Intracranial contrast transit times on digital subtraction angiography decrease more in patients with delayed intraparenchymal hemorrhage after Pipeline

Abstract

Background

Pipeline embolization devices (PEDs) are used for endovascular treatment of cerebral aneurysms but can be associated with delayed ipsilateral intraparenchymal hemorrhage (DIPH). Changes in intracranial hemodynamics after PED are poorly understood.

Objective

Here, we assess hemodynamic changes after PED in patients and compare these changes in patients with and without DIPH (DIPH+ and DIPH–).

Methods

Records of patients with distal internal carotid artery (ICA) aneurysms treated with PED at our institution between 2012 and 2017 were retrospectively reviewed. Regions of interest were selected proximally to PED over the cavernous ICA and distally over the middle cerebral artery (MCA), and then transit times were determined using syngo iFlow software (Siemens). Ratio of MCA to ICA transit time was compared before, after treatment, and at follow-up. Ratios were also compared between DIPH+ and DIPH– subgroups. Correlations between aneurysm size, age, and ratios were investigated.

Results

Fifty-three patients were included. The ratio of MCA to ICA transit time decreased significantly after PED deployment (1.13 vs. 1.22, p < 0.01). The ratio in the DIPH + subgroup (n = 4) was significantly lower (1.00 vs. 1.14, p = 0.01) and decreased significantly more (21% vs. 4.4%, p = 0.02) compared to the DIPH– subgroup (n = 49). The ratio tended to be higher in larger aneurysms at baseline (r = 0.25, p = 0.07) but not after PED treatment (r = 0.11, p = 0.15). Age did not correlate with ratio.

Conclusion

The ratio of MCA to ICA transit time decreases following PED treatment and decreases more in patients with DIPH. These contrast transit time changes can be detected in real time immediately after PED deployment.

Introduction

Several large recent studies have shown the Pipeline embolization device (PED; ev3 Neurovascular, Irvine, CA) to be a highly effective and safe treatment option for complex intracerebral aneurysms, providing a physiologic reconstruction of the vessel lumen and blood flow diversion from the aneurysm sac to distal circulation.^1–3 However, procedure-related morbidity and mortality are not negligible, and with the increasing use of PEDs unexpected complications like delayed ipsilateral intraparenchymal hemorrhage (DIPH) became evident.^4–8

The etiology and pathogenesis of such adverse events remain unclear; several hypotheses have been theorized but none of them has proved to be conclusive.^4–13 We hypothesize that altered distal intracranial hemodynamics after PED treatment may be a possible contributing factor.^14–16 Here, we examine on digital subtraction angiography (DSA) contrast transit time changes after PED deployment and at follow-up, and compare transit time changes in patients with and without DIPH.

Methods

Patient selection

Following institutional review board approval, records of patients with distal internal carotid artery (ICA) aneurysms treated with PED at our institution between 2012 and 2017 were retrospectively reviewed. DSA performed the day of the procedure (n = 53) and follow-up DSA when available (n = 22, mean follow-up time = nine months) were evaluated. Our dataset was further investigated for DIPH and our cohort was divided into two subgroups: patients who developed DIPH during the perioperative period (the DIPH+ group, n = 4) and patients without DIPH (the DIPH– group, n = 49). The perioperative period of observation for DIPH was considered the first week after the procedure. All patient characteristics are summarized in Table 1.

Table 1.

Clinical and anatomical characteristics of study cohort and subgroups.

Clinical characteristics	Study cohort	DIPH–	DIPH+
Cohort (n, %)	53 (100%)	49 (92.4%)	4 (7.6%)
Mean age, years (range)	55 (29–79)	54 (29–79)	67 (61–74)
Aneurysm features
Location (n)
Cavernous	11	11	0
Ophthalmic	21	20	1
Paraclinoid	13	11	2
Posterior communicating	3	0	0
Anterior choroidal	1	0	0
Middle cerebral artery	1	0	1
Mean diameter (mm, range)	9.0 (2–28)	9.1 (2–28)	7.9 (2.5–16)

DIPH: delayed ipsilateral intraparenchymal hemorrhage.

