Effect of Remote Ischemic Conditioning in Ischemic Stroke Subtypes: A Post Hoc Subgroup Analysis From the RESIST Trial.

BACKGROUND: Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that has proved to be safe and feasible in numerous smaller clinical trials. Mixed results have been found in recent large randomized controlled trials. This is a post hoc subgroup analysis of the RESIST trial (Remote Ischemic Conditioning in Patients With Acute Stroke), investigating the effect of RIC in different acute ischemic stroke etiologies, and whether an effect was modified by treatment adherence. METHODS: Eligible patients were adults (aged ≥18 years), independent in activities of daily living, who had prehospital stroke symptoms with a duration of less than 4 hours. They were randomized to RIC or sham. The RIC treatment protocol consisted of 5 cycles with 5 minutes of cuff inflation alternating with 5 minutes with a deflated cuff. Acceptable treatment adherence was defined as when at least 80% of planned RIC cycles were received. The analysis was performed using the entire range (shift analysis) of the modified Rankin Scale (ordinal logistic regression). RESULTS: A total of 698 had acute ischemic stroke, 253 (36%) were women, and the median (interquartile range) age was 73 (63-80) years. Median (interquartile range) overall adherence to RIC/sham was 91% (68%-100%). In patients with a stroke due to cerebral small vessel disease, who were adherent to treatment, RIC was associated with improved functional outcome, and the odds ratio for a shift to a lower score on the modified Rankin Scale was 2.54 (1.03-6.25); P=0.042. The association remained significant after adjusting for potential confounders. No significant associations were found with other stroke etiologies, and the overall test for interaction was not statistically significant (χ2, 4.33, P=0.23). CONCLUSIONS: In patients with acute ischemic stroke due to cerebral small vessel disease, who maintained good treatment adherence, RIC was associated with improved functional outcomes at 90 days. These results should only serve as a hypothesis-generating for future trials. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Standard vs. targeted oxygen therapy prehospitally for chronic obstructive pulmonary disease (STOP-COPD): study protocol for a randomised controlled trial.

BACKGROUND: A high concentration of inspired supplemental oxygen may possibly cause hypercapnia and acidosis and increase mortality in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Even so, patients with AECOPD are being treated with high oxygen flow rates when receiving inhalation drugs in the prehospital setting. A cluster-randomised controlled trial found that reduced oxygen delivery by titrated treatment reduced mortality-a result supported by observational studies-but the results have never been reproduced. In the STOP-COPD trial, we investigate the effect of titrated oxygen delivery compared with usual care consisting of high flow oxygen delivery in patients with AECOPD in the prehospital setting. METHODS: In this randomised controlled trial, patients will be blinded to allocation. Patients with suspected AECOPD (n = 1888) attended by the emergency medical service (EMS) and aged > 40 years will be allocated randomly to either standard treatment or titrated oxygen, targeting a blood oxygen saturation of 88-92% during inhalation therapy. The trial will be conducted in the Central Denmark Region and include all ambulance units. The power to detect a 3% 30-day mortality risk difference is 80%. The trial is approved as an emergency trial. Hence, EMS providers will include patients without prior consent. DISCUSSION: The results will provide evidence on whether titrated oxygen delivery outperforms standard high flow oxygen when used to nebulise inhaled bronchodilators in AECOPD treatment. The trial is designed to ensure unselected inclusion of patients with AECOPD needing nebulised bronchodilators-a group of patients that receives high oxygen fractions when treated in the prehospital setting where the only compressed gas is generally pure oxygen. Conducting this trial, we aim to improve treatment for people with AECOPD while reducing their 30-day mortality. TRIAL REGISTRATION: European Union Clinical Trials (EUCT) number: 2022-502003-30-00 (authorised 06/12/2022), ClinicalTrials.gov number: NCT05703919 (released 02/02/2023), Universal trial number: U1111-1278-2162.

Effect of urgency level on prehospital emergency transport times: a natural experiment.

Accurate estimation of ambulance transport time from the scene of incident to arrival at the emergency department (ED) is important for effective resource management and emergency care system planning. Further, differences in transport times between different urgency levels highlight the benefits of ambulance transports with highest urgency level in a setting where ambulances are allowed to not follow standard traffic rules. The objective of the study is to compare ambulance urgency level on the differences in estimates of ambulance transport times generated by Google Maps and the observed transport times in a prehospital setting where emergency vehicles have their own traffic laws. The study was designed as a natural experiment and register study. Ambulance transports dispatched with different levels of urgency (Level A and B) were included in the Central Denmark Region (a mixed urban and rural area) from March 10 to June 11, 2021. Ambulance transports for highest urgency level were compared to lowest urgency level with Google Maps estimated transport times as reference. We analyzed 1981 highest urgency level and 8.958 lowest urgency level ambulance transports. Google Maps significantly overestimated the duration of transports operating at highest level of urgency (Level A) by 1.9 min/10 km (95% CI 1.8; 2.0) in average and 4.8 min/10 km (95% CI 3.9; 5.6) for the first driven 10 km. Contrary, Google Maps significantly underestimated the duration of transports operating at lowest level of urgency (Level B) by -1.8 min/10 km (95% CI -2.1; -1.5) in average and -4.4 min/10 km (95% CI -5.4; -3.5) for the first driven 10 km. Google Maps systematically overestimates transport times of ambulance transports driven with Level A, the highest level of urgency in a setting where ambulances are allowed to not follow standard traffic rules. The results highlight the benefit of using urgency Level A and provide valuable information for emergency care management.

B-cell hepatosplenic lymphoma presenting in adult patient after spontaneous splenic rupture followed by severe persistent hypoglycaemia: type B lactic acidosis and acute liver failure.

A patient was admitted to hospital with splenic rupture, four 4 days after colonoscopy was performed following one month's intermittent and aggravating abdominal pain. During recovery from splenectomy, the patient developed sudden tachycardic and tachypnoea. A blood sample revealed a very low blood glucose, high lactate and acidaemia.The patient required high-dose continuous intravenous glucose, while the lactate remained elevated. Decreasing consciousness with signs of acute liver failure necessitated transfer to an advanced intensive care unit. The patient's clinical status rapidly deteriorated despite therapeutic intervention. The patient died of multiorgan failure eleven days post-splenectomy. Based on the pathology of the spleen and a post-mortem liver specimen, the patient was diagnosed with a primary extra-nodal B-cell hepatosplenic lymphoma (BCHSL) - an extremely rare form of non-Hodgkin lymphomanon.Splenic rupture followed by lactic acidosis and hypoglycaemia should lead to suspicion of a cancer-mediated Warburg effect, and prompt urgent chemotherapy.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Treatment Delays and Chance of Reperfusion Therapy in Patients with Acute Stroke: A Danish Nationwide Study.

INTRODUCTION: We aimed to determine the treatment delay for ischemic stroke patients in Denmark. METHODS: A nationwide register-based study on acute ischemic stroke patients admitted through emergency medical services. Treatment delay comprised patient, prehospital, and in-hospital delay. Analyses were stratified according to length of prehospital delay (<3 vs. ≥3 h). RESULTS: A total of 5,356 ischemic stroke episodes were included. The median onset-to-door time was 187 min, and 2,405 (43%) arrived at the stroke unit within 3 h. Overall, the median patient delay was 115 min. For early arrival (n = 2,280), patient delay was 27 min compared to 437 min for late arrivals (n = 2,448). Median prehospital delay varied by 9 min between early- and late-arriving patients. Approximately 48% of the early-arriving patients compared to 9% of the late-arriving patients received i.v. thrombolysis. For thrombectomy, the numbers were 10% and 3%, respectively. This corresponded to an unadjusted relative risk (RR) of 0.18 (95% CI: 0.16-0.21) and adjusted (age, sex, cohabitation status, and stroke severity) RR of 0.20 (95% CI: 0.18-0.23) for i.v. thrombolysis when comparing patients arriving later than 3 h with patients arriving earlier. For thrombectomy, the unadjusted and adjusted RRs were 0.30 (95% CI: 0.23-0.39) and 0.40 (95% CI: 0.31-0.52), respectively. CONCLUSIONS: Patient delay remains the most important barrier for use of reperfusion therapy among acute ischemic stroke patients calling 1-1-2, whereas system delay seems independent of patient delay.

Help-seeking behaviour and subsequent patient and system delays in stroke.

OBJECTIVES: Prehospital delay is the main reason why only a limited number of stroke patients receive reperfusion therapy. We aimed to investigate help-seeking behaviour in patients and bystanders after onset of stroke and subsequent patient and system delay. MATERIALS & METHODS: We conducted a cross-sectional study of 332 patients with stroke. We performed structured interviews and used data from the medical records and the Danish Stroke Registry. Primary outcomes were patient delay and system delay. RESULTS: The median patient delay was 280 min, and the median system delay was 97 min. For a patient delay of <3 h, an additional non-significant system delay of median 30 min was seen for a first contact to a general practitioner (GP), and an additional significant delay of median 490 min was seen for the small group of patients with a first contact to 'other' healthcare professionals compared to the Emergency Medical Services (EMS). For a patient delay of more than 3 h, an additional system delay of median 78 min was found when the first contact was directed to the out-of-hours primary care (OOH-PC). A total of 17% of patients were admitted to another hospital or department before arrival at the stroke centre; this resulted in a substantially prolonged system delay of a median of 431 min. CONCLUSIONS: Patient delay remains the main reason for delayed arrival at the stroke centre. Appropriate help-seeking behaviour and efficient pre-hospital triage are essential for reducing the prehospital delay and increasing the proportion of patients receiving reperfusion therapy.

Disentangling Sex Differences in Use of Reperfusion Therapy in Patients With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Previous studies from local settings have reported that women with acute ischemic stroke have a lower chance of receiving reperfusion therapy treatment, including intravenous thrombolysis and thrombectomy, than men, but the underlying mechanisms of this disparity have not been identified. We aimed to examine sex differences in the utilization of reperfusion therapy focusing on all the phases of pre- and in-hospital time delay in a nationwide population-based cohort. METHODS: This study was based on data from nationwide public registries. The study population included patients aged at least 18 years admitted with acute ischemic stroke using emergency medical services in Denmark dispatched after an emergency call in the period 2016 to 2017. Study outcomes included time delays from symptom onset to start of reperfusion therapy and use of reperfusion therapy. Data were analyzed using multivariable quantile regression and logistic regression. RESULTS: A total of 5356 stroke events fulfilled the inclusion criteria. Women (26.6%) were less likely to receive intravenous thrombolysis than men (30.2 %), corresponding to an unadjusted odds ratio of 0.84 (95% CI, 0.74-0.95). In addition, women experienced a 20 minutes longer median time delay from stroke symptom onset to stroke unit arrival than men. Adjusting for onset-to-door time only appeared to have a limited effect on the sex differences in use of intravenous thrombolysis, whereas the odds ratio was 1.06 (95% CI, 0.93-1.21) when adjusting for age at stroke, stroke severity, and cohabitation status. No sex difference was observed for the use of thrombectomy. CONCLUSIONS: Women received less reperfusion therapy than men and had a longer time delay from symptom onset to stroke unit arrival, primarily due to a longer delay from symptom onset to emergency medical services call. These differences appeared to be due to the higher age and the higher proportion of women living alone at the time of the stroke.

[Fatal outcome after overdosage with antidepressants]. / Fatalt forløb efter overdosering med serotonin- og noradrenalingenoptagelseshæmmere.

Serotonin syndrome (SS) is a complication after overdosage with antidepressants. SS increases the level of circulating serotonin. Fatal outcome of SS is most often seen in cases where there has been an overdosage with selective serotonin reuptake inhibitors (SSRI)/selective noradrenaline reuptake inhibitors (SNRI) in combination with other serotonin increasing drugs. This case report describes the rapid development of symptoms in a 54-year-old man who ingested a total amount of 6.5 g of SSRI and SNRI drugs as the only drug types. It proves the importance of being aware of the symptoms of SS when the patient is first seen in the emergency department.