Is periprocedural sedation during acute stroke therapy associated with poorer functional outcomes?

BACKGROUND: To safely perform acute intra-arterial revascularization procedures, use of sedative medications and paralytics is often necessary. During the conduct of the Interventional Management of Stroke trials (I and II), the level of sedation used periprocedurally varied. At some institutions, patients were paralyzed and intubated as part of the procedural standard of care while at other institutions no routine sedation protocol was followed. The aim of this study was to identify patient characteristics that would correlate with the need for deeper sedation and to explore whether levels of sedation relate to patient outcome. METHODS: 75 of 81 patients in the Interventional Management of Stroke II Study were studied. Patients had anterior circulation strokes and underwent angiography and/or intervention. Four sedation categories were defined and tested for factors potentially associated with the level of sedation. Clinical outcomes were also analyzed, including successful angiographic reperfusion and the occurrence of clinical complications. RESULTS: Only baseline National Institutes of Health Stroke Scale varied significantly by sedation category (p=0.01). Patients that were in the lower sedation category fared better, having a higher rate of good outcomes (p<0.01), lower death rates (p=0.02) and higher successful angiographic reperfusion rates (p=0.01). There was a significantly higher infection rate in patients receiving heavy sedation or pharmacologic paralysis (p=0.02) and a trend towards fewer groin related complications. CONCLUSION: In this small sample, patients not receiving sedation fared better, had higher rates of successful angiographic reperfusion and had fewer complications. Further examination of the indications for procedural sedation or paralysis and their effect on outcome is warranted.

Endovascular Therapy of M2 Occlusion in IMS III: Role of M2 Segment Definition and Location on Clinical and Revascularization Outcomes.

BACKGROUND AND PURPOSE: Uncertainty persists regarding the safety and efficacy of endovascular therapy of M2 occlusions following IV tPA. We reviewed the impact of revascularization on clinical outcomes in 83 patients with M2 occlusions in the Interventional Management of Stroke III trial according to specific M1-M2 segment anatomic features. MATERIALS AND METHODS: Perfusion of any M2 branch distinguished M2-versus-M1 occlusion. Prespecified modified TICI and arterial occlusive lesion revascularization and clinical mRS 0-2 end points at 90 days for endovascular therapy-treated M2 occlusions were analyzed. Post hoc analyses of the relationship of outcomes to multiple baseline angiographic M2 and M1 subgroup characteristics were performed. RESULTS: Of 83 participants with M2 occlusion who underwent endovascular therapy, 41.0% achieved mRS 0-2 at 90 days, including 46.6% with modified TICI 2-3 reperfusion compared with 26.1% with modified TICI 0-1 reperfusion (risk difference, 20.6%; 95% CI, -1.4%-42.5%). mRS 0-2 outcome was associated with reperfusion for M2 trunk (n = 9) or M2 division (n = 42) occlusions, but not for M2 branch occlusions (n = 28). Of participants with trunk and division occlusions, 63.2% with modified TICI 2a and 42.9% with modified TICI 2b reperfusion achieved mRS 0-2 outcomes; mRS 0-2 outcomes for M2 trunk occlusions (33%) did not differ from distal (38.2%) and proximal (26.9%) M1 occlusions. CONCLUSIONS: mRS 0-2 at 90 days was dependent on reperfusion for M2 trunk but not for M2 branch occlusions. For M2 division occlusions, good outcome with modified TICI 2b reperfusion did not differ from that in modified TICI 2a. M2 segment definition and occlusion location may contribute to differences in revascularization and good outcome between Interventional Management of Stroke III and other endovascular therapy studies.

Multimodal CT Imaging: Time to Treatment and Outcomes in the IMS III Trial.

BACKGROUND AND PURPOSE: The importance of time in acute stroke is well-established. Using the Interventional Management of Stroke III trial data, we explored the effect of multimodal imaging (CT perfusion and/or CT angiography) versus noncontrast CT alone on time to treatment and outcomes. MATERIALS AND METHODS: We examined 3 groups: 1) subjects with baseline CTP and CTA (CTP+CTA), 2) subjects with baseline CTA without CTP (CTA), and 3) subjects with noncontrast head CT alone. The demographics, treatment time intervals, and clinical outcomes in these groups were studied. RESULTS: Of 656 subjects enrolled in the Interventional Management of Stroke III trial, 90 (13.7%) received CTP and CTA, 216 (32.9%) received CTA (without CTP), and 342 (52.1%) received NCCT alone. Median times for the CTP+CTA, CTA, and NCCT groups were as follows: stroke onset to IV tPA (120.5 versus 117.5 versus 120 minutes; P = .5762), IV tPA to groin puncture (77.5 versus 81 versus 91 minutes; P = .0043), groin puncture to endovascular therapy start (30 versus 38 versus 44 minutes; P = .0001), and endovascular therapy start to end (63 versus 46 versus 74 minutes; P < .0001). Compared with NCCT, the CTA group had better outcomes in the endovascular arm (OR, 2.12; 95% CI, 1.36-3.31; adjusted for age, NIHSS score, and time from onset to IV tPA). The CTP+CTA group did not have better outcomes compared with the NCCT group. CONCLUSIONS: Use of CTA with or without CTP did not delay IV tPA or endovascular therapy compared with NCCT in the Interventional Management of Stroke III trial.

Outcome Differences between Intra-Arterial Iso- and Low-Osmolality Iodinated Radiographic Contrast Media in the Interventional Management of Stroke III Trial.

BACKGROUND AND PURPOSE: Intracarotid arterial infusion of nonionic, low-osmolal iohexol contrast medium has been associated with increased intracranial hemorrhage in a rat middle cerebral artery occlusion model compared with saline infusion. Iso-osmolal iodixanol (290 mOsm/kg H2O) infusion demonstrated smaller infarcts and less intracranial hemorrhage compared with low-osmolal iopamidol and saline. No studies comparing iodinated radiographic contrast media in human stroke have been performed, to our knowledge. We hypothesized that low-osmolal contrast media may be associated with worse outcomes compared with iodixanol in the Interventional Management of Stroke III Trial (IMS III). MATERIALS AND METHODS: We reviewed prospective iodinated radiographic contrast media data for 133 M1 occlusions treated with endovascular therapy. We compared 5 prespecified efficacy and safety end points (mRS 0-2 outcome, modified TICI 2b-3 reperfusion, asymptomatic and symptomatic intracranial hemorrhage, and mortality) between those receiving iodixanol (n = 31) or low-osmolal contrast media (n = 102). Variables imbalanced between iodinated radiographic contrast media types or associated with outcome were considered potential covariates for the adjusted models. In addition to the iodinated radiographic contrast media type, final covariates were those selected by using the stepwise method in a logistic regression model. Adjusted relative risks were then estimated by using a log-link regression model. RESULTS: Of baseline or endovascular therapy variables potentially linked to outcome, prior antiplatelet agent use was more common and microcatheter iodinated radiographic contrast media injections were fewer with iodixanol. Relative risk point estimates are in favor of iodixanol for the 5 prespecified end points with M1 occlusion. The percentage of risk differences are numerically greater for microcatheter injections with iodixanol. CONCLUSIONS: While data favoring the use of iso-osmolal iodixanol for reperfusion of M1 occlusion following IV rtPA are inconclusive, potential pathophysiologic mechanisms suggesting clinical benefit warrant further investigation.

Is periprocedural sedation during acute stroke therapy associated with poorer functional outcomes?

BACKGROUND: To safely perform acute intra-arterial revascularization procedures, use of sedative medications and paralytics is often necessary. During the conduct of the Interventional Management of Stroke trials (I and II), the level of sedation used periprocedurally varied. At some institutions, patients were paralyzed and intubated as part of the procedural standard of care while at other institutions no routine sedation protocol was followed. The aim of this study was to identify patient characteristics that would correlate with the need for deeper sedation and to explore whether levels of sedation relate to patient outcome. METHODS: 75 of 81 patients in the Interventional Management of Stroke II Study were studied. Patients had anterior circulation strokes and underwent angiography and/or intervention. Four sedation categories were defined and tested for factors potentially associated with the level of sedation. Clinical outcomes were also analyzed, including successful angiographic reperfusion and the occurrence of clinical complications. RESULTS: Only baseline National Institutes of Health Stroke Scale varied significantly by sedation category (p=0.01). Patients that were in the lower sedation category fared better, having a higher rate of good outcomes (p<0.01), lower death rates (p=0.02) and higher successful angiographic reperfusion rates (p=0.01). There was a significantly higher infection rate in patients receiving heavy sedation or pharmacologic paralysis (p=0.02) and a trend towards fewer groin related complications. CONCLUSION: In this small sample, patients not receiving sedation fared better, had higher rates of successful angiographic reperfusion and had fewer complications. Further examination of the indications for procedural sedation or paralysis and their effect on outcome is warranted.

Good clinical outcome after ischemic stroke with successful revascularization is time-dependent.

BACKGROUND: Trials of IV recombinant tissue plasminogen activator (rt-PA) have demonstrated that longer times from ischemic stroke symptom onset to initiation of treatment are associated with progressively lower likelihoods of clinical benefit, and likely no benefit beyond 4.5 hours. How the timing of IV rt-PA initiation relates to timing of restoration of blood flow has been unclear. An understanding of the relationship between timing of angiographic reperfusion and clinical outcome is needed to establish time parameters for intraarterial (IA) therapies. METHODS: The Interventional Management of Stroke pilot trials tested combined IV/IA therapy for moderate-to-severe ischemic strokes within 3 hours from symptom onset. To isolate the effect of time to angiographic reperfusion on clinical outcome, we analyzed only middle cerebral artery and distal internal carotid artery occlusions with successful reperfusion (Thrombolysis in Cerebral Infarction 2-3) during the interventional procedure (<7 hours). Time to angiographic reperfusion was defined as time from stroke onset to procedure termination. Good clinical outcome was defined as modified Rankin Score 0-2 at 3 months. RESULTS: Among the 54 cases, only time to angiographic reperfusion and age independently predicted good clinical outcome after angiographic reperfusion. The probability of good clinical outcome decreased as time to angiographic reperfusion increased (unadjusted p = 0.02, adjusted p = 0.01) and approached that of cases without angiographic reperfusion within 7 hours. CONCLUSIONS: We provide evidence that good clinical outcome following angiographically successful reperfusion is significantly time-dependent. At later times, angiographic reperfusion may be associated with a poor risk-benefit ratio in unselected patients.

Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics.

This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.