PED procedure

Dual antiplatelet therapy was started 10 days before PED deployment all patients, and sensitivity was confirmed on the morning of the procedure. Sensitivities were confirmed to be within therapeutic range for all patients before the beginning of the procedure. All procedures were performed under general anesthesia. Target systemic systolic blood pressure was between 100 mmHg and 140 mmHg during the procedure and in the perioperative period. All patients were heparinized at the start of the procedure (bolus of 70 UI/kg) and reversed with protamine sulfate prior to femoral closure.

Image acquisition

All DSA studies were performed using the same protocol: Through a transfemoral approach the cervical ICA was injected with 12 ml of the iodine-based contrast agent iohexol (300 mg/ml, Omnipaque, GE Healthcare, Chicago, IL) by a power-contrast injector (Medrad, Bayer HealthCare, Whippany, NJ) over 2 s. The power-contrast injector was synchronized to a fluoroscopy angiographic machine with a 1.2 s delay in the contrast injection. All DSA runs were performed with the same catheter before and after PED deployment and the catheter was positioned within the proximal cervical ICA. Angiographic images were acquired at a rate of three frames/second in anterior-posterior, lateral, and oblique transorbital projections using a biplane neuroangiography suite (Artis zee, Siemens Healthineers, Erlangen, Germany).

Transit time measurements

Transit time was determined using the commercially available post-processing software syngo iFlow (Siemens Healthineers, Erlangen, Germany) and the regions of interest (ROIs) were selected proximally to PED over the cavernous ICA and distally over the ipsilateral middle cerebral artery (MCA). The ratio of MCA to ICA transit time was calculated in order to mitigate inherent limitations of syngo iFlow analysis, including location of the catheter during the angiogram, volume of contrast injected, and duration of the contrast injection. Ratios were obtained at baseline, immediately after PED deployment, and at follow-up.

Statistical analysis

The ratio of MCA to ICA transit time was compared in all patients before and after treatment using the Wilcoxon matched-pairs signed-ranks test. These parameters were also compared at follow-up using the same statistical test. The ratio of MCA to ICA transit time was compared between the DIPH+ and – subgroups before and after treatment with the two-sample Wilcoxon rank-sum test. Pearson’s correlation was used to analyze the relationship of aneurysm size and age with baseline, post-PED, and follow-up ratio in the entire study cohort. Aneurysm size and age were also analyzed between DIPH+ and – subgroups with the two-sample Wilcoxon rank-sum test. Analyses were performed with Stata (Version 12.0, StataCorp, College Station, TX).

Results

Transit time before, after PED, and at follow-up in entire study cohort

The ratio of MCA to ICA transit time decreased significantly after PED deployment (1.13 vs. 1.22, p < 0.01), but showed a tendency to increase at follow-up (1.16 vs. 1.10, p = 0.08) toward baseline values (1.16 vs. 1.18, p = 0.71). All results are shown in Table 2 and Figure 1(a).

Table 2.

Comparison of MCA to ICA transit time ratio before, after PED deployment, and at follow-up in entire study cohort.

	Study cohort				p value	% change
MCA/ICA transit time ratio	Before PED (n = 53)	1.22	After PED (n = 53)	1.13	<0.01 a	−7.4%
	After PED (n = 22)	1.10	Follow-up (n = 22)	1.16	0.08	+5.5%
	Before PED (n = 22)	1.18	Follow-up (n = 22)	1.16	0.71	−1.7%

^ap ≤ 0.05. MCA: middle cerebral artery; ICA: internal carotid artery; PED: Pipeline embolization device.

Figure 1.

