Inflammatory response after prehospital high-dose glucocorticoid to patients resuscitated from out-of-hospital cardiac arrest: A sub-study of the STEROHCA trial.

BACKGROUND: The post-cardiac arrest syndrome (PCAS) after out-of-hospital cardiac arrest (OHCA) is characterized by a series of pathological events, including inflammation. In the randomized "STERoid for OHCA" (STEROHCA) trial, prehospital high-dose glucocorticoid decreased interleukin (IL) 6 and C-reactive protein levels following resuscitated OHCA. The aim of this predefined sub-study was to assess the inflammatory response the first three days of admission. METHODS: The STEROHCA trial enrolled 137 OHCA patients randomized to either a single prehospital injection of methylprednisolone 250 mg or placebo. Inflammatory markers, including pro- and anti-inflammatory cytokines, were analyzed in plasma samples, from 0-, 24-, 48-, and 72 h post-admission. Mixed-model analyses were applied using log-transformed data to assess group differences. RESULTS: The 137 patients included in this sub-study had a median age of 67 years (57 to 74), and the 180-day survival rates were 75% (n = 51/68) and 64% (n = 44/69) in the glucocorticoid and placebo group, respectively. A total of 130 (95%) patients had at least one plasma sample available. The anti-inflammatory cytokine IL-10 was increased at hospital admission in the glucocorticoid group (ratio 2.74 (1.49-5.05), p = 0.006), but the intervention showed the strongest effect after 24 h, decreasing pro-inflammatory levels of IL-6 (ratio 0.06 (0.03-0.10), p < 0.001), IL-8 (ratio 0.53 (0.38-0.75), p < 0.001), macrophage chemokine protein-1 (MCP-1, ratio 0.02 (0.13-0.31), p < 0.001), macrophage inflammatory protein-1-beta (MIP-1b, ratio 0.28 (0.18-0.45), p < 0.001), and tumor necrosis factor-α (TNF-α, ratio 0.6 (0.4-0.8), p = 0.01). CONCLUSION: Administering high-dose glucocorticoid treatment promptly after resuscitation from OHCA influenced the inflammatory response with a reduction in several systemic proinflammatory cytokines after 24 h. TRIAL REGISTRATION: EudraCT number: 2020-000855-11; submitted March 30, 2020. URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT04624776.

Validating quantitative pupillometry thresholds for neuroprognostication after out-of-hospital cardiac arrest. A predefined substudy of the Blood Pressure and Oxygenations Targets After Cardiac Arrest (BOX)-trial.

PURPOSE: Out-of-hospital cardiac arrest (OHCA) survivors face significant risks of complications and death from hypoxic-ischemic brain injury leading to withdrawal of life-sustaining treatment (WLST). Accurate multimodal neuroprognostication, including automated pupillometry, is essential to avoid inappropriate WLST. However, inconsistent study results hinder standardized threshold recommendations. We aimed to validate proposed pupillometry thresholds with no false predictions of unfavorable outcomes in comatose OHCA survivors. METHODS: In the multi-center BOX-trial, quantitative measurements of automated pupillometry (quantitatively assessed pupillary light reflex [qPLR] and Neurological Pupil index [NPi]) were obtained at admission (0 h) and after 24, 48, and 72 h in comatose patients resuscitated from OHCA. We aimed to validate qPLR < 4% and NPi ≤ 2, predicting unfavorable neurological conditions defined as Cerebral Performance Category 3-5 at follow-up. Combined with 48-h neuron-specific enolase (NSE) > 60 µg/L, pupillometry was evaluated for multimodal neuroprognostication in comatose patients with Glasgow Motor Score (M) ≤ 3 at ≥ 72 h. RESULTS: From March 2017 to December 2021, we consecutively enrolled 710 OHCA survivors (mean age: 63 ± 14 years; 82% males), and 266 (37%) patients had unfavorable neurological outcomes. An NPi ≤ 2 predicted outcome with 0% false-positive rate (FPR) at all time points (0-72 h), and qPLR < 4% at 24-72 h. In patients with M ≤ 3 at ≥ 72 h, pupillometry thresholds significantly increased the sensitivity of NSE, from 42% (35-51%) to 55% (47-63%) for qPLR and 50% (42-58%) for NPi, maintaining 0% (0-0%) FPR. CONCLUSION: Quantitative pupillometry thresholds predict unfavorable neurological outcomes in comatose OHCA survivors and increase the sensitivity of NSE in a multimodal approach at ≥ 72 h.

Relevance of Age and Hypertension for Blood-Pressure Targets in Comatose Survivors of Cardiac Arrest - A BOX-trial sub study.

