Preventive Antibacterial Therapy in Acute Ischemic Stroke: A Randomized Controlled Trial

BACKGROUND: Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients. METHODS: Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance. FINDINGS: On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections. INTERPRETATION: PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN74386719

Risk factors for stroke-associated infections – A sub-group analysis of the PANTHERIS-trial

Schlaganfall ist die zweit- bis dritthäufigste Todesursache in den Industrienationen mit einer Letalität von 25%. Die Mehrzahl der Patienten erleidet mindestens eine Komplikation innerhalb der ersten 3 Monate nach Insult. Komplikationen stehen im direkten Zusammenhang mit der Prognose. Deren Verhinderung stellt ein wichtiges Behandlungsziel des Schlaganfalls dar. Neben erhöhtem Hirndruck zählen Infektionen zu den häufigsten schwerwiegenden Komplikationen der Akutphase. Pneumonien bilden den höchsten attribuierten Anteil an der Letalität nach akutem Schlaganfall. Aspiration als Folge von Dysphagie ist ein bedeutender Grund für die hohe Pneumonierate, erklärt diese jedoch nicht vollständig. Experimentelle Daten zeigen, dass eine veränderte Immunantwort das Auftreten von bakteriellen Infektionen nach Insult fördert. Ziel dieser Studie ist es, die Bedeutung des Immunstatus im Vergleich zu anderen Risikofaktoren für das Eintreten von Infektionen nach schwerem ischämischen Schlaganfall zu untersuchen. Es werden 31 Patienten mit schwerem ischämischen Insult (NIHSS > 11) der MCA untersucht. Alle Patienten entstammen der Placebogruppe der PANTHERIS-Studie, einer prospektiven, multizentrischen, randomisierten Doppelblind-Studie. In einer Univariatanalyse werden zunächst Risikofaktoren für Infektionen identifiziert und danach in eine multivariate logistische Regressionsanalyse eingeschlossen. Ziel ist es, unabhängige Einflussfaktoren für schlaganfall-assoziierte Infektionen (SAI) zu ermitteln und den stärksten Prädiktor zu bestimmen. Die Univariatanalyse der Per- Protokoll-Population identifizierte die HLA-DR-Expression auf Monozyten am Aufnahmetag sowie den Einsatz von maschineller Beatmung und nasogastraler Sondenernährung als Risikofaktoren für Infektionen. In der Multivariatanalyse kann eine eingeschränkte Immunkompetenz, gemessen anhand einer verringerten HLA-DR-Expression am Aufnahmetag (10-36h), als stärkster und einziger unabhängiger Prädiktor für SAI bestimmt werden. Patienten mit einer HLA-DR- Expression unterhalb von 20300 Antikörpern pro Monozyt zeigen ein fast 6faches Infektionsrisiko. Eine schlaganfallbedingte Immundepression, gemessen anhand der HLA-DR-Expression auf Monozyten, stellt einen unabhängigen Prädiktor für das Eintreten von Infektionen nach schwerem ischämischen Schlaganfall im Stromgebiet der MCA dar. Dieser Immunmarker kann Hochrisikopatienten für SAI identifizieren und ist für neue Therapieansätze wie die präventive antibiotische Therapie von begründendem Wert. Größere prospektive Studien sind jedoch notwendig, um besonders den Einfluss von Dysphagie im Vergleich zur Immundepression auf das Infektionsrisiko nach Schlaganfall zu untersuchen.Stroke is the second to third most common cause of death in the industrial world. Twenty five percent of all stroke patients die of its consequences. Stroke patients suffer at least one complication within the first 3 months after apoplexy. Complications worsen the outcome after stroke. Avoiding them is one of the main goal of post-stroke treatment. Infections and increased intracranial pressure are the most severe complications during the acute phase. Pneumonia has the highest attributable proportion of death after ischemic stroke. Aspiration as a result of dysphagia is an important cause of pneumonia, but does not explain sufficiently its high incidence after stroke. Experimental trials demonstrate that an impaired immune response after stroke favors bacterial upper respiratory tract infections. Aim of this study is to identify predictors for stroke-associated infections (SAI) and to compare the importance of the immune system to other risk factors. The study population includes thirty-one patients with severe acute ischemic stroke (NIHSS > 11) of the middle cerebral artery (MCA). This group is identical to the placebo arm of the PANTHERIS-trial, a prospective, multi-centered, randomized and double blind study. The primary endpoint is the occurrence of infections within 11 days after apoplexy. Risk factors for infection are identified using univariate analyses. In a second step they are compared towards their predictive value and independence by including them in a multivariate logistic regression analysis. The univariate analysis reveals that the expression of HLA-DR on monocytes and the application of mechanical ventilation and tube feeding are risk factors for infection after acute stroke. The multivariate analysis shows that an impaired immune response measured by a lower expression of HLA-DR on admission (10 to 36 hrs) is the only independent predictor for SAI. Patients with an HLA-DR-expression below 20300 antibodies per monocyte have a six-fold increased risk of infection within the first 11 days after severe ischemic stroke. A stroke-associated immunodepression measured by the HLA-DR-expression on monocytes is an independent predictor for infection after severe acute ischemic stroke of the MCA. This immune parameter can help to identify patients at high risk for SAI in order to apply special treatments to avoid infections such as a preventive antibiotic therapy. Larger prospective studies are necessary in order to verify these results for a greater range of stroke subtypes. Future studies should especially focus on the predictive values of dysphagia compared to the impaired immune response after stroke

Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial

International audienceBackground and Purpose— Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods— FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results— FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 ( P =0.169) and shift analysis ( P =0.086) but reached significance for mRS score of 0 to 2 ( P =0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions— In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I 2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None