(a) MCA to ICA transit time ratio before (n = 53), after PED (n = 53), and at follow-up (n = 22) in entire study cohort; (b) MCA to ICA transit time ratio percentage decrease after PED deployment in DIPH+ vs. DIPH– subgroups. MCA: middle cerebral artery; ICA: internal carotid artery; PED: Pipeline embolization device; DIPH: delayed ipsilateral intraparenchymal hemorrhage.

Transit time before and after PED in DIPH+ versus DIPH– subgroups

No baseline difference was noticed in MCA to ICA transit time ratio between DIPH+ and DIPH– subgroups (1.28 vs. 1.21, p = 0.27). However, after treatment the DIPH+ subgroup had a significantly lower ratio (1.00 vs. 1.14, p = 0.01) with a significantly higher percentage decrease compared to the DIPH– subgroup (21.0% vs. 4.4%, p = 0.02, Figure 1(b)). No follow-up DSA was performed in the DIPH+ subgroup.

Transit time versus aneurysm size and age before, after PED, and at follow-up

Before PED deployment, MCA to ICA transit time ratio showed a slight correlation with aneurysm size in our study cohort (r = 0.25, p = 0.07), but the ratio was unrelated to the size of the treated aneurysm immediately after treatment (r = 0.20, p = 0.15) and at follow-up (r = –0.11, p = 0.61). No differences in aneurysm size were noticed between the DIPH+ and – subgroups (7.9 mm vs. 9.1 mm, p = 0.79).

MCA to ICA transit time ratio did not correlate with age of the entire study cohort (r = 0.03, p = 0.83 before and r = 0.07, p = 0.63 after PED deployment), but the DIPH+ subgroup showed a trend toward older age (67 years vs. 54 years in DIPH–, p = 0.06).

PED numbers and platelet sensitivity testing in DIPH+ versus DIPH– subgroups

A single PED was deployed in all patients, except for two patients for whom multiple PEDs were necessary to cover the neck of the aneurysm—a 27 mm anterior choroidal artery aneurysm (two PEDs) and a 25 mm cavernous ICA aneurysm (four PEDs)—and neither of them developed DIPH.

No differences were noticed in dual antiplatelet sensitivity between the two subgroups before and after PED deployment and no technical difficulties were recorded during the procedure in the DIPH+ subgroup.

Discussion

Flow diverters like the PED redirect blood flow away from the aneurysm sac and into the parent vessel and distal cerebrovasculature. Intuitively, distal intracranial hemodynamics are likely altered after PED deployment but these changes are still poorly understood.^14–17 Moreover, whether these hemodynamic changes can lead to DIPH is unknown. DIPH is an unexpected and devastating complication, with an incidence ranging from 0% to 10% among reported series.^1–8 Multiple etiologies and mechanisms have been proposed,^4–14 including disrupted cerebral hemodynamics,^{5,6,8,11,13–17} but no mechanism has been definitively proven.^4–17

Here, we evaluate short- and long-term intracranial hemodynamic changes following PED deployment by analyzing contrast transit times on DSA using syngo iFlow software. We found that MCA to ICA transit time ratio decreased immediately after treatment (1.13 vs. 1.22, p < 0.01), corroborating the results of faster blood flow in the distal circulation following PED deployment published in previous studies conducted with syngo iFlow analysis, ¹⁷ quantitative magnetic resonance angiography (MRA), ¹⁴ and transcranial Doppler. ¹⁶ This finding is probably a consequence of blood flow redirection from the ICA aneurysm sac to the distal circulation. However, this condition seems to be transient, since ratios at follow-up tended to match baseline values (1.18 vs. 1.16, p = 0.71). Our results might further support the hypothesis that PED does cause immediate disruption of cerebral autoregulation,^8,11 but the cerebrovasculature readjusts over time.

