Treatment Restrictions and the Risk of Death in Patients With Ischemic Stroke or Intracerebral Hemorrhage

BACKGROUND AND PURPOSE: Do-not-resuscitate (DNR) orders in the first 24 hours after intracerebral hemorrhage have been associated with an increased risk of early death. This relationship is less certain for ischemic stroke. We assessed the relation between treatment restrictions and mortality in patients with ischemic stroke and in patients with intracerebral hemorrhage. We focused on the timing of treatment restrictions after admission and the type of treatment restriction (DNR order versus more restrictive care). METHODS: We retrospectively assessed demographic and clinical data, timing and type of treatment restrictions, and vital status at 3 months for 622 consecutive stroke patients primarily admitted to a Dutch university hospital. We used a Cox regression model, with adjustment for age, sex, comorbidities, and stroke type and severity. RESULTS: Treatment restrictions were installed in 226 (36%) patients, more frequently after intracerebral hemorrhage (51%) than after ischemic stroke (32%). In 187 patients (83%), these were installed in the first 24 hours. Treatment restrictions installed within the first 24 hours after hospital admission and those installed later were independently associated with death at 90 days (adjusted hazard ratios, 5.41 [95% CI, 3.17-9.22] and 5.36 [95% CI, 2.20-13.05], respectively). Statistically significant associations were also found in patients with ischemic stroke and in patients with just an early DNR order. In those who died, the median time between a DNR order and death was 520 hours (interquartile range, 53-737). CONCLUSIONS: The strong relation between treatment restrictions (including DNR orders) and death and the long median time between a DNR order and death suggest that this relation may, in part, be causal, possibly due to an overall lack of aggressive care

Regulatory delays in a multinational clinical stroke trial

INTRODUCTION: The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. MATERIALS AND METHODS: We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. RESULTS: The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586–1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93–293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = –0.002; p = 0.02). DISCUSSION: CONCLUSION: In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials

PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke: rationale and design of a randomised, open, phase III, clinical trial with blinded outcome assessment

Background: Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency. Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. Design: International, 3 × 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score ≥ 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier. Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (± 14 days), as analysed with multiple regression. Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs. Planning: First patient included in May 2016; final follow-up of the last patient by April 202

Time Since Stroke Onset, Quantitative Collateral Score, and Functional Outcome After Endovascular Treatment for Acute Ischemic Stroke

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke undergoing endovascular treatment (EVT), time to treatment and collateral status are important prognostic factors and may be correlated. We aimed to assess the relation between time to CT angiography (CTA) and a quantitatively determined collateral score and to assess whether the collateral score modified the relation between time to recanalization and functional outcome. METHODS: We analyzed data from patients with acute ischemic stroke included in the Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke Registry between 2014 and 2017, who had a carotid terminus or M1 occlusion and were treated with EVT within 6.5 hours of symptom onset. A quantitative collateral score (qCS) was determined from baseline CTA using a validated automated image analysis algorithm. We also determined a 4-point visual collateral score (vCS). Multivariable regression models were used to assess the relations between time to imaging and the qCS and between the time to recanalization and functional outcome (90-day modified Rankin Scale score). An interaction term (time to recanalization × qCS) was entered in the latter model to test whether the qCS modifies this relation. Sensitivity analyses were performed using the vCS. RESULTS: We analyzed 1,813 patients. The median time from symptom onset to CTA was 91 minutes (interquartile range [IQR] 65–150 minutes), and the median qCS was 49% (IQR 25%–78%). Longer time to CTA was not associated with the log-transformed qCS (adjusted β per 30 minutes, 0.002, 95% CI −0.006 to 0.011). Both a higher qCS (adjusted common odds ratio [acOR] per 10% increase: 1.06, 95% CI 1.03–1.09) and shorter time to recanalization (acOR per 30 minutes: 1.17, 95% CI 1.13–1.22) were independently associated with a shift toward better functional outcome. The qCS did not modify the relation between time to recanalization and functional outcome (p for interaction: 0.28). Results from sensitivity analyses using the vCS were similar. DISCUSSION: In the first 6.5 hours of ischemic stroke caused by carotid terminus or M1 occlusion, the collateral status is unaffected by time to imaging, and the benefit of a shorter time to recanalization is independent of baseline collateral status

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment

BackgroundInfections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. MethodsWe conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR 1 harm). This trial is registered (ISRCTN82217627). FindingsFrom April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81–1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77–1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96–1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. InterpretationWe observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. FundingThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No: 634809

Complications, treatment restrictions and end-of-life care in patients with acute stroke

The long-term outcome after acute stroke is negatively impacted by secondary complications, such as dysphagia, aspiration pneumonia, urinary tract infections and fever. In current clinical practice, these complications are treated by medication such as metoclopramide, antibiotics and paracetamol, but it is unknown if the use of these medications in the acute phase of stroke may prevent secondary complications and improve functional outcome. The first chapters of this thesis focus on the rationale and design of the PRECIOUS trial, which aims to answer this question. The trial may show effectiveness, particularly because of its very early treatment and focus on elderly patients with severe stroke. The results of PRECIOUS could not be included in this thesis as a consequence of a two-year extension of the trial. One of the major delaying factors was obtaining legal and regulatory approval for the trial, especially the execution of legal agreements with each study site. Centres that were opened later were less likely to recruit patients in the first six months, possibly reflecting declining motivation of participating investigators. Multinational trials may strongly benefit from internationally accepted templates for research contracts and formal deadlines for legal review. One of the most life-threatening complications of acute supratentorial ischemic stroke is space-occupying edema. In an individual patient data meta-analysis of randomised controlled trials surgical decompression in patients with space occupying edema strongly reduces mortality and improves the chance of a favorable functional outcome. The effect appears to be independent of the presence of aphasia, stroke severity, age, and affected vascular territory. The benefit of surgery after 48 hours and in elderly patients remains uncertain. Most in-hospital stroke-related deaths occur after a decision to withhold life-sustaining treatments, such as cardiopulmonary resuscitation. The decision to install treatment restrictions implies that prognosis is accurate and indisputably poor. However, the results of our analysis suggest that the presence of a treatment restriction (such as a do-not-resuscitate order) is associated with mortality, even when adjustments are made for important prognostic factors. Treatment restrictions may lead to an overall milieu of nihilism that influences attitudes of care beyond the orders themselves and may have the potential of a “self-fulfilling prophecy” when estimating prognosis for stroke patients. When death is regarded as inevitable, a transition from curative to palliative treatment is made in many stroke patients. In after-death interviews, relatives of patients that died on the stroke unit are generally satisfied with the end-of-life phase. Negative experiences are mostly related to feeding, inability to say goodbye to loved ones, appearing not to have control and not retaining a sense of dignity. Breathing difficulties frequently occur during the dying phase, but palliative medication adequately resolves discomfort in most patients. Counseling family members on what to expect in terms of signs and symptoms during the end-of-life phase is extremely important

Complications, treatment restrictions and end-of-life care in patients with acute stroke

