Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking.
We randomly assigned comatose patients who ...had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause to device-based temperature control targeting 36°C for 24 hours followed by targeting of 37°C for either 12 or 48 hours (for total intervention times of 36 and 72 hours, respectively) or until the patient regained consciousness. The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category of 3 or 4 (range, 1 to 5, with higher scores indicating more severe disability; a category of 3 or 4 indicates severe cerebral disability or coma) within 90 days after randomization. Secondary outcomes included death from any cause and the Montreal Cognitive Assessment score (range, 0 to 30, with higher scores indicating better cognitive ability) at 3 months.
A total of 393 patients were randomly assigned to temperature control for 36 hours, and 396 patients were assigned to temperature control for 72 hours. At 90 days after randomization, a primary end-point event had occurred in 127 of 393 patients (32.3%) in the 36-hour group and in 133 of 396 patients (33.6%) in the 72-hour group (hazard ratio, 0.99; 95% confidence interval, 0.77 to 1.26; P = 0.70) and mortality was 29.5% in the 36-hour group and 30.3% in the 72-hour group. At 3 months, the median Montreal Cognitive Assessment score was 26 (interquartile range, 24 to 29) and 27 (interquartile range, 24 to 28), respectively. There was no significant between-group difference in the incidence of adverse events.
Active device-based fever prevention for 36 or 72 hours after cardiac arrest did not result in significantly different percentages of patients dying or having severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).
Blood levels of Glial Fibrillary Acidic protein (GFAP) reflect processes associated with different types of CNS injury. Evidence suggests that GFAP is cleaved by caspases during CNS injury, hence ...positioning GFAP fragments as potential biomarkers of injury-associated processes. We set out to develop an assay detecting the neo-epitope generated by caspase-6 cleavage of GFAP (GFAP-C6), and to assess the ability of GFAP-C6 to reflect pathological processes in patients suffering a cardiac arrest and subsequent global cerebral ischemia. Anti-GFAP-C6 antibodies recognized their specific target sequence, and dilution and spike recoveries in serum were within limits of ±20% reflecting high precision and accuracy of measurements. Intra- and inter-assay CVs were below limits of 10% and 15%, respectively. Serological levels of GFAP-C6 were significantly elevated 72 hours after CA (Mean±SD) (20.39±10.59 ng/mL) compared to time of admission (17.79±10.77 ng/mL, p<0.0001), 24 hours (17.40±7.99 ng/mL, p<0.0001) and 48 hours (17.87±8.56 ng/mL, p<0.0001) after CA, but were not related to neurological outcome at day 180. GFAP-C6 levels at admission, 24, 48, and 72 hours after cardiac arrest correlated with two proteolytic fragments of tau, tau-A (r = 0.30, r = 0.40, r = 0.50, r = 0.53, p < 0.0001) and tau-C (r = 54, r = 0.48, r = 0.55, r = 0.54, p < 0.0001), respectively. GFAP-C6 levels did not correlate with other markers of CNS damage; total tau, NSE and S100B. In conclusion, we developed the first assay detecting a caspase-6 cleaved fragment of GFAP in blood. Increased levels at 72 hours after cardiac arrest as well as moderate correlations between GFAP-C6 and two other blood biomarkers of neurodegeneration suggest the ability of GFAP-C6 to reflect pathological processes of the injured brain. Investigations into the potential of GFAP-C6 in other types of CNS injury are warranted.
The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, ...brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via
F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (- 8.4%, P = 0.032 vs 15.7%, P < 0.0005) and S1P (- 41.0%, P < 0.0005 vs 19.1%, P < 0.005) plasma levels, respectively. Long-term cooling (n = 44) did not affect plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the individual studies. However, short-term studies combined, showed that increased changes in plasma apoM correlated with BAT metabolic activity (β: 0.44, 95% CI 0.06-0.81, P = 0.024) after adjusting for study design but not BAT volume (β: 0.39, 95% CI - 0.01-0.78, P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism.
In cardiogenic shock (CS), contractile failure is often accompanied by a systemic inflammatory response syndrome. In contrast, many patients with septic shock (SS) develop cardiac dysfunction. A ...similar hemodynamic support strategy is often deployed in both syndromes but it is unclear whether this is justified based on profiles of biomarkers expressing neurohormonal activation and cardiovascular stress.
In this prospective, multicenter cohort, 111 patients with acute myocardial infarction related CS were identified, and matched to patients with SS. Clinical parameters were collected and blood samples were obtained on day 1–3 of Intensive Care admission.
In this shock cohort comprising 222 patients, with a mean age of 61 (±13.5) years and of whom 161 (37 %) were male, we found that despite obvious clinical disparities on admission, mortality at 30-days did not differ (CS: 40.5 % vs. SS 43.1 %, p = 0.56). Overall, plasma concentrations of all biomarkers were higher in SS patients, with the largest difference on the first day. However, only in CS patients the biomarker concentrations were associated with mortality.
