Sex differences in patients with and without high-risk factors associated with aneurysmal subarachnoid hemorrhage.

BACKGROUND: Controversy remains regarding the appropriate screening for intracranial aneurysms or for the treatment of aneurysmal subarachnoid hemorrhage (aSAH) for patients without known high-risk factors for rupture. This study aimed to assess how sex affects both aSAH presentation and outcomes for aSAH treatment. METHOD: A retrospective cohort study was conducted of all patients treated at a single institution for an aSAH during a 12-year period (August 1, 2007-July 31, 2019). An analysis of women with and without high-risk factors was performed, including a propensity adjustment for a poor neurologic outcome (modified Rankin Scale [mRS] score > 2) at follow-up. RESULTS: Data from 1014 patients were analyzed (69% [n = 703] women). Women were significantly older than men (mean ± SD, 56.6 ± 14.1 years vs 53.4 ± 14.2 years, p < 0.001). A significantly lower percentage of women than men had a history of tobacco use (36.6% [n = 257] vs 46% [n = 143], p = 0.005). A significantly higher percentage of women than men had no high-risk factors for aSAH (10% [n = 70] vs 5% [n = 16], p = 0.01). The percentage of women with an mRS score > 2 at the last follow-up was significantly lower among those without high-risk factors (34%, 24/70) versus those with high-risk factors (53%, 334/633) (p = 0.004). Subsequent propensity-adjusted analysis (adjusted for age, Hunt and Hess grade, and Fisher grade) found no statistically significant difference in the odds of a poor outcome for women with or without high-risk factors for aSAH (OR = 0.7, 95% CI = 0.4-1.2, p = 0.18). CONCLUSIONS: A higher percentage of women versus men with aSAH had no known high-risk factors for rupture, supporting more aggressive screening and management of women with unruptured aneurysms.

Modafinil Therapy and Mental Status Following Aneurysmal Subarachnoid Hemorrhage: Comprehensive Stroke Center Analysis.

BACKGROUND: Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating fatigue in stroke survivors, but data pertaining to its use in the acute setting are scarce. This study sought to assess the effects of modafinil use on mental status after aSAH. METHODS: Modafinil timing and dosage, neurological examination, intubation status, and physical and occupational therapy participation were documented. Repeated-measures paired tests were used for a before-after analysis of modafinil recipients. Propensity score matching (1:1 nearest neighbor) for modafinil and no-modafinil cohorts was used to compare outcomes. RESULTS: Modafinil (100-200 mg/day) was administered to 21% (88/422) of aSAH patients for a median (IQR) duration of 10.5 (4-16) days and initiated 14 (7-17) days after aSAH. Improvement in mentation (alertness, orientation, or Glasgow Coma Scale score) was documented in 87.5% (77/88) of modafinil recipients within 72 hours and 86.4% (76/88) at discharge. Of 37 intubated patients, 10 (27%) were extubated within 72 hours after modafinil initiation. Physical and occupational therapy teams noted increased alertness or participation in 47 of 56 modafinil patients (83.9%). After propensity score matching for baseline covariates, the modafinil cohort had a greater mean (SD) change in Glasgow Coma Scale score than the no-modafinil cohort at discharge (2.2 [4.0] vs. -0.2 [6.32], P = 0.003). CONCLUSIONS: A temporal relationship with improvement in mental status was noted for most patients administered modafinil after aSAH. These findings, a favorable adverse-effect profile, and implications for goals-of-care decisions favor a low threshold for modafinil initiation in aSAH patients in the acute-care setting.

Treatment of intraorbital arteriovenous fistulas with direct puncture: a case series and review of treatments since 1978.

Intraorbital arteriovenous fistulas (IOAVFs) are rare vascular pathologies that may be effectively treated with direct puncture (DP) of the venous supply and may offer a definitive and safe cure when done under ultrasound or stereotactic guidance. Here we present three new cases of DP treatment of IOAVFs, indications for safe use, and their potential complications in comparison to the existing literature on DP and other modalities.Three patients with IOAVFs were treated with DP with ultrasound guidance, stereotactic guidance, and fluoroscopy. Final digital subtraction angiography (DSA) revealed complete cure of IOAVFs. A literature review via PubMed was performed on treatments of IOAVFs since 1978.All three cases of DP resulted in successful cures with 2/3 cases resulting in complications from orbital hematoma formation. 49 total treatments including the cases herein have been documented. DP treatment constituted 5/49, conservative management 17/49, transarterial 8/49, transvenous 18/49, and surgical 3/49. Some cases received more than one mode of treatment. Transarterial and surgical managements were found to have higher complication rates than transvenous and DP.DP is a safe and effective treatment of IOAVFs that can be performed via multiple image guided methods and guarantees a definitive cure. Orbital hematomas are a potential complication of which operators should be aware.

