A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. IV vs. IA TPA in acute ischemic stroke with CT angiographic evidence of major vessel occlusion: a feasibility study. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. [Early intravenous thrombolysis with recombinant tissue plasminogen activator for acute cerebral infarction]. SYNTHESIS expansion: design of a nonprofit, pragmatic, randomized, controlled trial on the best fast-track endovascular treatment vs. standard intravenous alteplase for acute ischemic stroke. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Intra-arterial or intravenous thrombolysis for acute ischemic stroke? The SYNTHESIS pilot trial. Comparison of intravenous and intra-arterial urokinase thrombolysis for acute ischaemic stroke. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial.
Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent.
                In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits).
                The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02).
                Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.). Studies suggest that stroke patients with thrombus in a major cerebral vessel respond less favorably to intravenous (IV) thrombolysis. The purpose of this study was to test the feasibility of a protocol comparing IV versus intra-arterial (IA) recombinant tissue plasminogen activator (TPA) in an acute ischemic stroke with major vessel occlusion.
                Consecutive ischemic stroke patients presenting <3 h from symptom onset with major vessel occlusion on CT angiogram (CTA) were randomly assigned to IV TPA (per NINDS protocol) or IA TPA (22 mg over 2 h). Demographics, times to presentation and thrombolysis, presenting NIH stroke scale (NIHSS) and 90-day NIHSS, Barthel Index, and modified Rankin Scale were recorded. CT-scans at 24-h were reviewed for presence of hemorrhage. Recanalization was determined by post-procedure MR angiograms, which are obtained the day after thrombolytic therapy.
                Seven patients (median NIHSS = 16) were randomized to IV (N = 4) or IA (N = 3) TPA. There were no significant differences in the presentation NIHSS, time to presentation, or time to treatment between the two groups. Hemorrhage was noted in one patient in the IA group (asymptomatic) and one patient in the IV group (symptomatic). Recanalization was seen in all patients treated with IA TPA and none treated with IV TPA (P = 0.03, Fisher's Exact test).
                We found that it is feasible to conduct a trial comparing IV vs. IA TPA in ischemic stroke patients with major vessel occlusion presenting <3 h from onset. Patients treated with IA TPA showed a trend toward higher rate of recanalization. A larger trial may be designed to test safety and effectiveness of IA TPA in this specific group of stroke patients. Most acute ischemic stroke patients arrive after the 3-hour time window for recombinant tissue plasminogen activator (rtPA) administration. The Desmoteplase In Acute Ischemic Stroke trial (DIAS) was a dose-finding randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific and nonneurotoxic thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI.
                DIAS was a placebo-controlled, double-blind, randomized, dose-finding phase II trial. Patients with National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch were eligible. Of 104 patients, the first 47 (referred to as Part 1) were randomized to fixed doses of desmoteplase (25 mg, 37.5 mg, or 50 mg) or placebo. Because of an excessive rate of symptomatic intracranial hemorrhage (sICH), lower weight-adjusted doses escalating through 62.5 microg/kg, 90 microg/kg, and 125 microg/kg were subsequently investigated in 57 patients (referred to as Part 2). The safety endpoint was the rate of sICH. Efficacy endpoints were the rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by NIHSS, modified Rankin scale, and Barthel Index at 90 days.
                Part 1 was terminated prematurely because of high rates of sICH with desmoteplase (26.7%). In Part 2, the sICH rate was 2.2%. No sICH occurred with placebo in either part. Reperfusion rates up to 71.4% (P=0.0012) were observed with desmoteplase (125 microg/kg) compared with 19.2% with placebo. Favorable 90-day clinical outcome was found in 22.2% of placebo-treated patients and between 13.3% (62.5 microg/kg; P=0.757) and 60.0% (125 microg/kg; P=0.0090) of desmoteplase-treated patients. Early reperfusion correlated favorably with clinical outcome (P=0.0028). Favorable outcome occurred in 52.5% of patients experiencing reperfusion versus 24.6% of patients without reperfusion.
                Intravenous desmoteplase administered 3 to 9 hours after acute ischemic stroke in patients selected with perfusion/diffusion mismatch is associated with a higher rate of reperfusion and better clinical outcome compared with placebo. The sICH rate with desmoteplase was low, using doses up to 125 microg/kg. The purpose of this study was to test the feasibility, efficacy, and safety of combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (r-TPA) therapy for stroke within 3 hours of onset of symptoms.
