Víctor Obach

The Early Systemic Prophylaxis of Infection After Stroke Study: A Randomized Clinical Trial

Background and Purpose— Early infection after stroke is frequent but the clinical value of antibiotic prophylaxis in acute stroke has never been explored. Objective and Methods— The Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) is a randomized, double-blind, placebo-controlled study of antibiotic prophylaxis in patients older than 18 years with nonseptic ischemic or hemorrhagic stroke enrolled within 24 hours from clinical onset. Interventions included intravenous levofloxacin (500 mg/100 mL/d, for 3 days) or placebo (0.9% physiological serum) in addition to optimal care. A sample size of 240 patients was calculated to identify a 15% absolute risk reduction of the primary outcome measure, which was the incidence of infection at day 7 after stroke. Secondary outcome measures were neurological outcome and mortality at day 90. Results— Based on a preplanned futility analysis, the study was interrupted prematurely when 136 patients had been included. Levofloxacin and placebo patients had a cumulative rate of infection of 6% and 6% (P=0.96) at day 1; 10% and 12% (P=0.83) at day 2; 12% and 15% (P=0.66) at day 3; 16% and 19% (P=0.82) at day 7; and 30% and 33% (P=0.70), at day 90. Using logistic regression, favorable outcome at day 90 was inversely associated with baseline National Institutes of Health Stroke Scale (OR, 0.72; 95% CI, 0.59 to 0.89; P=0.002) and allocation to levofloxacin (OR, 0.19; 95% CI, 0.04 to 0.87; P=0.03). Conclusions— Prophylactic administration of levofloxacin (500 mg/100 mL/day for 3 days) is not better than optimal care for the prevention of infections in patients with acute stroke.

Catecholamines, infection, and death in acute ischemic stroke

Experimental studies have recently suggested that acute ischemia may facilitate the appearance of fatal infections as part of a brain-induced immunodepression syndrome. However, the mechanisms and neurological consequences of infections complicating acute ischemic stroke have received much less attention at the bedside. The incidence of infection and death after non-septic stroke was compared in this prospective study with longitudinal changes of cytokines, leukocytes, normetanephrine (NMN) and metanephrine (MN) in 75 consecutive patients. In multivariate analysis, infection, n = 13 (17%), was associated with the upper quartile of MN (OR 3.51, 95% CI 1.30-9.51), neurological impairment (NIHSS) on admission (OR 3.99, 95% CI 1.34-11.8), monocyte count (OR 1.78, 95% CI 1.13-2.79), and increased interleukin (IL)-10 (OR 1.54, 95% CI 1.00-2.38). Mortality at 3 months, n = 16 (21%), was associated with increased levels of NMN on admission (OR 2.34 95% CI 1.15-4.76), NIHSS score (OR 2.57, 95% CI 1.29-5.11), and higher IL-6 levels (OR 1.29, 95% 1.00-1.67). These findings suggest that acute ischemic stroke is associated with an early activation of the sympathetic adrenomedullar pathway that lowers the threshold of infection and increases the risk of death. Moreover, these findings are independent of the blood borne effects of pro- and anti-inflammatory cytokines, and circulating leukocytes.

Monocyte subtypes predict clinical course and prognosis in human stroke

The number of circulating monocytes increases after stroke. In this study, we assessed the time course and phenotype of monocyte subsets and their relationship with the clinical course and outcome in 46 consecutive stroke patients and 13 age-matched controls. The proportion of the most abundant ‘classical’ CD14highCD16 monocytes did not change after stroke, whereas that of CD14highCD16+ monocytes increased and CD14dimCD16+ monocytes decreased. CD14highCD16 + monocytes had the highest expression of TLR2, HLA-DR and the angiogenic marker, Tie-2; CD14dimCD16+ monocytes had the highest expression of costimulatory CD86 and adhesion molecule CD49d. Platelet-monocyte interactions were highest in CD14highCD16 monocytes and lowest in CD14dimCD16+ monocytes. In adjusted models, 1/CD14highCD16 monocytes were associated with poor outcome (OR: 1.38), higher mortality (OR: 1.40) and early clinical worsening (OR: 1.29); 2/CD14highCD16+ monocytes were inversely related to mortality (OR: 0.32); and 3/CD14dimCD16+ monocytes were inversely related to poor outcome (OR: 0.74) and infarction size (r= 0.45; P = 0.02). These results illustrate that the predominant monocyte subtype conveys harmful effects after stroke, which include stronger interaction with platelets. Alternatively, rarer subpopulations of monocytes are beneficial with a phenotype that could promote tissue repair and angiogenesis. Therefore, monitoring of monocyte subtypes may emerge as a useful tool at the bedside for stroke patients.