Additionally, a comparison of MCA to ICA transit time ratios between DIPH+ and – subgroups revealed no statistical difference at baseline, but after PED deployment patients with DIPH had a higher percentage decrease from baseline ratio compared to the DIPH– subgroup (21% vs. 4.4%, p = 0.02). The inability of the cerebrovasculature to accommodate increased blood flows immediately post-PED in DIPH+ patients, as suggested by faster transit times on DSA, supports a hemodynamic cause of DIPH. An illustrative case is depicted in Figure 2.

Figure 2.

Illustrative case. Comparison of iFlow change before and after PED deployment between a DIPH– vs. DIPH+ patient. (a) and (b) DIPH– patient. MCA/ICA ratio decreased 2.9% from (a) 1.19 before to (b) 1.15 after. (c) and (d) DIPH+ patient. MCA/ICA ratio decreased 17.3% from (v) 1.21 before to (d) 1.00 after. PED: Pipeline embolization device; DIPH: delayed ipsilateral intraparenchymal hemorrhage; MCA: middle cerebral artery; ICA: internal carotid artery.

Contrast transit time changes after PED deployment did not correlate with aneurysm size in this study, which varies from the findings that we reported in another study that used a different post-processing transit time technique. ¹⁵ This discrepancy is likely due to the varying hemodynamic assessment techniques and the small sample sizes. Nonetheless, previous studies suggest no differences in aneurysm size between DIPH+ and – subgroups.^1,3

Age was not correlated with contrast transit time both before and after treatment, even though DIPH showed a tendency to develop in an older age population. This result could find its logical explanation in increased arterial rigidity and reduced vascular compliance with increased age, ¹⁸ but the small sample size of our study and the weak correlation noticed do not allow any conclusive consideration.

We found no correlation between the number of PEDs used and DIPH risk as shown in other studies,^2,3 probably because 96% of our cohort was treated with a single PED.

Also, dual antiplatelet sensitivities did not appear to play a role in DIPH in our study, since all patients were within therapeutic range before and after treatment, which differs from other reported series.^4,10

Limitations of our study are its retrospective nature and the small sample size that does not allow conclusive assertions, especially for long-term findings since less than half of our patients had follow-up DSA available for iFlow analysis. Additionally, iFlow provides an indirect extrapolation of blood flow through consecutive DSA imaging color-coded map reconstruction.^19,20 Cerebral hemodynamics are currently assessed with other modalities such as arterial spin labeling (ASL) MR perfusion^21,22 or quantitative MRA (noninvasive optimal vessel analysis (NOVA)) ²³ that proved to be more reliable than indirect blood flow quantification based on DSA. Those imaging studies, though, present longer times for data acquisition and post-processing, making MR imaging less suitable for real-time evaluation of hemodynamic changes caused by PED deployment.

iFlow measurements can also be affected by vessel orientation to the fluoroscopic machine. ²⁰ Our use of the ratio of MCA to ICA transit time attempts to mitigate variability in the data associated with location of the catheter during the angiogram, volume of contrast injected, and duration of the contrast injection.

Although the inclusion of one case of MCA aneurysm could affect the homogeneity of the aneurysm location in the study cohort providing a possible bias in DIPH+ transit time analysis, its specific site at the mid-M1 segment allowed ROI selection proximal and distal to PED comparable to the rest of the cohort.

Thus, without adding extra radiation exposure or contrast dye to conventional DSA imaging acquisition, iFlow transit time allows objective indirect quantification of blood flow and hemodynamic changes in real time in the neuroangiography suite immediately after PED deployment. Evaluation of these hemodynamic changes could help to identify patients at increased risk for DIPH immediately after PED deployment and may suggest the need for additional precautions and therapeutic measures during the postoperative period.

Conclusion

PED deployment for anterior circulation aneurysm treatment may cause transient distal intracranial hemodynamic changes characterized by faster contrast transit times that tend to normalize over time. The larger percentage decrease in transit times observed in patients who developed DIPH in our study cohort might hint at a possible hemodynamic etiology of DIPH.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.