                This was a double-blind, randomized, placebo-controlled multi-center Phase I study of IV r-TPA or IV placebo followed by immediate cerebral arteriography and local IA administration of r-TPA by means of a microcatheter. Treatment activity was assessed by improvement on the National Institutes of Health Stroke Scale Score (NIHSSS) at 7 to 10 days. The Barthel Index, modified Rankin Scale, and the Glasgow Outcome Scale measured 3-month functional outcome. Arterial recanalization rates and their relation to total r-TPA dose and time to lysis were measured. Rates of life-threatening bleeding, intracerebral hemorrhage (ICH), or other bleeding complications assessed safety.
                Thirty-five patients were randomly assigned, 17 into the IV/IA group and 18 into the placebo/IA group. There was no difference in the 7- to 10-day or the 3-month outcomes, although there were more deaths in the IV/IA group. Clot was found in 22 of 34 patients. Recanalization was better (P=0. 03) in the IV/IA group with TIMI 3 flow in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA patients and correlated to the total dose of r-TPA (P=0.05). There was no difference in the median treatment intervals from time of onset to IV treatment (2.6 vs 2.7 hours), arteriography (3.3 vs 3.0 hours), or clot lysis (6.3 vs 5.7 hours) between the IV/IA and placebo/IA groups, respectively. A direct relation between NIHSSS and the likelihood of the presence of a clot was identified. Eight ICHs occurred; all were hemorrhagic infarctions. There were no parenchymal hematomas. Symptomatic ICH within 24 hours occurred in 1 placebo/IA patient only. Beyond 24 hours, symptomatic ICH occurred in 2 IV/IA patients only. Life-threatening bleeding complications occurred in 2 patients, both in the IV/IA group. Moderate to severe bleeding complications occurred in 2 IV/IA patients and 1 placebo/IA patient.
                This pilot study demonstrates combined IV/IA treatment is feasible and provides better recanalization, although it was not associated with improved clinical outcomes. The presence of thrombus on initial arteriography was directly related to the baseline NIHSSS. This approach is technically feasible. The numbers of symptomatic ICH were similar between the 2 groups, which suggests that this approach may be safe. Further study is needed to determine the safety and effectiveness of this new method of treatment. Such studies should address not only efficacy and safety but also the cost-benefit ratio and quality of life, given the major investment in time, personnel, and equipment required by combined IV and IA techniques. To evaluate the efficacy and safety of recombinant tissue plasminogen activator (rt-PA) and to explore the most suitable dosage of rt-PA in the early treatment of the Chinese patients with acute cerebral infarction (ACI).
                The patients who suited for the standard were divided into three groups. Group A received rt-PA at 0.9 mg/kg, group B received rt-PA at 0.7 mg/kg, and group C did not receive any thrombolytic therapy. In thrombolytic groups, rt-PA at 8 mg was injected intravenously in a bolus at first and then the rest was given over 60 minutes. The maximal dosage was 90 mg. The Chinese stroke scale (CSS) and Barthel Index (BI) were used to evaluate the recovery of neurological functions after rt-PA treatment for 24 hours and 90 days. The hemorrhagic rate and 30 days mortality rate were also analysed.
                In group A the CSS significant effective rate was 41.18 percent at 24 hours and 76.47 percent at 90 days after thrombolysis. At 90 days BI significant effective rate was 58.82 percent. At 30 days hemorrhagic rate was 8.82 percent and mortality rate was 5.88 percent. In group B, the CSS significant effective rate was 39.39 percent at 24 hours and 69.70 percent at 90 days. At 90 days, BI significant effective rate was 54.55 percent, and at 30 days, hemorrhagic rate was 9.09 percent and mortality rate was 9.09 percent. In group C, the CSS significant effective rate was 21.21 percent, at 24 hours and 30.30 percent at 90 days (P>0.05). At 90 days, BI was 21.21 percent the mortality rate was 9.09 percent. At 30 days the mortality rate was no significant difference within three groups At 90 days, significant effective rate was 73.13 percent vs. 30.30 percent in thrombolytic and control groups (P=0.001 7). The significant disability rate was 13.43 percent vs. 24.24 percent.