Flow diversion for basilar quadrifurcation aneurysms.

BACKGROUND: Flow-diverting devices (FDDs), such as the Pipeline Embolization Device, have been gaining traction for treating challenging posterior circulation aneurysms. Few previous studies have focused on using FDDs to treat aneurysms of the basilar quadrifurcation. METHODS: We retrospectively reviewed the use of FDDs to treat patients with basilar quadrifurcation aneurysms. Patients were assessed for aneurysm type, previous aneurysm treatment, technical success, periprocedural complications, and long-term aneurysm occlusion. RESULTS: 34 patients were assessed; aneurysms of the basilar apex (n=23) or superior cerebellar artery (SCA) (n=7), or both (n=1), and posterior cerebral artery (PCA) (n=3). The mean (SD) largest aneurysm dimension was 8.7 (6.1) mm (range 1.9-30.8 mm). 14 aneurysms were previously surgically clipped or endovascularly coiled. All aneurysms had a saccular morphology. Complete or near-complete occlusion was achieved in 30 of 34 patients (88%) at final angiographic follow-up, a mean (SD) of 6.6 (5.4) months (range 0-19 months) postoperatively. No patient experienced postoperative symptomatic occlusions of the SCA or PCA; 4 patients developed asymptomatic posterior communicating artery occlusions; 28 patients (82%) experienced no complications; whereas 3 (9%) experienced major complications and 3 (9%) experienced minor complications; and 1 patient died as a result of subarachnoid hemorrhage. CONCLUSION: Flow diversion may be a safe and effective option to treat basilar quadrifurcation aneurysms. Previously treated basilar quadrifurcation aneurysms with recurrence or residual lesion may benefit from additional treatment with an FDD. Further prospective studies should be directed toward validating these findings.

A Review of Preoperative Embolization Effectiveness in Patients With Arteriovenous Malformations.

BACKGROUND AND OBJECTIVES: Preoperative embolization of arteriovenous malformations (AVMs) remains controversial. This study sought to analyze the cost-effectiveness of preoperative embolization of AVMs. METHODS: Patients who underwent AVM resection at a single institute (January 1, 2015-December 31, 2020) were analyzed. Patients with preoperative embolization (embolization cohort) were compared with those without preoperative embolization (nonembolization cohort). Cost-effectiveness score (CE) was the primary outcome of interest and was determined by dividing the total 1-year cost by effectiveness, which was derived from a validated preoperative to last follow-up change in the modified Rankin Scale utility score. A lower CE signifies a more cost-effective treatment strategy. RESULTS: Of 188 patients, 88 (47%) underwent preoperative embolization. The mean (SD) total cost was higher in the embolization group than in the nonembolization group ($117 594 [$102 295] vs $84 348 [$82 326]; P < .001). The mean (SD) CE was higher in the embolization cohort ($336 476 [$1 303 842]) than in the nonembolization cohort ($100 237 [$246 255]; P < .001). Among patients with Spetzler-Martin (SM) grade I and II AVMs, the mean (SD) CE was higher in the embolization (n = 40) than in the nonembolization (n = 72) cohort ($164 950 [$348 286] vs $69 021 [$114 938]; P = .004). Among patients with SM grade III AVMs, the mean (SD) CE was lower in the embolization (n = 33) than in the nonembolization (n = 25) cohort ($151 577 [$219 130] vs $189 195 [$446 335]; P = .006). The mean (SD) CE was not significantly different between cohorts among patients with higher-grade AVMs (embolization cohort [n = 3] vs nonembolization cohort [n = 15]: $503 639 [$776 492] vs $2 048 419 [$4 794 758]; P = .49). The mean CE for embolized SM grade III aneurysms was nonsignificant in the ruptured group; however, for the unruptured group, CE was significantly higher in the embolization cohort (n = 26; $160 871 [$240 535]) relative to the nonembolization cohort (n = 15; $108 152 [$166 446]) ( P = .006). CONCLUSION: Preoperative embolization was cost-effective for patients with SM grade III AVMs but not for patients with lower-grade AVMs.