BACKGROUND: To assess whether the optimal mean arterial blood pressure (MAP) target after out-of-hospital cardiac arrest (OHCA) is influenced by age and a history of arterial hypertension. METHODS: Post-hoc analysis of data from the Blood Pressure and Oxygenation Targets in Post Resuscitation Care (BOX) trial. The trial included 789 comatose patients randomized to a MAP target of 63mmHg or 77mmHg. The primary outcome of this sub-study was one-year all-cause mortality. Cox proportional-hazards regression and restricted cubic splines were used to examine whether prevalent hypertension and age modified the effect of low versus high MAP target on all-cause mortality. RESULTS: Of the 789 patients randomized, 393 were assigned to a high MAP target, and 396 to a low MAP target. Groups were well balanced for mean age (high MAP target 63±13 years versus low 62±14 years) and hypertension (45% versus 47% respectively). At one year, the primary outcome occurred in 143 patients (36%) with high MAP target and 138 (35%) with low MAP target. The risk of the primary outcome increased linearly with increasing age (P<0.001). The effect of a high versus low MAP target on the primary outcome was modified by age when tested continuously, potentially favoring low MAP target in younger patients (P for interaction=0.03). Prevalent hypertension did not modify the effect of a high versus low MAP target on the primary outcome (P for interaction=0.67). CONCLUSIONS: Among patients resuscitated after OHCA, older patients and those with a history of hypertension did not benefit from a higher MAP target.

Impact of Blood Pressure Targets in Patients With Heart Failure Undergoing Postresuscitation Care: A Subgroup Analysis From a Randomized Controlled Trial.

BACKGROUND: To assess the effect of targeting higher or lower blood pressure during postresucitation intensive care among comatose patients with out-of-hospital cardiac arrest with a history of heart failure. METHODS: The BOX trial (Blood Pressure and Oxygenation Targets After Out-of-Hospital Cardiac Arrest) was a randomized, controlled, double-blinded, multicenter study comparing titration of vasopressors toward a mean arterial pressure (MAP) of 63 versus 77 mm Hg during postresuscitation intensive care. Patients with a history of heart failure were included in this substudy. Pulmonary artery catheters were inserted shortly after admission. History of heart failure was assessed through chart review of all included patients. The primary outcome was cardiac index during the first 72 hours. Secondary outcomes were left ventricular ejection fraction, heart rate, stroke volume, renal replacement therapy and all-cause mortality at 365 days. RESULTS: A total of 134 patients (17% of the BOX cohort) had a history of heart failure (patients with left ventricular ejection fraction, ≤40%: 103 [77%]) of which 71 (53%) were allocated to a MAP of 77 mm Hg. Cardiac index at intensive care unit arrival was 1.77±0.11 L/min·m-2 in the MAP63-group and 1.78±0.17 L/min·m-2 in the MAP77, P=0.92. During the next 72 hours, the mean difference was 0.15 (95% CI, -0.04 to 0.35) L/min·m-2; Pgroup=0.22. Left ventricular ejection fraction and stroke volume was similar between the groups. Patients allocated to MAP77 had significantly elevated heart rate (mean difference 6 [1-12] beats/min, Pgroup=0.03). Vasopressor usage was also significantly increased (P=0.006). At 365 days, 69 (51%) of the patients had died. The adjusted hazard ratio for 365 day mortality was 1.38 (0.84-2.27), P=0.20 and adjusted odds ratio for renal replacement therapy was 2.73 (0.84-8.89; P=0.09). CONCLUSIONS: In resuscitated patients with out-of-hospital cardiac arrest with a history of heart failure, allocation to a higher blood pressure target resulted in significantly increased heart rate in the higher blood pressure-target group. However, no certain differences was found for cardiac index, left ventricular ejection fraction or stroke volume. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03141099.

Arterial Spin Labeling Magnetic Resonance Imaging for Acute Disorders of Consciousness in the Intensive Care Unit.