                For Chinese individuals, with ACI, rt-PA thrombolysis was effective and safe. The dosage of 0.9 mg/kg for foreign people also fitted for Chinese individuals. Rationale Reperfusion in ischemic stroke can be pursued by either systemic intravenous thrombolysis or endovascular treatment. However, systemic intravenous thrombolysis with alteplase within 4·5 h of symptom onset in selected patients is the only medication of proven efficacy. No randomized-controlled trials have so far compared the two modalities. To explore this, after a pilot phase, we started the SYNTHESIS Expansion trial. Aims To determine whether endovascular treatment (i.e., intra-arterial thrombolysis with alteplase - if necessary, associated to or substituted by mechanical clot disruption and/or retrieval) compared with systemic intravenous thrombolysis with alteplase, administered according to European labelling, increases the proportion of independent survivors at three-months. Design SYNTHESIS Expansion is an open-label, multicenter randomized-controlled trial, with blinded follow-up. Eligibility applies to; patients with symptomatic ischemic stroke, seen within 4·5 h of onset; being able to initiate intravenous alteplase immediately, and endovascular treatment as soon as possible (not later than six-hours of stroke onset). The study is pragmatically based on the 'uncertainty principle' between endovascular treatment and systemic intravenous thrombolysis for patients eligible for intravenous alteplase. There are no prespecified clinical or instrumental criteria to further select a patient, although investigators are left free to use them. Enrollment will be completed with 350 randomized patients. Primary analysis is on an intent-to-treat basis. Study outcomes Primary: modified Rankin scale score of 0 or 1 at three-months. Secondary: neurological deficit seven-days after thrombolysis and the safety of the procedure on the basis of events reported within seven-days following thrombolysis - symptomatic cerebral hemorrhage, fatal and nonfatal stroke, death from any cause, neurological deterioration.
                © 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization. Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI).
                In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852.
                Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo).
                The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase.
                PAION Deutschland GmbH; Forest Laboratories. To determine the effect of intravenous recombinant tissue plasminogen activator (rt-PA) on vascular and neurologic outcomes, we enrolled 31 patients with acute carotid artery-territory ischemic stroke within 6 hours from symptom onset in a randomized, double-blind, placebo-controlled study. We gave either rt-PA (duteplase at the dose of 20 or 30 mega-international units [MIU]) or placebo intravenously for 60 minutes in patients randomly assigned to the three groups. A comparison between the baseline and postinfusion angiograms showed that complete or partial reperfusion occurred in 50% (5/10) of patients treated with 30 MIU rt-PA, 44% (4/9) of those treated with 20 MIU rt-PA, and 17% (2/12) in the control group. In patients with middle cerebral artery occlusions, reperfusion occurred in 71% (5/7) of the 30-MIU group, in 67% (4/6) of the 20-MIU group, and in 13% (1/8) of the control group. Patients treated with 30 MIU rt-PA showed a significantly early and better clinical improvement, as measured by the neurologic scale, than did those treated with placebo. Parenchymal hemorrhage occurred in one patient in each group, and frequency of clinically insignificant hemorrhagic infarction was comparable among the treatment groups. No major systemic complications occurred in any group. These results support the efficacy of intravenous infusion of rt-PA soon after the onset of stroke in producing rapid thrombolysis and neurologic recovery; it may be of particular value in patients with thromboembolic occlusion in the middle cerebral artery. Desmoteplase is a novel plasminogen activator with favorable features in vitro compared with available agents. This study evaluated safety and efficacy of intravenous (IV) desmoteplase in patients with perfusion/diffusion mismatch on MRI 3 to 9 hours after onset of acute ischemic stroke.
                DEDAS was a placebo-controlled, double-blind, randomized, dose-escalation study investigating doses of 90 microg/kg and 125 microg/kg desmoteplase. Eligibility criteria included baseline National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20 and MRI evidence of perfusion/diffusion mismatch. The safety end point was the rate of symptomatic intracranial hemorrhage. Primary efficacy co-end points were MRI reperfusion 4 to 8 hours after treatment and good clinical outcome at 90 days. The primary analyses were intent-to-treat. Before unblinding, a target population, excluding patients violating specific MRI criteria, was defined.