Early Treatment of Ruptured Cerebral Arteriovenous Malformations: Analysis of Neurological Outcomes and Health Care Costs.

BACKGROUND: The timing of surgical resection is controversial when managing ruptured arteriovenous malformations (AVMs) and varies considerably among centers. OBJECTIVE: To retrospectively analyze clinical outcomes and hospital costs associated with delayed treatment in a ruptured cerebral AVM patient cohort. METHODS: Patients undergoing surgical treatment for a ruptured cerebral AVM (January 1, 2015-December 31, 2020) were retrospectively analyzed. Patients who underwent emergent treatment of a ruptured AVM because of acute herniation were excluded, as were those treated >180 days after rupture. Patients were stratified by the timing of surgical intervention relative to AVM rupture into early (postbleed days 1-20) and delayed (postbleed days 21-180) treatment cohorts. RESULTS: Eighty-seven patients were identified. The early treatment cohort comprised 75 (86%) patients. The mean (SD) length of time between AVM rupture and surgical resection was 5 (5) days in the early cohort and 73 (60) days in the delayed cohort ( P < .001). The cohorts did not differ with respect to patient demographics, AVM size, Spetzler-Martin grade, frequency of preoperative embolization, or severity of clinical presentation ( P ≥ .15). Follow-up neurological status was equivalent between the cohorts ( P = .65). The associated mean health care costs were higher in the delayed treatment cohort ($241 597 [$99 363]) than in the early treatment cohort ($133 989 [$110 947]) ( P = .02). After adjustment for length of stay, each day of delayed treatment increased cost by a mean of $2465 (95% CI = $967-$3964, P = .002). CONCLUSION: Early treatment of ruptured AVMs was associated with significantly lower health care costs than delayed treatment, but surgical and neurological outcomes were equivalent.

Transvenous Embolization of Dural Arteriovenous Fistulas Through the Galenic (Deep Venous) System: Multicenter Case Series and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Arteriovenous fistulas involving the deep venous system have often been treated with microsurgery or transarterial embolization. Increasing familiarity with transvenous navigation and improved endovascular access systems may facilitate transvenous embolization (TVE) for these rare and challenging lesions. METHODS: We performed a retrospective study of neurointerventional databases of 6 high-volume centers. We identified all cases of arteriovenous fistulas with deep transvenous embolizations for arteriovenous fistula. Details regarding demographics, fistula characteristics, treatment considerations, clinical outcomes, and fistula occlusion were obtained and analyzed. The meta-analysis used the same inclusion criteria. RESULTS: Seventeen cases of TVE were identified. The most common reasons for TVE included prior treatment failure with microsurgery (n = 2) or transarterial embolization (n = 3) or inaccessible arterial pedicles (n = 4). For patients with full clinical outcome data (n = 14), 2 patients had worsened modified Rankin Scale, 8 patients had no change, and 4 were improved at a median clinical follow-up of 3.5 months. Angiographic obliteration was achieved in 15/17 cases (88.2%). In 1 case, catheterization around a sharp turn in the basal vein of Rosenthal could not be performed. In another case, despite successful TVE, there was residual lesion which was treated 1 year later by microsurgical clipping and excision. CONCLUSION: Transvenous approaches for embolization of deep arteriovenous fistulas have become possible with modern endovascular catheter systems and liquid embolics. These lesions can be treated safely and effectively through endovascular approaches, which may spare patients the traversal of deep structures needed for microsurgical approaches to these regions. The outcomes of TVE are comparable with published outcomes of microsurgical interruption.

Endovascular Embolization of Basilar Artery Fenestration Aneurysms: A 21-Year Institutional Case Series.

BACKGROUND AND OBJECTIVES: Basilar artery fenestration is a rare phenomenon sometimes associated with basilar artery fenestration aneurysms (BAFAs). This review investigates the natural history and management outcomes of BAFAs and describes the outcomes of BAFAs treated with embolization. METHODS: A single-center database was queried for all cases of endovascular BAFA treatment. Data on complications, clinical and angiographic outcomes, and retreatment rates were collected. RESULTS: Seventeen aneurysms across 17 patients were treated. The mean (SD) age was 56 (13) years, and 15 (88%) patients were women. Among 15 aneurysms with data available, 2 arose from the fenestration limbs and 13 from both limbs and the vertebral artery. Of 16 aneurysmal projections available, 7 projected anteriorly, 7 posteriorly, and 2 superiorly. Among 17 patients, balloon-assisted coiling was the most common treatment (n = 10), followed by primary coiling (n = 3), stent-assisted coiling (n = 2), coiling with flow diversion (n = 1), and balloon-assisted coiling and flow diversion (n = 1). Complications noted in 5 patients included hemorrhage, thromboembolism, paresthesias, vasospasm, and transient hemiparesis. Among 16 patients with postoperative results available, 12 showed favorable clinical outcomes, 3 were disabled, and 1 died. The rates of postoperative complete (Raymond-Roy Occlusion Classification 1) and incomplete (Raymond-Roy Occlusion Classification 2 and 3) occlusion among 15 patients with available data were 6 and 9, respectively. CONCLUSION: Endovascular management of these rare aneurysms is feasible and safe, with high rates of favorable radiographic and clinical outcomes. This series reflects a general preference toward coiling and stent-assisted coiling, although flow diversion may be considered in select cases.

Cerebrospinal Fluid Biomarkers for Diagnosis and the Prognostication of Acute Ischemic Stroke: A Systematic Review.

Despite the high incidence and burden of stroke, biological biomarkers are not used routinely in clinical practice to diagnose, determine progression, or prognosticate outcomes of acute ischemic stroke (AIS). Because of its direct interface with neural tissue, cerebrospinal fluid (CSF) is a potentially valuable source for biomarker development. This systematic review was conducted using three databases. All trials investigating clinical and preclinical models for CSF biomarkers for AIS diagnosis, prognostication, and severity grading were included, yielding 22 human trials and five animal studies for analysis. In total, 21 biomarkers and other multiomic proteomic markers were identified. S100B, inflammatory markers (including tumor necrosis factor-alpha and interleukin 6), and free fatty acids were the most frequently studied biomarkers. The review showed that CSF is an effective medium for biomarker acquisition for AIS. Although CSF is not routinely clinically obtained, a potential benefit of CSF studies is identifying valuable biomarkers from the pathophysiologic microenvironment that ultimately inform optimization of targeted low-abundance assays from peripheral biofluid samples (e.g., plasma). Several important catabolic and anabolic markers can serve as effective measures of diagnosis, etiology identification, prognostication, and severity grading. Trials with large cohorts studying the efficacy of biomarkers in altering clinical management are still needed.

Association between external ventricular drain removal or replacement and prophylactic anticoagulation in patients with aneurysmal subarachnoid hemorrhage: a propensity-adjusted analysis.

BACKGROUND: Withholding prophylactic anticoagulation from patients with aneurysmal subarachnoid hemorrhage (aSAH) before external ventricular drain (EVD) removal or replacement remains controversial. This study analyzed whether prophylactic anticoagulation was associated with hemorrhagic complications related to EVD removal. METHOD: All aSAH patients treated from January 1, 2014, to July 31, 2019, with an EVD placed were retrospectively analyzed. Patients were compared based on the number of prophylactic anticoagulant doses withheld for EVD removal (> 1 vs. ≤ 1). The primary outcome analyzed was deep venous thrombosis (DVT) or pulmonary embolism (PE) after EVD removal. A propensity-adjusted logistic-regression analysis was performed for confounding variables. RESULTS: A total of 271 patients were analyzed. For EVD removal, > 1 dose was withheld from 116 (42.8%) patients. Six (2.2%) patients had a hemorrhage associated with EVD removal, and 17 (6.3%) patients had a DVT or PE. No significant difference in EVD-related hemorrhage after EVD removal was found between patients with > 1 versus ≤ 1 dose of anticoagulant withheld (4 of 116 [3.5%] vs. 2 of 155 [1.3%]; p = 0.41) or between those with no doses withheld compared to ≥ 1 dose withheld (1 of 100 [1.0%] vs. 5 of 171 [2.9%]; p = 0.32). After adjustment, withholding > 1 dose of anticoagulant versus ≤ 1 dose was associated with the occurrence of DVT or PE (OR 4.8; 95% CI, 1.5-15.7; p = 0.009). CONCLUSIONS: In aSAH patients with EVDs, withholding > 1 dose of prophylactic anticoagulant for EVD removal was associated with an increased risk of DVT or PE and no reduction in catheter removal-associated hemorrhage.

