Admission risk factors for cerebral vasospasm in ruptured brain arteriovenous malformations: An observational study

Cerebral vasospasm has been extensively studied following aneurismal subarachnoid hemorrhage (SAH) and has also been reported after traumatic brain injury [1] or neurosurgery [2]. After aneurismal SAH, several risk factors present at admission have been identified, such as younger age, cigarette smoking, poor clinical grade, arterial hypertension, intracerebral hemorrhage, and thick cisternal clot [3‐5].

Although rupture of a brain arteriovenous malformation (BAVM) is a cause of SAH, few data are available on the incidence of cerebral vasospasm after BAVM rupture. In a series of 100 patients admitted between 1957 and 1977, Parkinson et al. [6] found a single case of symptomatic vasospasm. In recent years, however, transcranial Doppler (TCD) and CT/MRI cerebral angiography have contributed to improve the detection of vasospasm. Severe vasospasm associated with delayed cerebral infarction (CI) was reported recently in young adults [7‐11] and children [10, 12, 13] with BAVM rupture. Medical treatments may be effective in minimizing the adverse consequences of vasospasm and improving outcomes after aneurismal SAH [14]. These treatments may also be effective in ruptured BAVM. Early vasospasm detection in patients with ruptured BAVM would allow evaluations of therapeutic interventions such as calcium-channel blockers and triple-H therapy. The identification of risk factors for vasospasm would be expected to assist in early vasospasm detection.

Here, our aim was to identify risk factors for cerebral vasospasm present at admission to the intensive care unit (ICU) for intracerebral bleeding following BAVM rupture.

This observational study was conducted in compliance with STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [15], with the slight adjustments detailed below.

To the best of our knowledge, this is the first cohort study describing the incidence and risk factors for cerebral vasospasm after BAVM rupture. Although rare (3.0% of admissions to our ICU), BAVM rupture was complicated by vasospasm within a few days in 17% of patients (TCD-VS) or 8% of patients (CI) depending on the definition used. In our study, the prevalence of cerebral vasospasm was lower than in studies of the main other causes of cerebral vasospasm. TCD-VS was diagnosed in 31% to 70% of patients after aneurismal SAH [4, 23] and in 20% to 50% patients with traumatic brain injury [1, 24‐26]. We found that time to TCD-VS was 4 to 11 days in 92% of patients (median, 9 days). In the case-reports of BAVM rupture published over the last two decades, median time from bleeding to vasospasm was 13 days [7‐13].

Similarly, in a study of 50 patients, angiographic cerebral vessel narrowing was noted 3 to 12 days after BAVM rupture [27]. Furthermore, the time to vasospasm in our study of BAVM rupture was comparable to that reported after SAH [28] and traumatic brain injury [1].

We identified three early risk factors for vasospasm: age, gender, and GCS score. All three factors can be easily assessed at admission, which may help to stratify patients presenting with BAVM rupture. Interestingly, although no previous studies are available for comparison, there are eight published case-reports of vasospasm after BAVM rupture, all in young patients (mean age was 26 ± 12 years), six of whom are females [7‐13]. This is in accordance with our finding that female gender and younger age were associated with vasospasm. The third independent risk factor for vasospasm in our study was a lower GCS score. Similarly, in previous studies, lower levels of consciousness predicted vasospasm after SAH [29] and traumatic brain injury [1]. In the present study, intraventricular hemorrhage was present in 83% and 100% of the patients with TCD-VS and CI, respectively, in accordance with the occurrence of IVH in all eight previously reported cases of vasospasm following BAVM rupture. The amount of blood in the subarachnoid spaces as assessed by the Fisher score has been recognized as a strong predictor of cerebral vasospasm after SAH [5]. However, the Fisher score did not significantly predict cerebral vasospasm in our study, and vasospasm has been reported after BAVM rupture without SAH [7, 8, 10, 13]. Although the exact pathophysiology of cerebral vasospasm remains unknown, our data and previously published cases suggest that IVH, but not SAH, may be associated with the development of vasospasm after BAVM rupture. Experimental evidence suggests that oxyhemoglobin release secondary to blood clot elimination may initiate the cascade involving vasoactive substances such as endothelium-derived nitrite oxide and endothelin-1, which leads to cerebral vasospasm [30, 31]. Further research is needed to clarify the pathophysiology of vasospasm after BAVM rupture and to explain the different impacts of subarachnoid and intraventricular clots on the genesis of vasospasm. Due to the small number of patients included in the present study, we were not able to identify additional predictors, although we found a trend toward an association between angio-architectural BAVM features and cerebral vasospasm. The high proportion of patients who received norepinephrine in the TCD-VS and CI groups compared to the group without vasospasm is ascribable to our policy of inducing arterial blood pressure elevation in patients diagnosed with vasospasm, as part of "triple-H" therapy.