BACKGROUND: To investigate patients with disorders of consciousness (DoC) for residual awareness, guidelines recommend quantifying glucose brain metabolism using positron emission tomography. However, this is not feasible in the intensive care unit (ICU). Cerebral blood flow (CBF) assessed by arterial spin labeling magnetic resonance imaging (ASL-MRI) could serve as a proxy for brain metabolism and reflect consciousness levels in acute DoC. We hypothesized that ASL-MRI would show compromised CBF in coma and unresponsive wakefulness states (UWS) but relatively preserved CBF in minimally conscious states (MCS) or better. METHODS: We consecutively enrolled ICU patients with acute DoC and categorized them as being clinically unresponsive (i.e., coma or UWS [≤ UWS]) or low responsive (i.e., MCS or better [≥ MCS]). ASL-MRI was then acquired on 1.5 T or 3 T. Healthy controls were investigated with both 1.5 T and 3 T ASL-MRI. RESULTS: We obtained 84 ASL-MRI scans from 59 participants, comprising 36 scans from 35 patients (11 women [31.4%]; median age 56 years, range 18-82 years; 24 ≤ UWS patients, 12 ≥ MCS patients; 32 nontraumatic brain injuries) and 48 scans from 24 healthy controls (12 women [50%]; median age 50 years, range 21-77 years). In linear mixed-effects models of whole-brain cortical CBF, patients had 16.2 mL/100 g/min lower CBF than healthy controls (p = 0.0041). However, ASL-MRI was unable to discriminate between ≤ UWS and ≥ MCS patients (whole-brain cortical CBF: p = 0.33; best hemisphere cortical CBF: p = 0.41). Numerical differences of regional CBF in the thalamus, amygdala, and brainstem in the two patient groups were statistically nonsignificant. CONCLUSIONS: CBF measurement in ICU patients using ASL-MRI is feasible but cannot distinguish between the lower and the upper ends of the acute DoC spectrum. We suggest that pilot testing of diagnostic interventions at the extremes of this spectrum is a time-efficient approach in the continued quest to develop DoC neuroimaging markers in the ICU.

Acute kidney injury after out-of-hospital cardiac arrest.

BACKGROUND: Acute kidney injury (AKI) is a significant risk factor associated with reduced survival following out-of-hospital cardiac arrest (OHCA). Whether the severity of AKI simply serves as a surrogate measure of worse peri-arrest conditions, or represents an additional risk to long-term survival remains unclear. METHODS: This is a sub-study derived from a randomized trial in which 789 comatose adult OHCA patients with presumed cardiac cause and sustained return of spontaneous circulation (ROSC) were enrolled. Patients without prior dialysis dependent kidney disease and surviving at least 48 h were included (N = 759). AKI was defined by the kidney disease: improving global outcome (KDIGO) classification, and patients were divided into groups based on the development of AKI and the need for continuous kidney replacement therapy (CKRT), thus establishing three groups of patients-No AKI, AKI no CKRT, and AKI CKRT. Primary outcome was overall survival within 365 days after OHCA according to AKI group. Adjusted Cox proportional hazard models were used to assess overall survival within 365 days according to the three groups. RESULTS: In the whole population, median age was 64 (54-73) years, 80% male, 90% of patients presented with shockable rhythm, and time to ROSC was median 18 (12-26) min. A total of 254 (33.5%) patients developed AKI according to the KDIGO definition, with 77 requiring CKRT and 177 without need for CKRT. AKI CKRT patients had longer time-to-ROSC and worse metabolic derangement at hospital admission. Overall survival within 365 days from OHCA decreased with the severity of kidney injury. Adjusted Cox regression analysis found that AKI, both with and without CKRT, was significantly associated with reduced overall survival up until 365 days, with comparable hazard ratios relative to no AKI (HR 1.75, 95% CI 1.13-2.70 vs. HR 1.76, 95% CI 1.30-2.39). CONCLUSIONS: In comatose patients who had been resuscitated after OHCA, patients developing AKI, with or without initiation of CKRT, had a worse 1-year overall survival compared to non-AKI patients. This association remains statistically significant after adjusting for other peri-arrest risk factors. TRIAL REGISTRATION: The BOX trial is registered at ClinicalTrials.gov: NCT03141099.

Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock.

BACKGROUND: The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock remains unclear. METHODS: In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation. RESULTS: A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval [CI], 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09). CONCLUSIONS: The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).

Covert Consciousness in Acute Brain Injury Revealed by Automated Pupillometry and Cognitive Paradigms.

BACKGROUND: Identifying covert consciousness in intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can detect residual consciousness in ICU patients with DoC. METHODS: We prospectively enrolled clinically low-response or unresponsive patients with traumatic or nontraumatic DoC from ICUs of a tertiary referral center. Age-matched and sex-matched healthy volunteers served as controls. Patients were categorized into clinically unresponsive (coma or unresponsive wakefulness syndrome) or clinically low-responsive (minimally conscious state or better). Using automated pupillometry, we recorded pupillary dilation to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with task-specific success criteria (e.g., ≥ 3 of 5 pupillary dilations on five consecutive mental arithmetic tasks). RESULTS: We obtained 699 pupillometry recordings at 178 time points from 91 ICU patients with brain injury (mean age 60 ± 13.8 years, 31% women, and 49.5% nontraumatic brain injuries). Recordings were also obtained from 26 matched controls (59 ± 14.8 years, 38% women). Passive paradigms yielded limited distinctions between patients and controls. However, active paradigms enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥ 3 pupillary dilations were seen in 17.8% of clinically unresponsive patients and 50.0% of clinically low-responsive patients (odds ratio 4.56, 95% confidence interval 2.09-10.10; p < 0.001). In comparison, 76.9% healthy controls responded with ≥ 3 pupillary dilations (p = 0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman's rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho = 1, p = 0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior 2 weeks before overt signs of awareness, suggesting prolonged cognitive motor dissociation. CONCLUSIONS: Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence covert consciousness, in ICU patients with acute DoC.

Toxicological profile using mass spectrometry in sudden cardiac arrest survivors admitted to a tertiary centre.

BACKGROUND: There has been no previous thorough toxicological examination of a cohort of patients with resuscitated sudden cardiac arrest. We aimed to determine the qualitative and quantitative drug composition in a resuscitated sudden cardiac arrest population, using forensic toxicology, with focus on prescribed, non-prescribed, and commonly abused drugs. METHODS: Individuals aged 18-90 years with resuscitated sudden cardiac arrest of presumed cardiac causes were prospectively included from a single tertiary center. Data from the sudden cardiac arrest hospitalization was collected from medical reports. Drugs used during resuscitation or before the blood sampling were identified and excluded in each patient. Mass spectrometry-based toxicology was performed to determine the absence or presence of most drugs and to quantify the findings. RESULTS: Among 186 consecutively enrolled resuscitated sudden cardiac arrest patients (median age 62 years, 83% male), 90% had a shockable rhythm, and were primarily caused by ischemic heart disease (66%). In total, 90 different drugs (excluding metabolites) were identified, and 82% of patients had at least one drug detected (median of 2 detected drugs (IQR:1-4)) (polypharmacy). Commonly abused drugs were present in 16%, and QT-prolonging drugs were present in 12%. Polypharmacy (≥5drugs) were found in 19% of patients. Importantly, none had potentially lethal concentrations of any drugs. CONCLUSION: In resuscitated sudden cardiac arrest patients with cardiac arrest of presumed cardiac cause, routine toxicological screening provides limited extra information. However, the role of polypharmacy in sudden cardiac arrest requires further investigation. No occult overdose-related cardiac arrests were identified.

Return to Work After Refractory Out-of-Hospital Cardiac Arrest in Patients Managed With or Without Extracorporeal Cardiopulmonary Resuscitation: A Nationwide Register-Based Study.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly used for refractory out-of-hospital cardiac arrest (OHCA). However, survivors managed with ECPR are at risk of poor functional status. The purpose of this study was to investigate return to work (RTW) after refractory OHCA. METHODS AND RESULTS: Of 44 360 patients with OHCA in the period of 2011 to 2020, this nationwide registry-based study included 805 patients with refractory OHCA in the working age (18-65 years) who were employed before OHCA (2% of the total OHCA cohort). Demographics, prehospital characteristics, status at hospital arrival, employment status, and survival were retrieved through the Danish national registries. Sustainable RTW was defined as RTW for ≥6 months without any long sick leave relapses. Median follow-up time was 4.1 years. ECPR and standard advanced cardiovascular life support were applied in 136 and 669 patients, respectively. RTW 1 year after OHCA was similar (39% versus 54%; P=0.2) and sustainable RTW was high in both survivors managed with ECPR and survivors managed with standard advanced cardiovascular life support (83% versus 85%; P>0.9). Younger age and shorter length of hospitalization were associated with RTW in multivariable Cox analysis, whereas ECPR was not. CONCLUSIONS: In refractory OHCA-patients employed prior to OHCA, approximately 1 out of 2 patients were employed after 1 year with no difference between patients treated with ECPR or standard advanced cardiovascular life support. Younger age and shorter length of hospitalization were associated with RTW while ECPR was not.

Invasive mechanical ventilation in cardiogenic shock complicating acute myocardial infarction: A contemporary Danish cohort analysis.

PURPOSE: Invasive mechanical ventilation (IMV) is widely used in patients with cardiogenic shock following acute myocardial infarction (AMICS), but evidence to guide practice remains sparse. We sought to evaluate trends in the rate of IMV utilization, applied settings, and short term-outcome of a contemporary cohort of AMICS patients treated with IMV according to out-of-hospital cardiac arrest (OHCA) at admission. METHODS: Consecutive AMICS patients receiving IMV in an intensive care unit (ICU) at two tertiary centres between 2010 and 2017. Data were analysed in relation to OHCA. RESULTS: A total of 1274 mechanically ventilated AMICS patients were identified, 682 (54%) with OHCA. Frequency of IMV increased during the study period, primarily due to higher occurrence of OHCA admissions. Among 566 patients with complete ventilator data, positive-end-expiratory pressure, inspired oxygen fraction, and minute ventilation during the initial 24 h in ICU were monitored. No differences were observed between 30-day survivors and non-survivors with OHCA. In non-OHCA, these ventilator requirements were significantly higher among 30-day non-survivors (P for all<0.05), accompanied by a lower PaO2/FiO2 ratio (median 143 vs. 230, P < 0.001) and higher arterial lactate levels (median 3.5 vs. 1.5 mmol/L, P < 0.001) than survivors. Physiologically normal PaO2 and pCO2 levels were achieved in all patients irrespective of 30-day survival and OHCA status. CONCLUSION: In the present contemporary cohort of AMICS patients, physiologically normal blood gas values were achieved both in OHCA and non-OHCA in the early phase of admission. However, increased demand of ventilatory support was associated with poorer survival only in non-OHCA patients.

The ROCK trial-a multidisciplinary Rehabilitation intervention for sudden Out-of-hospital Cardiac arrest survivors focusing on return-to-worK: a pragmatic randomized controlled trial protocol.

INTRODUCTION: Most cardiac arrest survivors are classified with mild to moderate cognitive impairment; roughly, 50% experience long-term neurocognitive impairment. Postarrest challenges complicate participation in society and are associated with social issues such as failure to resume social activities and impaired return to work. The effectiveness of rehabilitation interventions for out-of-hospital cardiac arrest survivors are sparsely described, but the body of evidence describes high probabilities of survivors not returning to work, returning to jobs with modified job descriptions, returning to part-time employment, and often in combination with extensive unmet rehabilitation needs. Hence, there is a need to develop and test a pragmatic individual targeted intervention to facilitate return to work (RTW) in survivors of OHCA. The overall aim of the ROCK trial is to evaluate the effectiveness of a comprehensive individually tailored multidisciplinary rehabilitation intervention for survivors of OHCA on RTW compared to usual care. METHODS AND ANALYSIS: The ROCK trial is a two-arm parallel group multicentre investigator-initiated pragmatic randomized controlled superiority trial with primary endpoint measured 12 months after the cardiac arrest. Adult survivors who were part of the labour force prior to the OCHA and had at least 2 years until they are qualified to receive retirement state pensions are eligible for inclusion. Survivors will be randomized 1:1 to usual care group or usual care plus a comprehensive tailored rehabilitation intervention focusing on supporting RTW. After comprehensive assessment of individual rehabilitation needs, the intervention is ongoingly coordinated within a multidisciplinary rehabilitation team, and the intervention can be delivered for up until 12 months. Data for the primary outcome will be obtained from the national register on social transfer payments. The primary outcome will be analysed using logistic regression assessing RTW status at 12 months adjusting for the intervention and age at OHCA, sex, marital status, and occupation prior to OHCA. DISCUSSION: The ROCK trial is the first RCT to investigate the effectiveness of a rehabilitation intervention focusing on return to work after cardiac arrest. TRIAL REGISTRATION: ClinicalTrials.gov NCT05173740. Registered on May 2018.

Health-related quality of life and cognitive function after out-of-hospital cardiac arrest; a comparison of prehospital return-of-spontaneous circulation and refractory arrest managed with extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) for selected refractory out-of-hospital cardiac arrest (OHCA) is increasingly used. Detailed knowledge of health-related quality of life (HRQoL) and long-term cognitive function is limited. HRQoL and cognitive function were assessed in ECPR-survivors and OHCA-survivors with prehospital return of spontaneous circulation after standard advanced cardiac life support (sACLS). METHODS: Fifteen ECPR-survivors and 22 age-matched sACLS-survivors agreed to participate in this follow-up study. Participants were examined with echocardiography, 6-minute walk test, and neuropsychological testing, and answered HRQoL (EQ-5D-5L and Short Form 36 (SF-36)), and mental health questionnaires. RESULTS: Most patients were male (73 % and 82 %) and median age at follow-up was similar between groups (55 years and 60 years). Low flow time was significantly longer for ECPR-survivors (86 min vs. 15 min) and lactate levels were significantly higher (14.1 mmol/l vs. 3.9 mmol/l). No between-group difference was found in physical function nor in cognitive function with scores corresponding to the 23rd worst percentile of the general population. SACLS-survivors had HRQoL on level with the Danish general population while ECPR-survivors scored lower in both EQ-5D-5L (index score 0.73 vs. 0.86, p = 0.03, visual analog scale: 70 vs. 84, p = 0.04) and in multiple SF-36 health domains (role physical, bodily pain, general health, and mental health). CONCLUSIONS: Despite substantially longer low flow times with thrice as high lactate levels, ECPR-survivors were similar in cognitive and physical function compared to sACLS-survivors. Nonetheless, ECPR-survivors reported lower HRQoL overall and related to mental health, pain management, and the perception of limitations in physical role.

Accuracy of a zero-heat-flux thermometer in cardiac surgery, a prospective, multicentre, method comparison study.

Accurate measurement of core temperature is of utmost importance during on-pump cardiac surgery, for detection of hypothermia before cardiopulmonary bypass (CPB), guidance of temperature management on CPB, active rewarming on CPB and guidance of warming therapy after CPB. Most temperature measurement methods are known to become inaccurate during rapid changes in core temperature and suffer from delayed detection of temperature changes. Zero-heat-flux temperature (ZHF) measurement from the lateral forehead may be an alternative, non-invasive method quantifying the core temperature. A prospective, observational, multicentre study was conducted in one hundred patients scheduled for on-pump coronary artery bypass grafting. Core temperatures were measured every minute by two zero-heat-flux thermometer (SpotOn™) and a bladder thermometer and a pulmonary artery catheter (PAC) in the period after induction of anesthesia until CPB. Accuracy and precision of both methods were compared against core temperature measured in the pulmonary artery using the method of Bland and Altman. A high accuracy (around 0.1 °C) and a very good precision (Limits of agreement (LoA) - 0.6; 0.4 °C) were found between zero-heat-flux thermometer and core temperature measured by PAC. Among the two ZHF thermometers the bias was negligible (- 0.003 °C) with narrow LoA of - 0.42 °C and 0.41 °C. In contrast, bias between bladder temperature and PAC temperature was large (0.51 °C) with corresponding LoA of - 0.06 °C and 1.1 °C. ZHF thermometers are in contrast to bladder temperature a reliable core temperature monitor in cardiac surgery during the period after induction of anestesia until CPB. The zero-heat-flux method can provide clinicians reliably with continuous and non-invasive measurements of core temperature in normothermic and mild hypothermic temperature ranges and therefore can be helpful to guide temperature management.

The Feasibility of C-Reactive Protein Point-of-Care Testing to Reduce Overuse of Antibiotics in Children with Acute Respiratory Tract Infections in Rural Kyrgyzstan: A Pilot Study.

Background: In Kyrgyzstan, the morbidity prevalence of and morbidity from acute respiratory tract infections (ARTI) in children is high. Local healthcare workers (HCW) often prescribe antibiotics that are not indicative due to a mix of professional and societal factors. It is suggested to precede with a decision on antibiotics by a point-of-care test (POCT) on the appropriateness of the treatment, eg, a measurement of C-reactive protein (CRP). CRP-guided antibiotic stewardship in children with ARTI has not previously been studied in Central Asia. Purpose: This pilot study was conducted to examine the feasibility of the methods and procedures to be used in the upcoming randomised controlled COORDINATE clinical trial (NCT05195866) and in daily clinical practice in primary care. Patients and methods: HCWs from three selected rural healthcare facilities were trained in the CRP POCT and in interpretation of results. Children aged 6 months to 12 years attending the primary healthcare facilities with respiratory symptoms were randomly assigned to CRP-guided management or standard care, guided by clinical findings only. Children were followed up for 14 days by scheduled telephone calls to caregivers. Results: Eighty-one children participated in this pilot study. The CRP POCT and the trial procedures were acceptable to the target group as well as to the HCWs. Children from both groups recovered equally well, with an observed significant lower use of antibiotics in the CRP group. HCWs generally adhered to the CRP guidelines, and only once was an antibiotic prescribed despite low CRP results. No safety concerns were observed. Four parents provided wrong phone numbers impeding follow-up. We will collect all mobile phone numbers in the household for the main trial. Conclusion: The pilot provided satisfactory results, suggesting that the COORDINATE trial of CRP POCT is effective, feasible with minor adjustments and without apparent safety concerns for the participants.

Lower versus higher blood pressure targets in comatose patients resuscitated from out-of-hospital cardiac arrest-Protocol for a secondary Bayesian analysis of the box trial.

BACKGROUND: The management of blood pressure targets during intensive care after out-of-hospital cardiac arrest (OHCA) remains a topic of debate. The blood Pressure and Oxygenation Targets After OHCA (BOX) trial explored the efficacy of two different blood pressure targets in 789 patients during intensive care after OHCA. In the primary frequentist analysis, no statistically significant differences were found for neurological outcome after 90 days. METHODS: This protocol outlines secondary Bayesian analyses of 365-day all-cause mortality and two secondary outcomes: neurological outcome after 365 days, and plasma neuron-specific enolase, a biomarker of brain injury, after 48 h. We will employ adjusted Bayesian logistic and linear regressions, presenting results as relative and absolute differences with 95% confidence intervals. We will use weakly informative priors for the primary analyses, and skeptical and evidence-based priors (where available) in sensitivity analyses. Exact probabilities for any benefit/harm will be presented for all outcomes, along with probabilities of clinically important benefit/harm (risk differences larger than 2%-points absolute) and no clinically important differences for the binary outcomes. We will assess whether heterogeneity of treatment effects on mortality is present according to lactate at admission, time to return of spontaneous circulation, primary shockable rhythm, age, hypertension, and presence of ST-elevation myocardial infarction. DISCUSSION: This secondary analysis of the BOX trial aim to complement the primary frequentist analysis by quantifying the probabilities of beneficial or harmful effects of different blood pressure targets. This approach seeks to provide clearer insights for researchers and clinicians into the effectiveness of these blood pressure management strategies in acute medical conditions, particularly focusing on mortality, neurological outcomes, and neuron-specific enolase.

Combined effects of targeted blood pressure, oxygenation, and duration of device-based fever prevention after out-of-hospital cardiac arrest on 1-year survival: post hoc analysis of a randomized controlled trial.

BACKGROUND: The "Blood Pressure and Oxygenation Targets in Post Resuscitation Care" (BOX) trial investigated whether a low versus high blood pressure target, a restrictive versus liberal oxygenation target, and a shorter versus longer duration of device-based fever prevention in comatose patients could improve outcomes. No differences in rates of discharge from hospital with severe disability or 90-day mortality were found. However, long-term effects and potential interaction of the interventions are unknown. Accordingly, the objective of this study is to investigate both individual and combined effects of the interventions on 1-year mortality rates. METHODS: The BOX trial was a randomized controlled two-center trial that assigned comatose resuscitated out-of-hospital cardiac arrest patients to the following three interventions at admission: A blood pressure target of either 63 mmHg or 77 mmHg; An arterial oxygenation target of 9-10 kPa or 13-14 kPa; Device-based fever prevention administered as an initial 24 h at 36 °C and then either 12 or 48 h at 37 °C; totaling 36 or 72 h of temperature control. Randomization occurred in parallel and simultaneously to all interventions. Patients were followed for the occurrence of death from all causes for 1 year. Analyzes were performed by Cox proportional models, and assessment of interactions was performed with the interventions stated as an interaction term. RESULTS: Analysis for all three interventions included 789 patients. For the intervention of low compared to high blood pressure targets, 1-year mortality rates were 35% (138 of 396) and 36% (143 of 393), respectively, hazard ratio (HR) 0.92 (0.73-1.16) p = 0.47. For the restrictive compared to liberal oxygenation targets, 1-year mortality rates were 34% (135 of 394) and 37% (146 of 395), respectively, HR 0.92 (0.73-1.16) p = 0.46. For device-based fever prevention for a total of 36 compared to 72 h, 1-year mortality rates were 35% (139 of 393) and 36% (142 of 396), respectively, HR 0.98 (0.78-1.24) p = 0.89. There was no sign of interaction between the interventions, and accordingly, no combination of randomizations indicated differentiated treatment effects. CONCLUSIONS: There was no difference in 1-year mortality rates for a low compared to high blood pressure target, a liberal compared to restrictive oxygenation target, or a longer compared to shorter duration of device-based fever prevention after cardiac arrest. No combination of the interventions affected these findings. Trial registration ClinicalTrials.gov NCT03141099, Registered 30 April 2017.

Effect of prehospital high-dose glucocorticoid on hemodynamics in patients resuscitated from out-of-hospital cardiac arrest: a sub-study of the STEROHCA trial.

BACKGROUND: Following resuscitated out-of-hospital cardiac arrest (OHCA), inflammatory markers are significantly elevated and associated with hemodynamic instability and organ dysfunction. Vasopressor support is recommended to maintain a mean arterial pressure (MAP) above 65 mmHg. Glucocorticoids have anti-inflammatory effects and may lower the need for vasopressors. This study aimed to assess the hemodynamic effects of prehospital high-dose glucocorticoid treatment in resuscitated comatose OHCA patients. METHODS: The STEROHCA trial was a randomized, placebo-controlled, phase 2 trial comparing one prehospital injection of methylprednisolone 250 mg with placebo immediately after resuscitated OHCA. In this sub-study, we included patients who remained comatose at admission and survived until intensive care unit (ICU) admission. The primary outcome was cumulated norepinephrine use from ICU admission until 48 h reported as mcg/kg/min. Secondary outcomes included hemodynamic status characterized by MAP, heart rate, vasoactive-inotropic score (VIS), and the VIS/MAP-ratio as well as cardiac function assessed by pulmonary artery catheter measurements. Linear mixed-model analyses were performed to evaluate mean differences between treatment groups at all follow-up times. RESULTS: A total of 114 comatose OHCA patients were included (glucocorticoid: n = 56, placebo: n = 58) in the sub-study. There were no differences in outcomes at ICU admission. From the time of ICU admission up to 48 h post-admission, patients in the glucocorticoid group cumulated a lower norepinephrine use (mean difference - 0.04 mcg/kg/min, 95% CI - 0.07 to - 0.01, p = 0.02). Moreover, after 12-24 h post-admission, the glucocorticoid group demonstrated a higher MAP with mean differences ranging from 6 to 7 mmHg (95% CIs from 1 to 12), a lower VIS (mean differences from - 4.2 to - 3.8, 95% CIs from - 8.1 to 0.3), and a lower VIS/MAP ratio (mean differences from - 0.10 to - 0.07, 95% CIs from - 0.16 to - 0.01), while there were no major differences in heart rate (mean differences from - 4 to - 3, 95% CIs from - 11 to 3). These treatment differences between groups were also present 30-48 h post-admission but to a smaller extent and with increased statistical uncertainty. No differences were found in pulmonary artery catheter measurements between groups. CONCLUSIONS: Prehospital treatment with high-dose glucocorticoid was associated with reduced norepinephrine use in resuscitated OHCA patients. TRIAL REGISTRATION: EudraCT number: 2020-000855-11; submitted March 30, 2020. URL: https://www. CLINICALTRIALS: gov ; Unique Identifier: NCT04624776.

Treatment of hepatitis C in children with direct-acting antiviral drugs.

The primary purpose of treating chronic hepatitis C (HCV) is to prevent the development of liver fibrosis, cirrhosis, and cancer. In the last decade, direct-acting antiviral medicine (DAA) has been approved to treat children with HCV. This treatment has a higher efficacy, shorter duration, and milder side effects than the previously approved treatment. In this review, it is recommended to track down children who might be infected with HCV to enhance early treatment to prevent transmission of the virus and the possible complications.

Detecting signatures of consciousness in acute brain injury after stimulation with apomorphine and methylphenidate: protocol for a placebo-controlled, randomized, cross-over study.

Introduction: Acute brain injury can lead to states of decreased consciousness, that is, disorder of consciousness (DoC). Detecting signs of consciousness early is vital for DoC management in the intensive care unit (ICU), neurorehabilitation and long-term prognosis. Our primary objective is to investigate the potential of pharmacological stimulant therapies in eliciting signs of consciousness among unresponsive or low-responsive acute DoC patients. Methods: In a placebo-controlled, randomised, cross-over setting, we evaluate the effect of methylphenidate and apomorphine in 50 DoC patients with acute traumatic or non-traumatic brain injury admitted to the ICU. Patients are examined before and after administration of the trial drugs using (1) neurobehavioural scales to determine the clinical level of consciousness, (2) automated pupillometry to record pupillary responses as a signature for awareness and (3) near-infrared spectroscopy combined with electroencephalography to record neurovascular coupling as a measure for cortical activity. Primary outcomes include pupillary dilations and increase in cortical activity during passive and active paradigms. Ethics: The study has been approved by the ethics committee (Journal-nr: H-21022096) and follows the principles of the Declaration of Helsinki. It is deemed to pose minimal risks and to hold a significant potential to improve treatment options for DoC patients. If the stimulants are shown to enhance cortical modulation of pupillary function and neurovascular coupling, this would warrant a large multicentre trial to evaluate their clinical impact. Dissemination: Results will be available on EudraCT, clinicaltrialsregister.eu and published in an international peer-reviewed journal. Trial registration number: EudraCT Number: 2021-001453-31.