Middle meningeal artery embolization associated with reduced chronic subdural hematoma volume and midline shift in the acute postoperative period.

BACKGROUND: Middle meningeal artery (MMA) embolization for endovascular treatment of chronic subdural hematoma (cSDH) is growing in popularity. cSDH volume and midline shift were analyzed in the immediate postoperative window after MMA embolization. METHODS: A retrospective analysis of cSDHs managed via MMA embolization from January 1, 2018 to March 30, 2021 was performed at a large quaternary center. Pre- and postoperative cSDH volume and midline shift were quantified with CT. Postoperative CT was obtained 12 to 36 hours after embolization. Paired t-tests were used to determine significant reduction. Multivariate analysis was performed using logistic and linear regression for percent improvement from baseline volume. RESULTS: In total, 80 patients underwent MMA embolization for 98 cSDHs during the study period. The mean (SD) initial cSDH volume was 66.54 (34.67) mL, and the mean midline shift was 3.79 (2.85) mm. There were significant reductions in mean cSDH volume (12.1 mL, 95% CI 9.32 to 14.27 mL, P<0.001) and midline shift (0.80 mm, 95% CI 0.24 to 1.36 mm, P<0.001). In the immediate postoperative period, 22% (14/65) of patients had a>30% reduction in cSDH volume. A multivariate analysis of 36 patients found that preoperative antiplatelet and anticoagulation use was significantly associated with an expansion in volume (OR 0.028, 95% CI 0.000 to 0.405, P=0.03). CONCLUSION: MMA embolization is safe and effective for the management of cSDH and is associated with significant reductions in hematoma volume and midline shift in the immediate postoperative period.

Efficacy of a prolonged stability melphalan formulation for intra-arterial treatment of retinoblastoma.

BACKGROUND: Melphalan, which is poorly soluble at room temperature, is widely used for the treatment of retinoblastoma by selective ophthalmic artery infusion. Evomela, a propylene glycol-free formulation of melphalan with improved solubility and stability, has recently been used as an alternative.To compare the safety and efficacy of Evomela with standard-formulation melphalan (SFM) in the treatment of retinoblastoma by selective ophthalmic artery infusion. METHODS: We performed a retrospective case-control study of patients with retinoblastoma undergoing selective ophthalmic artery infusion with SFM or Evomela at a single institution. Cycle-specific percent tumor regression (CSPTR) was estimated by comparing photos obtained during pretreatment examination under anesthesia (EUA) with those obtained during post-treatment EUA 3-4 weeks later. CSPTR, ocular salvage rates, complication rates, operation times (unadjusted and adjusted for difficulty of ophthalmic artery catheterization), and intraprocedural dose expiration rates were compared between Evomela- and SFM-treated groups. Univariate and multivariate analyses were performed. RESULTS: Ninety-seven operations (melphalan: 45; Evomela: 52) for 23 patients with 27 retinoblastomas were studied. The ocular salvage rate was 79% in the SFM-treated group and 69% in the Evomela-treated group. Multivariate regression controlling for tumor grade, patient age, and treatment history revealed no significant differences in ocular salvage rate, CSPTR, complication rates, or operation times. Although the dose expiration rate was higher for the SFM-treated group, the difference was not statistically significant. Notably, there were no ocular or cerebral ischemic complications. CONCLUSION: Evomela has non-inferior safety and efficacy relative to SFM when used for the treatment of retinoblastoma by selective ophthalmic artery infusion.

Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage Receiving Sulfonylureas: A Propensity-Adjusted Analysis.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with increased blood-brain barrier permeability, disrupted tight junctions, and increased cerebral edema. Sulfonylureas are associated with reduced tight-junction disturbance and edema and improved functional outcome in aSAH animal models, but human data are scant. We analyzed neurological outcomes in aSAH patients prescribed sulfonylureas for diabetes mellitus. METHODS: Patients treated for aSAH at a single institution (August 1, 2007-July 31, 2019) were retrospectively reviewed. Patients with diabetes were grouped by presence or absence of sulfonylurea therapy at hospital admission. The primary outcome was favorable neurologic status at last follow-up (modified Rankin Scale score ≤2). Variables with an unadjusted P-value of <0.20 were included in a propensity-adjusted multivariable logistic regression analysis to identify predictors of favorable outcomes. RESULTS: Of 1013 aSAH patients analyzed, 129 (13%) had diabetes at admission, and 16 of these (12%) were receiving sulfonylureas. Fewer diabetic than nondiabetic patients had favorable outcomes (40% [52/129] vs. 51% [453/884], P = 0.03). Among diabetic patients, sulfonylurea use (OR 3.90, 95% CI 1.05-15.9, P = 0.046), Charlson Comorbidity Index <4 (OR 3.66, 95% CI 1.24-12.1, P = 0.02), and absence of delayed cerebral infarction (OR 4.09, 95% CI 1.20-15.5, P = 0.03) were associated with favorable outcomes in the multivariable analysis. CONCLUSIONS: Diabetes was strongly associated with unfavorable neurologic outcomes. An unfavorable outcome in this cohort was mitigated by sulfonylureas, supporting some preclinical evidence of a possible neuroprotective role for these medications in aSAH. These results warrant further study on dose, timing, and duration of administration in humans.

Rapid ventricular overdrive pacing and other advanced flow-control techniques for the endovascular embolization of vein of galen malformations.

Endovascular embolization is the primary strategy in the management for vein of Galen malformations (VOGM). However, despite significant advances in endovascular embolization technologies and techniques, VOGMs remain very technically challenging lesions largely due to the high-flow arteriovenous shunts present in these malformations. A variety of advanced flow-control techniques can be implemented to mitigate the risk of venous escape and increase the safety and efficacy of endovascular treatment. These techniques include regionally targeted strategies (transvenous embolization and balloon-assisted transarterial embolization) and global flow-control methods (pharmacologic cardiac arrest and rapid ventricular overdrive pacing). Each of these strategies are associated with unique advantages and disadvantages, highlighting the importance of a patient-specific approach when treating these challenging lesions.

Socioeconomic Drivers of Outcomes After Aneurysmal Subarachnoid Hemorrhage Treatment at a Large Comprehensive Stroke Center.

BACKGROUND: Sparse data exist on socioeconomic disparities among patients treated for aneurysmal subarachnoid hemorrhage (aSAH). The authors analyzed factors possibly influencing patient outcomes, including having a primary care physician (PCP) at admission, family/caregiver support, a foreign language barrier, primary payer status, and race. METHODS: Socioeconomic data were abstracted for patients treated endovascularly or microsurgically for aSAH at a single center (January 1, 2014-July 31, 2019). Binary logistic regression analyses were used to identify independent predictors of an unfavorable outcome (modified Rankin Scale [mRS] score >2) and for predictive modeling. RESULTS: Among 422 patients, the median (interquartile range) follow-up was 2 (1-23) months. Lack of caregiver support was the only socioeconomic factor associated with an unfavorable outcome at discharge. Independent predictors of mRS score >2 at last follow-up included baseline markers of disease severity (P ≤ 0.03), nonwhite race (OR, 1.69; P = 0.047), lack of caregiver support (OR, 5.55; P = 0.007), and lack of a PCP (OR, 1.96; P = 0.007). Adjusting for follow-up mediated the effects of race and PCP, although caregiver support remained significant and PCP was associated with a lower mortality risk independent of follow-up (OR, 0.51; P = 0.047). Predischarge socioeconomic factors, alongside disease severity, predicted a follow-up mRS score >2 with excellent discrimination (area under the receiver operating curve, 0.81; 95% CI, 0.77-0.86). CONCLUSIONS: At a large, urban, comprehensive stroke center, patients with PCPs, caregiver support, and white race had significantly better long-term outcomes after aSAH. These results reflect disparities in access to healthcare after aSAH for vulnerable populations with extensive lifetime needs.