Discussion
abnormal coagulation, illness, primary injury, intracerebral haemorrhage, pyrexia
ABNORMAL COAGULATION, RECRUITMENT, HYPERGLYCAEMIA, INTRACEREBRAL HAEMORRHAGE, ADVERSE EVENTS, COMPRESSION OF BRAIN, RECRUITMENT, SECONDARY, ELEVATED BLOOD PRESSURE
This pragmatic stepped wedge, cluster randomised, controlled trial conducted in various health-care settings has shown that, in patients presenting within 6 h of the onset of acute intracerebral haemorrhage, the use of a care bundle protocol incorporating the early control of elevated blood pressure together with management algorithms for hyperglycaemia, pyrexia, and abnormal coagulation resulted in an improved functional outcome at 6 months. The positive result was consistent across a range of sensitivity analyses and secondary outcomes. Compared with usual care, implementation of the time-sensitive care bundle was also associated with improved survival, health-related quality of life, and serious adverse events during the follow-up of patients. Given that 118 of the participating hospitals admitted more than 100 patients with acute intracerebral haemorrhage per year, the size of the beneficial effect equates to an improved outcome for at least several similar such patients per site each year.To our knowledge, this is the first phase 3 multicentre randomised controlled trial to show a positive outcome for an acute treatment of intracerebral haemorrhage, and one of few trials that have used a stepped wedge, cluster randomised design across multiple countries.However, complex relationships are likely to exist between the fidelity of implementation and the effect of the intervention. Intensive blood pressure lowering was the central component of the care bundle, because it has strong supporting evidence, is applicable to a wide variety of settings, and has a plausible mechanism of action in that attenuating the growth of the intracerebral haemorrhage will reduce the primary injury of dissection and compression of brain tissue. Although the rapid control of blood pressure within an early 6 h inclusion time window was emphasised to investigators in this study, most of the growth in intracerebral haemorrhage occurs within a few hours of the onset of symptoms.The strengths of our trial include that it comprised an evaluation of a complex intervention, for both implementation in real-world settings and clinical effects, on a robust patient-centred outcome assessed at 6 months. The large sample size allowed for the detection of a modest, but still clinically worthwhile, benefit that is generalisable, because an ethnically and sociodemographically diverse population was included from different resource settings. The broad inclusion criteria allowed testing related to the usual triage and care of patients with acute intracerebral haemorrhage, and the analyses followed a prespecified analysis plan. The provision of the protocol, management algorithms, and a short training package, with individual patient management left to the discretion of the treating team and supported by performance monitoring, reflects how this intervention might be adopted more widely. Whether the implementation difficulties already noted to have happened in China,Our trial has limitations. We chose a stepped wedge cluster randomised design to allow large numbers of patients to be rapidly recruited within routine practice, including those with severe illness and requiring urgent neurosurgery, in whom it can be challenging to obtain early consent. The introduction of the care bundle necessitated a change in practice across different clinical services involved in the flow of patients in hospital. These issues made individual randomisation unfeasible, inequitable, and prone to contamination. However, an important potential limitation of this study design is confounding effects from secular trends by calendar time, related to the sequential implementation of the intervention across participating sites, and from disruption to the presentation and management of patients created by the COVID-19 pandemic. There was considerable heterogeneity in the recruitment of patients across sites and in the timing of the phases of the trial. Recruitment was also extended for patients in the intervention group towards the end of the trial, which might have introduced a degree of selection bias. To accommodate this heterogeneity, the extent of which was not fully appreciated until the unmasking of the data, we made a post-hoc decision to adjust the analyses according to calendar time instead of by trial period, as recommended in another stepped wedge trial with delays in cluster recruitment.In summary, the findings of our trial provide evidence to support the adoption of an active protocol for intensive blood pressure lowering and the associated management of key abnormal physiological variables within several hours after the onset of signs to improve the recovery of patients presenting with acute intracerebral haemorrhage.