Monocytes Are Major Players in the Prognosis and Risk of Infection After Acute Stroke

Background and Purpose— Monocytes participate in adaptive and innate immune responses. Monocyte numbers increase in patients with stroke associated infection (SAI) or severe stroke. Whether changes in monocytes are related to specific effects, or simply mark brain damage, remains unsettled. Methods— We used flow cytometry in 45 consecutive strokes and 12 healthy controls to assess the time course of monocytes, their phenotype, and the production of cytokines after stimulation. Cortisol, TNF-α, IFN-γ, and IL-10 were measured in serum and metanephrine in plasma. The effects of humoral and cellular parameters on the risk of SAI and poor outcome were tested in multivariate analyses adjusted for confounders (NIHSS score, age, and tube feeding). Results— Surface expression of human leukocyte antigen-DR, Toll-like receptor-2, and production of TNF-α in monocytes were independently associated with stroke. Distinct immune mechanisms were related with functional outcome and the risk of SAI; the signature of SAI included an increase of cortisol, metanephrine, and IL-10 in serum, and reduced production of TNF-α in monocytes; poor outcome was associated with increased expression of Toll-like receptor-4 in monocytes (OR, 9.61; 95% CI, 1.27–72.47). SAI did not predict poor outcome (OR, 5.63; 95% CI, 0.45–70.42; P=0.18). Conclusions— In human stroke, poor outcome is associated to innate responses mediated by Toll-like receptor-4 in monocytes. SAI may result from the immunosuppressive and antiinflammatory effects of corticoids, catecholamines, IL-10, and deactivated monocytes. Early treated SAI does not contribute significantly to additional brain damage. These findings encourage the exploration of strategies aimed to inhibit Toll-like receptor-4 signaling in acute stroke.

A Pilot Study of Dual Treatment With Recombinant Tissue Plasminogen Activator and Uric Acid in Acute Ischemic Stroke

Background and Purpose— Uric acid (UA) increases the neuroprotective effects of recombinant tissue plasminogen activator (rt-PA) in experimental ischemia. In patients with stroke, increased UA levels have been linked to better stroke recovery, but the clinical safety of dual administration of UA and rt-PA is unknown. Methods— Using a double-blind design, we assessed the safety of exogenous UA in patients with acute stroke treated with rt-PA. Patients were randomized to an intravenous solution of 500 mL of 5% mannitol/0.1% lithium carbonate (vehicle group, n=8) or 500 or 1000 mg of UA (n=16). Safety end points at day 90, lipid peroxidation (serum malondialdehyde), and serum kinetics of UA were established. Results— Twenty-four patients with stroke were treated with rt-PA within mean (SD) 133 (35) minutes of clinical onset (admission National Institutes of Health Stroke Scale score mean [SD] 11 [7], age 71 [10.6] years, 71% males). Levels of UA decreased in the vehicle group and increased for approximately 24 hours in the high dose of UA group, which also had lower levels of malondialdehyde at day 5. Mortality (12.5%), symptomatic central nervous system bleeding (0%), and outcome at day 90 were similar in the 3 treatment arms; one patient in the high-dose group had a mild gouty episode. Conclusions— The administration of UA appears to be safe, decreases lipid peroxidation, and prevents an early fall of UA in serum in patients treated with rt-PA within 3 hours of stroke onset. The clinical efficacy of dual administration of exogenous UA and rt-PA deserves further investigation in a larger acute stroke trial.

Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke

Background and purpose: : The pathophysiology of stroke-associated infection (SAI) is uncertain. The cytokine profile and peripheral white cell response were assessed in patients with or without SAI. Methods: The incidence of SAI was assessed in 110 patients with ischaemic stroke allocated antibiotic prophylaxis or placebo within 24 h of clinical onset. Peripheral white cell counts, interleukin (IL)6, tumour necrosis factor (TNF)α and IL10 were measured in plasma. Results: 17 (15%) patients developed infection and showed time-dependent increases of total white cell count, neutrophils, monocytes, lymphocytes, IL6 and IL10, whereas TNFα and the TNFα/IL10 ratio decreased. In logistic regression, IL10 (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 to 1.16), monocyte count (OR 1.42, 95% CI 1.08 to 1.87) and National Institute for Health Stroke Survey score on admission (OR 1.17, 95% CI 1.05 to 1.31) were independent predictors of systemic infection. Conclusions: SAI is associated with stroke severity, excessive IL10-mediated response and an increased number of circulating monocytes. These results support the finding that acute ischaemic brain injury triggers a blood-borne anti-inflammatory response that decreases the antimicrobial drive of the immune system.

Uric Acid Levels Are Relevant in Patients With Stroke Treated With Thrombolysis

Background and Purpose— Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke. Methods— A total of 317 consecutive patients treated with thrombolysis were included in a prospective stroke registry. Demographics, laboratory data, neurological course, and infarction volume were prospectively collected. Excellent outcome was defined as achieving a modified Rankin Scale score <2 at 90 days. Binary and ordinal logistic regression models were used to analyze modified Rankin Scale score at 90 days. Results— UA levels were significantly higher in patients with an excellent outcome than in patients with a poor outcome (5.82 [1.39] versus 5.42 [1.81], P=0.029). In multivariate models, increased UA levels (OR, 1.23; 95% CI, 1.03 to 1.49; P=0.025) were associated with an excellent outcome and with an increased risk of shifting to a better category across the modified Rankin Scale (OR, 1.19; 95% CI, 1.04 to 1.38; P=0.014) independently of the effect of confounders. The levels of UA and the volume of final infarction were inversely correlated (r=−0.216, P<0.001) and the inverse correlation remained after adjustment for age, sex, and baseline National Institutes of Health Stroke Scale score (t value=−2.54, P=0.01). Significantly lower UA levels were found in patients with malignant middle cerebral artery infarction and parenchymal hemorrhage postthrombolysis. Conclusions— Increased UA serum levels are associated with better outcome in patients with stroke treated with reperfusion therapies. These results support the assessment of the potential neuroprotective role of the exogenous administration of UA in patients with stroke treated with thrombolysis.

A -174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in the pathogenesis of stroke. A base pair substitution -174G/C in the promoter region of the IL-6 gene regulates IL-6 gene expression. We compared the prevalence of this polymorphism in patients with lacunar stroke and in an age- and sex-matched cohort of asymptomatic controls. Eighty-two patients with lacunar stroke and 82 asymptomatic controls were prospectively assessed and genotyped for the -174G/C polymorphism in the promoter region of the IL-6 gene. Demographics and vascular risk factors were recorded in both groups. A brain computed tomography scan/magnetic resonance imaging confirmed the clinical diagnosis of lacunar stroke in all patients. The prevalence of CC genotype (18.3 vs. 7.3%, P=0.03), and the frequency of C allele (42.7 vs. 31.1%, P=0.03) were statistically significantly higher in patients with lacunar stroke than in asymptomatic controls. Expectedly, patients with lacunar stroke had a higher prevalence of vascular risk factors than asymptomatic controls. A logistic regression model showed that independent variables associated with lacunar stroke included history of hypertension (odds ratio (OR), 7.02; 95% confidence interval (95% CI), 3.11-15.81), diabetes (OR, 5.37; 95% CI, 1.52-8.89), hyperlipidemia (OR, 3.43; 95% CI, 1.04-11.25), smoking (OR, 5.84; 95% CI, 2.15-15.84), and CC genotype of the -174G/C IL-6 gene polymorphism (OR, 4.28; 95% CI, 1.22-15.00). These findings suggest that lacunar stroke might result from genetic susceptibility to inflammation-mediated damage in concert with atherosclerotic risk factors.

The Basilar Artery International Cooperation Study (BASICS): study protocol for a randomised controlled trial

BackgroundDespite recent advances in acute stroke treatment, basilar artery occlusion (BAO) is associated with a death or disability rate of close to 70%. Randomised trials have shown the safety and efficacy of intravenous thrombolysis (IVT) given within 4.5 h and have shown promising results of intra-arterial thrombolysis given within 6 h of symptom onset of acute ischaemic stroke, but these results do not directly apply to patients with an acute BAO because only few, if any, of these patients were included in randomised acute stroke trials.Recently the results of the Basilar Artery International Cooperation Study (BASICS), a prospective registry of patients with acute symptomatic BAO challenged the often-held assumption that intra-arterial treatment (IAT) is superior to IVT. Our observations in the BASICS registry underscore that we continue to lack a proven treatment modality for patients with an acute BAO and that current clinical practice varies widely.DesignBASICS is a randomised controlled, multicentre, open label, phase III intervention trial with blinded outcome assessment, investigating the efficacy and safety of additional IAT after IVT in patients with BAO. The trial targets to include 750 patients, aged 18 to 85 years, with CT angiography or MR angiography confirmed BAO treated with IVT. Patients will be randomised between additional IAT followed by optimal medical care versus optimal medical care alone. IVT has to be initiated within 4.5 h from estimated time of BAO and IAT within 6 h. The primary outcome parameter will be favourable outcome at day 90 defined as a modified Rankin Scale score of 0–3.DiscussionThe BASICS registry was observational and has all the limitations of a non-randomised study. As the IAT approach becomes increasingly available and frequently utilised an adequately powered randomised controlled phase III trial investigating the added value of this therapy in patients with an acute symptomatic BAO is needed (clinicaltrials.gov: NCT01717755).

Single-Center Experience of Cerebral Artery Thrombectomy Using the TREVO Device in 60 Patients With Acute Ischemic Stroke

Background and Purpose— We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke. Methods— We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting <8 hours in the anterior circulation (n=54) or <12 hours in the vertebrobasilar circulation (n=6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms >4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b–3), good outcome (modified Rankin Scale score 0–2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment ≥4 points) were prospectively assessed. Results— Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12–22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173–296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45–114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected. Conclusions— The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials.