Christine Roffe

Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2)

The cardiovascular actions of the magnesium ion at pharmacological concentrations include coronary and systemic vasodilatation, platelet inhibition, and antiarrhythmic effects. Magnesium has also been reported to protect myocardial tissue in experimental models of ischaemia and reperfusion. Several small clinical trials in suspected acute myocardial infarction have suggested that early mortality can be reduced by intravenous infusion of magnesium salts in the acute phase, but none has been of sufficient size to be conclusive. We therefore conducted a randomised, double blind, placebo controlled study in 2316 patients with suspected acute myocardial infarction who received either intravenous magnesium sulphate (8 mmol over 5 min followed by 65 mmol over 24 h) or physiological saline. The primary outcome measure was 28-day mortality, which was ascertained in 99.3% of patients. The groups were well balanced for prognostic factors. By intention-to-treat analysis mortality from all causes was 7.8% in the magnesium group and 10.3% in the placebo group (2p = 0.04), a relative reduction of 24% (95% confidence interval 1-43%). Within the coronary care unit the incidence of left ventricular failure was reduced by 25% (7-39%) in the magnesium group (2p = 0.009). There was no significant difference between the groups in the incidence of heart block or the use of antiarrhythmic drugs, direct-current cardioversion, or temporary pacing. Myocardial infarction was confirmed in 65% of each group, with closely similar rises in cardiac enzymes. The side-effects of magnesium treatment were transient flushing, related to speed of injection of the loading dose, and an increased incidence of sinus bradycardia (2p = 0.02). Exploratory subgroup analyses of 28-day mortality did not indicate any effect modification by thrombolysis or aspirin, or by previous treatment with beta blockers, calcium antagonists, or diuretics. Intravenous magnesium sulphate is a simple, safe, and widely applicable treatment. Its efficacy in reducing early mortality of myocardial infarction is comparable to, but independent of, that of thrombolytic or antiplatelet therapy.

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

BACKGROUND Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).

An investigation into the agreement between clinical, biomechanical and neurophysiological measures of spasticity:

Objective: To quantify agreement between three clinically usable methods of measuring spasticity. Methods: Patients with a first stroke who had no useful functional movement in the upper limb within six weeks from stroke onset were eligible to participate. Spasticity at the wrist joint was simultaneously measured using three methods, during an externally imposed passive stretch at two (uncontrolled) displacement velocities. The measures used were a common clinical measure (modified Ashworth Scale), a biomechanical measure (resistance to passive movement) and a neurophysiological measure (muscle activity). Results: One hundred patients (54 men and 46 women) with a median age of 74 years (range 43—91) participated. Median time since stroke was three weeks (range 1—6), the right side was affected in 52 patients and the left in 48 patients. Based on muscle activity measurement, 87 patients had spasticity. According to the modified Ashworth score 44 patients had spasticity. Sensitivity of modified Ashworth score, when compared with muscle activity recordings, was 0.5 and specificity was 0.92. Based on muscle activity patterns, patients could be classified into five subgroups. The biomechanical measures showed no consistent relationship with the other measures. Conclusion: The presentations of spasticity are variable and are not always consistent with existing definitions. Existing clinical scales that depend on the quantification of muscle tone may lack the sensitivity to quantify the abnormal muscle activation and stiffness associated with common definitions of spasticity. Neurophysiological measures may provide more clinically useful information for the management and assessment of spasticity.

What Patients Want. Consumer Involvement in the Design of a Randomized Controlled Trial of Routine Oxygen Supplementation After Acute Stroke

Background and Purpose— To involve stroke patients and carers in the design of a study of oxygen supplementation in acute stroke and to obtain their views on the importance of the study, consent issues, relevance, and acceptability of the outcome measures, and the preferred method of follow-up. Methods— This study involved qualitative and quantitative research. Three focus group meetings were held with individuals who have had personal experience of stoke, mostly stoke patients and their partners or carers (an association of young stroke sufferers and 2 dysphasia support groups each from a different town in the West Midlands, UK). The researchers explained the planned oxygen supplementation study and encouraged participants to comment and make suggestions in a semistructured interview. The audience was then asked to complete a questionnaire relating to the study. Results— Seventy-three people (67% stroke patients and 33% carers; mean age 64; range 31 to 86 years; and 47% males) attended the 3 meetings. The overall response rate to the questionnaires was 70%. Most of the respondents considered the study worthwhile (97%) and the planned outcome measures relevant. In addition, assessment of speech, memory, sleep, and cognitive function was raised by >20% of respondents as important outcomes. Seventy-five percent would agree with assent from a family member on behalf of incompetent patients, and 92% would agree to a doctor recruiting incompetent patients to the study and seeking consent/assent later. The majority of respondents (80%) preferred personal contact with the researcher or a representative to a questionnaire for follow-up. Conclusions— Involvement of stroke patients and carers helped us identify outcome measures that are important to the stroke population but not routinely addressed in stroke assessment scales. A high proportion of respondents asked for waiver of consent and agreed to family’s assent on behalf of incompetent patients. Although consumer involvement has helped us to make the study more relevant to the public, it has also led to difficult scientific and ethical conflicts in protocol design.

Diagnosis of Stroke-Associated Pneumonia: Recommendations From the Pneumonia in Stroke Consensus Group

Background and Purpose— Lower respiratory tract infections frequently complicate stroke and adversely affect outcome. There is currently no agreed terminology or gold-standard diagnostic criteria for the spectrum of lower respiratory tract infections complicating stroke, which has implications for clinical practice and research. The aim of this consensus was to propose standardized terminology and operational diagnostic criteria for lower respiratory tract infections complicating acute stroke. Methods— Systematic literature searches of multiple electronic databases were undertaken. An evidence review and 2 rounds of consensus consultation were completed before a final consensus meeting in September 2014, held in Manchester, United Kingdom. Consensus was defined a priori as ≥75% agreement between the consensus group members. Results— Consensus was reached for the following: (1) stroke-associated pneumonia (SAP) is the recommended terminology for the spectrum of lower respiratory tract infections within the first 7 days after stroke onset; (2) modified Centers for Disease Control and Prevention (CDC) criteria are proposed for SAP as follows—probable SAP: CDC criteria met, but typical chest x-ray changes absent even after repeat or serial chest x-ray; definite SAP: CDC criteria met, including typical chest x-ray changes; (3) there is limited evidence for a diagnostic role of white blood cell count or C-reactive protein in SAP; and (4) there is insufficient evidence for the use of other biomarkers (eg, procalcitonin). Conclusions— Consensus operational criteria for the terminology and diagnosis of SAP are proposed based on the CDC criteria. These require prospective evaluation in patients with stroke to determine their reliability, validity, impact on clinician behaviors (including antibiotic prescribing), and clinical outcomes.

Spasticity and contractures at the wrist after stroke: time course of development and their association with functional recovery of the upper limb

Objective: To investigate the time course of development of spasticity and contractures at the wrist after stroke and to explore if these are associated with upper limb functional recovery. Design: Longitudinal observational study using secondary data from the control group of a randomized controlled trial. Setting: The Acute Stroke Unit at the University Hospital of North Staffordshire. Subjects: Patients without useful arm function (Action Research Arm Test — ARAT) score of 0 within 6 weeks of a first stroke. Main measures: Spasticity was measured by quantifying muscle activity during passively imposed stretches at two velocities. Contractures were measured by quantifying passive range of movement and stiffness. Upper limb functional movement was assessed using the ARAT. All assessments were conducted at baseline, and at 6, 12, 24 and 36 weeks after recruitment. Results: Thirty patients (43% male, median age 70 (range 52—90) years, median time since stroke onset 3 (range 1—5) weeks) were included. Twenty-eight (92%) demonstrated signs of spasticity throughout the study period. Participants who recovered arm function (n = 5) showed signs of spasticity at all assessment points but did not develop contractures. Patients who did not recover useful arm function (n = 25) had signs of spasticity and changes associated with contracture formation at all time points tested. Conclusion: In this group of patients who had no arm function within the first 6 weeks of stroke, spasticity was seen early, but did not necessarily hinder functional recovery. Contractures were more likely to develop in patients who did not recover arm function.

Does Sex Influence the Response to Intravenous Thrombolysis in Ischemic Stroke? Answers From Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register

Background and Purpose— Women are more likely to have a worse outcome after an acute stroke than men. Some studies have suggested that women also benefit less from intravenous thrombolysis after an acute ischemic stroke, but others found no sex differences in safety and efficacy. We aimed to evaluate differences in 3-month outcome between sexes in intravenous tissue-type plasminogen activator–treated patients registered in the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register. Methods— A total of 45 079 patients treated with intravenous alteplase were recorded from 2002 to 2011. Main outcome measures were symptomatic intracerebral hemorrhage, functional independence (modified Rankin Scale score, 0–2), and mortality at 3 months. Results— Among 25 777 (57.2%) men and 19 302 (42.8%) women, we found no difference in the rate of symptomatic intracerebral hemorrhage (P=0.13), a significantly higher likelihood of functional independence at 3 months in men (P<0.0001) and a higher mortality in women when compared with men (P<0.00001). After adjustment for confounding variables, we did not observe any difference between sexes in functional outcome (odds ratio, 1.03; 95% confidence interval, 0.97–1.09; P=0.39), whereas male sex was related to a higher risk of mortality (odds ratio, 1.19; 95% confidence interval, 1.10–1.29; P=0.00003) and symptomatic intracerebral hemorrhage (odds ratio, 1.25, 95% confidence interval, 1.04–1.51; P=0.02). Conclusions— Data from Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register suggest that intravenous thrombolysis may modify the observed survival and recovery advantage for men expected in the natural course of an ischemic stroke, with a possible larger beneficial treatment effect in women when compared with men.

Unexpected Nocturnal Hypoxia in Patients With Acute Stroke

Background and Purpose— Patients who have had a stroke are at risk of hypoxia through alterations in the central regulation of respiration, through aspiration, and through respiratory muscle weakness. Sleep-related breathing disorders are common and may lead to episodes of nocturnal hypoxia even when daytime oxygenation is normal. The aim of this study was to assess the prevalence of unexpected nocturnal hypoxia in stroke patients. Methods— Consecutive adult patients with stroke were recruited within 72 hours of admission to hospital. Patients with indications for oxygen treatment were excluded. Older adults from the local community were recruited as control subjects. Oxygenation was assessed by pulse oximetry (Minolta 3i) for 5 minutes when awake before bedtime and continuously from 11 pm until 7 am. Results— Of the 238 potentially eligible stroke patients, 120 were excluded because they required oxygen, 118 were recruited, and 100 had adequate pulse oximetry data. The mean±SD age was 74±8 years for stroke patients and 72±8 years for control subjects (n=85). Mean awake oxygen saturation (So2) was 94.5±1.7% for the stroke group and 95.8±1.7% for the control group (P <0.001). Mean nocturnal So2 was 93.5±1.9% in stroke patients and 94.3±1.9% in control subjects (P <0.01). Stroke patients had a higher oxygen desaturation index (ODI 4%) (8.9 versus 2.1, P <0.001). In addition, 23% of stroke patients spent >30 minutes with So2 <90% during the night. Conclusions— Oxygen saturation at night is ≈1% lower than when awake. Almost a quarter of stroke patients who are normoxic at screening during the day spend >30 minutes with an oxygen saturation <90%.

How Is Pneumonia Diagnosed in Clinical Stroke Research? A Systematic Review and Meta-Analysis

Background and Purpose— Diagnosis of pneumonia complicating stroke is challenging, and there are currently no consensus diagnostic criteria. As a first step in developing such consensus-based diagnostic criteria, we undertook a systematic review to identify the existing diagnostic approaches to pneumonia in recent clinical stroke research to establish the variation in diagnosis and terminology. Methods— Studies of ischemic stroke, intracerebral hemorrhage, or both, which reported occurrence of pneumonia from January 2009 to March 2014, were considered and independently screened for inclusion by 2 reviewers after multiple searches using electronic databases. The primary analysis was to identify existing diagnostic approaches for pneumonia. Secondary analyses explored potential reasons for any heterogeneity where standard criteria for pneumonia had been applied. Results— Sixty-four studies (56% ischemic stroke, 6% intracerebral hemorrhage, 38% both) of 639 953 patients were included. Six studies (9%) reported no information on the diagnostic approach, whereas 12 (19%) used unspecified clinician-reported diagnosis or initiation of antibiotics. The majority used objective diagnostic criteria: 20 studies (31%) used respiratory or other published standard criteria; 26 studies (41%) used previously unpublished ad hoc criteria. The overall occurrence of pneumonia was 14.3% (95% confidence interval 13.2%–15.4%; I2=98.9%). Occurrence was highest in studies applying standard criteria (19.1%; 95% confidence interval 15.1%–23.4%; I2=98.5%). The substantial heterogeneity observed was not explained by stratifying for other potential confounders. Conclusions— We found considerable variation in terminology and the diagnostic approach to pneumonia. Our review supports the need for consensus development of operational diagnostic criteria for pneumonia complicating stroke.

Does low-dose botulinum toxin help the recovery of arm function when given early after stroke? A phase II randomized controlled pilot study to estimate effect size

Objective: Spasticity after stroke may be associated with worse functional outcome. Our study aim is to establish whether a low dose of botulinum toxin, given early post stroke before clinically evident spasticity warrants treatment, will improve recovery of arm function. Design: A double-blind randomized placebo-controlled trial. Setting: An acute stroke unit. Subjects: Individuals recruited within three weeks of stroke onset with severe arm function deficits. Interventions: Injections of quarter and half standard dose botulinum toxin A to the upper limb, with a control of normal saline injections. Main measures: Arm function, active and passive movement, and spasticity at elbow and wrist were recorded at baseline, and at 4, 8, 12 and 20 weeks post intervention. A pre-planned subgroup analysis included only subjects with no arm function at baseline (Action Research Arm Test score = 0). Results: Thirty subjects were recruited, and 21 completed all assessments. Arm function scores improved in all three groups between baseline and week 20. There was no benefit for active treatment over control in the whole group analysis. In the subgroup analysis the active groups improved when compared with the control group and effect sizes for improvement in this subgroup were 0.6 and 0.5 for the quarter dose and half dose groups respectively. Conclusions: Individuals with no arm function within three weeks of stroke may benefit functionally from botulinum toxin. Using the effect size of 0.5, further studies would need a minimum of 101 participants in each group to confirm this finding.