Although evidence is lacking that treatments such as triple-H therapy, transluminal balloon angioplasty, or selective intraarterial vasodilator infusion are effective in SAH patients, these strategies are commonly used in this group of patients. Based on the current data it would be worthwhile to investigate the efficacy of these treatments in patients with ruptured BAVMs. No clear recommendations about arterial blood pressure management after BAVM treatment are available. Hyperemia has been documented after BAVM treatment. Although the underlying mechanism seems unrelated to systemic hemodynamic changes [32], induced moderate hypertension may cause cerebral and systemic complications. Nevertheless, preventive strategies, such as nimodipine, might deserve evaluation in patients with BAVM rupture who are at high risk for vasospasm.

CI has been identified as the only outcome predictor in patients with SAH [4]. In the present study, TCD-VS and CI were associated with a non-significant increase in the risk of poor outcomes. Although the 21% death rate found in our study is close to the 18% 30-day rate reported by Brown et al. [33], it was lower than the 29% rate found by the same group in patients with previously untreated BAVM [34]. Nevertheless, the Colombia group found a lower mortality rate [35] and another study found no mortality at all [36]. Furthermore, in a defined-population study, the case-fatality rate in patients younger than 60 years was about 10% [37]. The comparatively high mortality rate in our patients may be ascribable to differences in severity at admission. In our series, all the patients required ICU admission and 40% were comatose. Since no high-level evidence exists concerning the management of unruptured BAVM, heterogeneity in the treatment methods may contribute to explain mortality rate differences across studies. The ongoing Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) [38] comparing treatment versus conservative management of unruptured BAVM can be expected to provide answers on this last point.

Unfortunately, the number of patients included was too small to determine whether TCD-VS and CI were independently associated with a poor outcome. Several definitions of cerebral vasospasm are commonly used, including TCD velocity elevation above 120 cm/s, symptomatic vasospasm, angiographic vasospasm, and CI diagnosed by CT or MRI. TCD is a well-validated tool for detecting vasospasm [39, 40] with acceptable positive and negative predictive values for angiographic vasospasm but low sensitivity for predicting the neurological outcome [41]. Moreover, intra- and inter-observer variability is of concern and should be taken into account when interpreting velocity changes over time. Nevertheless, intra-observer bias may be minimized by having the same neurointensivist perform all TCD investigations in a given patient [42], as was the case in the present study. Furthermore, mean flow velocities were well above 120 cm/s, and using a higher cut-off point of 150 cm/s would not have changed our results. In our study, TCD was performed in unconscious patients and in awake patients with symptoms. Since not all patients with vasospasm have symptoms, this approach may have underestimated the true incidence of TCD-VS. Angiographic vasospasm was not considered in our study. The absence of recommendations about vasospasm management after BAVM rupture and the poor clinical condition of some patients precluding transport to the radiology department explain that DSA was not performed routinely. This weakness of our study is mitigated by the good reported correlation between TCD and DSA [39] for vasospasm assessment. Furthermore, DSA may require general anesthesia and is associated with a small risk of procedure-related stroke. Finally, no treatment recommendations are available for BAVM rupture with vasospasm. Conceivably, the local cerebral blood flow modifications induced by intra-arterial treatments may lead to re-bleeding, especially when the BAVM has not been secured.

There are several limitations to our study. First, we used a retrospective design in a small number of patients from a single center. However, given the prevalence of BAVM of only about 0.01% in the general population [43], a retrospective design was appealing to ensure study completion within a reasonable timeframe. Second, our data from a single center may not apply to all other centers. Third, vasospasm following BAVM rupture is rare and, consequently, our sample size was small, limiting the statistical power of our study, which may have led us to miss a number of risk factors. Moreover, the number of patients included in the present study was too small to investigate properly whether TCD-VS and CI were independent predictors of a poor outcome. This crucial point will have to be determined in a larger study. In addition, the number of patients with CI was also too small for a separate multivariate analysis of risk factors for this event.

After BAVM rupture, TCD-VS occurred in 17% of patients and CI in 8%. Admission risk factors for TCD-VS were low GCS, younger age, and female gender. A non-significant trend toward poorer outcome exists in patients with TDC-VS and CI. Prospective, multicenter studies are needed to further assess the incidence and significance of vasospasm and CI after BAVM rupture and to identify additional predictors.