                Thirty-seven patients were randomized and received treatment (intent-to-treat; placebo: n=8; 90 microg/kg: n=14; 125 microg/kg: n=15). No symptomatic intracranial hemorrhage occurred. Reperfusion was achieved in 37.5% (95% CI [8.5; 75.5]) of placebo patients, 18.2% (2.3; 51.8) of patients treated with 90 microg/kg desmoteplase, and 53.3% (26.6; 78.7) of patients treated with 125 microg/kg desmoteplase. Good clinical outcome at 90 days occurred in 25.0% (3.2; 65.1) treated with placebo, 28.6% (8.4; 58.1) treated with 90 microg/kg desmoteplase and 60.0% (32.3; 83.7) treated with 125 microg/kg desmoteplase. In the target population (n=25), the difference compared with placebo increased and was statistically significant for good clinical outcome with 125 microg/kg desmoteplase (P=0.022).
                Treatment with IV desmoteplase 3 to 9 hours after ischemic stroke onset appears safe. At a dose of 125 microg/kg desmoteplase appeared to improve clinical outcome, especially in patients fulfilling all MRI criteria. The results of DEDAS generally support the results of its predecessor study, Desmoteplase in Acute Ischemic Stroke (DIAS). OBJECTIVE To assess the feasibility, safety and preliminary efficacy of intra-arterial thrombolysis (IAT) compared with standard intravenous thrombolysis (IVT) for acute ischemic stroke. METHODS Eligible patients with ischemic stroke, who were devoid of contraindications, started IVT within 3 h or IAT as soon as possible within 6 h. Patients were randomized within 3 h of onset to receive either intravenous alteplase, in accordance with the current European labeling, or up to 0.9 mg/kg intra-arterial alteplase (maximum 90 mg), over 60 min into the thrombus, if necessary with mechanical clot disruption and/or retrieval. The purpose of the study was to determine the proportion of favorable outcome at 90 days. Safety endpoints included symptomatic intracranial hemorrhage (SICH), death and other serious adverse events. RESULTS 54 patients (25 IAT) were enrolled. Median time from stroke onset to start to treatment was 3 h 15 min for IAT and 2 h 35 min for IVT (p<0.001). Almost twice as many patients on IAT as those on IVT survived without residual disability (12/25 vs 8/29; OR 3.2; 95% CI 0.9 to 11.4; p=0.067). SICH occurred in 2/25 patients on IAT and in 4/29 on IVT (OR 0.5; CI 0.1 to 3.3; p=0.675). Mortality at day 7 was 5/25 (IAT) compared with 4/29 (IVT) (OR 1.6; CI 0.4 to 6.7; p=0.718). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS Rapid initiation of IAT is a safe and feasible alternative to IVT in acute ischemic stroke. Intravenous fibrinolysis (IVF) with rt-PA (alteplase) provides significant benefits in acute ischaemic stroke when it is given within the first three hours following stroke onset. Intra-arterial fibrinolysis (IAF) with pro-urokinase in PROACT II study provides quite the same benefit in the first 6 hours. IVF and IAF have never been compared. To compare the efficacy and safety of IVF and IAF with urokinase given within the first 6 hours of acute ischaemic stroke. Patients fulfilling the selection criteria were randomly assigned to receive urokinase 900,000 units via intravenous or intra-arterial routes. This randomised monocentre study was done between December 1995 and August 1997. The primary outcome was defined as the number of patients with a modified Rankin score of 2 or less. Secondary outcomes included mortality, frequency of symptomatic intracranial haemorrhage (SIH), neurological and functional scores. Fourteen patients were given IVF and 13 IAF. The study was terminated by the National Health Authorities when 27 patients had been included because of the mortality rate. Seven patients (26%) died, 4 in the IV group (oedematous infarct in 3 and recurrence in 1), 3 in the IA group (SIH in 2, and oedematous infarct in 1). Patients given IVF were treated significantly earlier (4:16 h vs 5:24 h; p=.007). Although IA patients showed greater and earlier improvement there was no significant difference in primary and secondary outcomes. Because of premature termination, the trial was too small to provide any reliable and conclusive results. Intra-arterial fibrinolysis began significantly later than IV fibrinolysis but it gave non-significantly better results in this prematurely terminated study. Intravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA.
                The trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III.
                The trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established.
                This prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.
These limited data suggest that higher doses of thrombolytic agents may lead to higher rates of bleeding. However, the evidence is inadequate to conclude whether lower doses of thrombolytic agents are more effective than higher doses, or whether one agent is better than another, or which route of administration is the best, for acute ischaemic stroke. At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials.