). Nosocomial infection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.09-11.2, p = 0.04), ventriculitis (OR 25.3, 95% CI 1.39-458.7, p = 0.03), aneurysm re-rupture (OR 7.55, 95% CI 1.02-55.7, p = 0.05), and clinical vasospasm (OR 43.4, 95% CI 13.1-143.4, p < 0.01) were independently associated with the development of DCI. Diagnosis of nosocomial infection preceded the diagnosis of DCI in 15 (71.4%) of 21 patients. Patients diagnosed with nosocomial infection experienced significantly worse outcomes as measured by the modified Rankin Scale score at discharge and 1 year (p < 0.01 and p = 0.03, respectively).
Nosocomial infection is independently associated with DCI. This association is hypothesized to be partly causative through the exacerbation of systemic inflammation leading to thrombosis and subsequent ischemia 15).
A post hoc analysis of the CONSCIOUS-1 study (Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage) was performed. Using multivariate logistic regression analysis and propensity matching, independent clinical risk factors associated with infarctions were identified, and the contribution of cerebral infarcts to long-term outcomes was evaluated.
Within the cohort of 413 subjects, early infarcts were present in 76 subjects (18%), whereas delayed infarcts occurred in 79 subjects (19%), and 36 subjects (9%) had new infarctions that were present on both early and delayed imaging. Propensity score matching revealed a significantly higher proportion of early infarcts after clipping (odds ratio, 4.62; 95% confidence interval, 1.99-11.57; P=0.00012). Multivariate logistic regressions identified clipping as an independent risk factor for early cerebral infarction (odds ratio, 0.26; 95% confidence interval, 0.15-0.48; P<0.001), and angiographic vasospasm was an independent risk factor for delayed cerebral infarction (odds ratio, 1.79; 95% confidence interval, 1.03-3.13; P=0.039). Early infarcts were a significant independent risk factor for poor long-term outcomes at 3 months (odds ratio, 2.34; 95% confidence interval, 1.18-4.67; P=0.015).
Clipping is an independent risk factor for the development of early cerebral infarcts, whereas delayed cerebral infarcts are associated with angiographic vasospasm. Early cerebral infarcts are stronger predictors of worse outcome than delayed infarction 16).