The long-term outcome after acute stroke is negatively impacted by secondary complications, such as dysphagia, aspiration pneumonia, urinary tract infections and fever. In current clinical practice, these complications are treated by medication such as metoclopramide, antibiotics and paracetamol, but it is unknown if the use of these medications in the acute phase of stroke may prevent secondary complications and improve functional outcome. The first chapters of this thesis focus on the rationale and design of the PRECIOUS trial, which aims to answer this question. The trial may show effectiveness, particularly because of its very early treatment and focus on elderly patients with severe stroke. The results of PRECIOUS could not be included in this thesis as a consequence of a two-year extension of the trial. One of the major delaying factors was obtaining legal and regulatory approval for the trial, especially the execution of legal agreements with each study site. Centres that were opened later were less likely to recruit patients in the first six months, possibly reflecting declining motivation of participating investigators. Multinational trials may strongly benefit from internationally accepted templates for research contracts and formal deadlines for legal review. One of the most life-threatening complications of acute supratentorial ischemic stroke is space-occupying edema. In an individual patient data meta-analysis of randomised controlled trials surgical decompression in patients with space occupying edema strongly reduces mortality and improves the chance of a favorable functional outcome. The effect appears to be independent of the presence of aphasia, stroke severity, age, and affected vascular territory. The benefit of surgery after 48 hours and in elderly patients remains uncertain. Most in-hospital stroke-related deaths occur after a decision to withhold life-sustaining treatments, such as cardiopulmonary resuscitation. The decision to install treatment restrictions implies that prognosis is accurate and indisputably poor. However, the results of our analysis suggest that the presence of a treatment restriction (such as a do-not-resuscitate order) is associated with mortality, even when adjustments are made for important prognostic factors. Treatment restrictions may lead to an overall milieu of nihilism that influences attitudes of care beyond the orders themselves and may have the potential of a “self-fulfilling prophecy” when estimating prognosis for stroke patients. When death is regarded as inevitable, a transition from curative to palliative treatment is made in many stroke patients. In after-death interviews, relatives of patients that died on the stroke unit are generally satisfied with the end-of-life phase. Negative experiences are mostly related to feeding, inability to say goodbye to loved ones, appearing not to have control and not retaining a sense of dignity. Breathing difficulties frequently occur during the dying phase, but palliative medication adequately resolves discomfort in most patients. Counseling family members on what to expect in terms of signs and symptoms during the end-of-life phase is extremely important

Surgical Decompression for Space-Occupying Hemispheric Infarction A Systematic Review and Individual Patient Meta-analysis of Randomized Clinical Trials

WOS: 000581906100005PubMed: 33044488IMPORTANCE in patients with space-occupying hemispheric infarction, surgical decompression reduces the risk of death and increases the chance of a favorable outcome. Uncertainties, however, still remain about the benefit of this treatment for specific patient groups. OBJECTIVE To assess whether surgical decompression for space-occupying hemispheric infarction is associated with a reduced risk of death and an increased chance of favorable outcomes, as well as whether this association is modified by patient characteristics. DATA SOURCES MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Stroke Trials Registry were searched from database inception to October 9, 2019, for English-language articles that reported on the results of randomized clinical trials of surgical decompression vs conservative treatment in patients with space-occupying hemispheric infarction. STUDY SELECTION Published and unpublished randomized clinical trials comparing surgical decompression with medical treatment alone were selected. DATA EXTRACTION AND SYNTHESIS Patient-level data were extracted from the trial databases according to a predefined protocol and statistical analysis plan. the Preferred Reporting Items for Systematic Reviews and Meta-analyses () reporting guideline and the Cochrane Collaboration's tool for assessing risk of bias were used. One-stage, mixed-effect logistic regression modeling was used for all analyses. MAIN OUTCOMES AND MEASURES the primary outcome was a favorable outcome (modified Rankin Scale [mRS] score <= 3) at 1 year after stroke. Secondary outcomes included death, reasonable (mRS score <= 4) and excellent (mRS score <= 2) outcomes at 6 months and 1 year, and an ordinal shift analysis across all levels of the mRS. Variables for subgroup analyses were age, sex, presence of aphasia, stroke severity, time to randomization, and involved vascular territories. RESULTS Data from 488 patients from 7 trials from 6 countries were available for analysis. the risk of bias was considered low to moderate for 6 studies. Surgical decompression was associated with a decreased chance of death (adjusted odds ratio, 0.16; 95% CI, 0.10-0.24) and increased chance of a favorable outcome (adjusted odds ratio, 2.95; 95% CI, 1.55-5.60), without evidence of heterogeneity of treatment effect across any of the prespecified subgroups. Too few patients were treated later than 48 hours after stroke onset to allow reliable conclusions in this subgroup, and the reported proportions of elderly patients reaching a favorable outcome differed considerably among studies. CONCLUSIONS AND RELEVANCE the results suggest that the benefit of surgical decompression for space-occupying hemispheric infarction is consistent across a wide range of patients. the benefit of surgery after day 2 and in elderly patients remains uncertain

Quality of dying after acute stroke

Introduction: There is a lack of evidence concerning the palliative needs of patients with acute stroke during end-of-life care. We interviewed relatives of patients who deceased in our stroke unit about the quality of dying and compared their experiences with those of nurses. Patients and Methods: Relatives of 59 patients were interviewed approximately 6 weeks after the patient had died. The primary outcome was a score assessing the overall quality of dying on a scale ranging from 0 to 10, with 0 representing the worst quality and 10 the best quality. We investigated the frequency and appreciation of specific aspects of the dying phase with an adapted version of the Quality of Death and Dying Questionnaire. The nurse who was most frequently involved in the end-of-life care of the patient completed a similar questionnaire. Results: Family members were generally satisfied with the quality of dying (median overall score 8; interquartile range, 6–9) as well as with the care provided by nurses (9; 8–10) and doctors (8; 7–9). Breathing difficulties were frequently reported (by 46% of the relatives), but pain was not. Unsatisfactory experiences were related to feeding (69% unsatisfactory), inability to say goodbye to loved ones (51%), appearing not to have control (47%), and not retaining a sense of dignity (41%). Two-thirds of the relatives reported that palliative medication adequately resolved discomfort. There was a good correlation between the experiences of relatives and nurses. Discussion and Conclusion: Most relatives were satisfied with the overall quality of dying. Negative experiences concerned feeding problems, not being able to say goodbye to loved ones, sense of self control and dignity, and breathing difficulties. Experiences of nurses may be a reasonable and practical option when evaluating the quality of dying in acute stroke patients

Surgical Decompression for Space-Occupying Hemispheric Infarction: A Systematic Review and Individual Patient Meta-analysis of Randomized Clinical Trials

Importance: In patients with space-occupying hemispheric infarction, surgical decompression reduces the risk of death and increases the chance of a favorable outcome. Uncertainties, however, still remain about the benefit of this treatment for specific patient groups. Objective: To assess whether surgical decompression for space-occupying hemispheric infarction is associated with a reduced risk of death and an increased chance of favorable outcomes, as well as whether this association is modified by patient characteristics. Data Sources: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Stroke Trials Registry were searched from database inception to October 9, 2019, for English-language articles that reported on the results of randomized clinical trials of surgical decompression vs conservative treatment in patients with space-occupying hemispheric infarction. Study Selection: Published and unpublished randomized clinical trials comparing surgical decompression with medical treatment alone were selected. Data Extraction and Synthesis: Patient-level data were extracted from the trial databases according to a predefined protocol and statistical analysis plan. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the Cochrane Collaboration's tool for assessing risk of bias were used. One-stage, mixed-effect logistic regression modeling was used for all analyses. Main Outcomes and Measures: The primary outcome was a favorable outcome (modified Rankin Scale [mRS] score ≤3) at 1 year after stroke. Secondary outcomes included death, reasonable (mRS score ≤4) and excellent (mRS score ≤2) outcomes at 6 months and 1 year, and an ordinal shift analysis across all levels of the mRS. Variables for subgroup analyses were age, sex, presence of aphasia, stroke severity, time to randomization, and involved vascular territories. Results: Data from 488 patients from 7 trials from 6 countries were available for analysis. The risk of bias was considered low to moderate for 6 studies. Surgical decompression was associated with a decreased chance of death (adjusted odds ratio, 0.16; 95% CI, 0.10-0.24) and increased chance of a favorable outcome (adjusted odds ratio, 2.95; 95% CI, 1.55-5.60), without evidence of heterogeneity of treatment effect across any of the prespecified subgroups. Too few patients were treated later than 48 hours after stroke onset to allow reliable conclusions in this subgroup, and the reported proportions of elderly patients reaching a favorable outcome differed considerably among studies. Conclusions and Relevance: The results suggest that the benefit of surgical decompression for space-occupying hemispheric infarction is consistent across a wide range of patients. The benefit of surgery after day 2 and in elderly patients remains uncertain.