In this prospective, multicenter cohort SS and CS patients showed similarities in baseline conditions and had similar mortality. However, several biomarkers only showed prognostic value in CS.
Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory biomarker related to acute kidney injury (AKI). Including 1892 consecutive patients with ST-elevation myocardial infarction ...(STEMI), in which NGAL was measured in 1624 (86%) on admission and in a consecutive subgroup at 6-12 h (n = 163) and 12-24 h (n = 222) after admission, this study aimed to evaluate the prognostic value of NGAL in predicting AKI and mortality. Patients were stratified based on whether their admission NGAL plasma concentration was greater than or equal to/less than the median. The primary endpoint was a composite of the first occurrence of AKI or all-cause death within 30 days. AKI was classified by the maximal plasma creatinine increase from baseline during index admission as KDIGO1 (<200% increase) or KDIGO23 (≥200% increase) according to the Kidney Disease Improving Global Outcomes (KDIGO) system. Admission NGAL > the median was independently associated with a higher risk of severe AKI (KDIGO2-3) and 30-day all-cause mortality when adjusted for age, admission systolic blood pressure and high-sensitivity C-reactive protein, left-ventricular ejection fraction, known kidney dysfunction, and cardiogenic shock with an odds ratio (95% confidence interval) of 2.26 (1.18-4.51),
= 0.014. Finally, we observed increasing predictive values in a subgroup during the first day of hospitalization suggesting that assessment of NGAL should be delayed for optimal prognostic purposes.
Combining the antibiotic azithromycin and hydroxychloroquine induces airway immunomodulatory effects, with the latter also having
antiviral properties. This may improve outcomes in patients ...hospitalised for coronavirus disease 2019 (COVID-19).
Placebo-controlled double-blind randomised multicentre trial. Patients aged ≥18 years, admitted to hospital for ≤48 h (not intensive care) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR test were recruited. The intervention was 500 mg daily azithromycin for 3 days followed by 250 mg daily azithromycin for 12 days combined with 200 mg twice-daily hydroxychloroquine for all 15 days. The control group received placebo/placebo. The primary outcome was days alive and discharged from hospital within 14 days (DAOH14).
After randomisation of 117 patients, at the first planned interim analysis, the data and safety monitoring board recommended stopping enrolment due to futility, based on pre-specified criteria. Consequently, the trial was terminated on 1 February 2021. 61 patients received the combined intervention and 56 patients received placebo. In the intervention group, patients had a median (interquartile range) 9.0 (3-11) DAOH14
9.0 (7-10) DAOH14 in the placebo group (p=0.90). The primary safety outcome, death from all causes on day 30, occurred for one patient in the intervention group
two patients receiving placebo (p=0.52), and readmittance or death within 30 days occurred for nine patients in the intervention group
six patients receiving placebo (p=0.57).
The combination of azithromycin and hydroxychloroquine did not improve survival or length of hospitalisation in patients with COVID-19.
ObjectiveTo determine the predictive value of pro-C-type natriuretic peptide (pro-CNP) measurement in plasma sampled on admission from patients presenting with ST-elevation myocardial infarction ...(STEMI).DesignProspective cohort study.SettingTwo University Hospitals in Denmark.Participants1760 consecutive patients (470 females and 1290 males) with confirmed STEMI.Main outcomes and measuresThe main outcome was all-cause mortality at 1 year after presentation and the primary measure was pro-CNP concentration in plasma at admission in all patients and longitudinal measurements in a consecutive subgroup of 287 patients. A reference population (n=688) defined cut-off values of increased pro-CNP concentrations.ResultsIn all patients, an increased pro-CNP concentration was associated with a higher all-cause mortality after 1 year (HR 1.6, 95% CI 1.1 to 2.4, Plogrank=0.009) including an interaction of sex (p=0.03). In separate sex-stratified analyses, female patients showed increased all-cause mortality (HR1 year 2.6, 95% CI 1.5 to 4.6), Plogrank <0.001), whereas no differences were found in male patients (HR1 year 1.1, 95% CI 0.7 to 1.9, Plogrank=0.66). After adjusting for potential risk factors, we found increased pro-CNP concentrations≥the median value to be independently associated with increased risk of mortality in female patients within 1 year (HR per 1 pmol/L increase: 1.04, 95% CI 1.01 to 1.06, p=0.007). Moreover, we found indications of sex differences in pro-CNP concentrations over time (higher pro-CNP in males (4.4, 95% CI −0.28 to 9.1 pmol/L, p=0.07) and interaction of sex and time (p=0.13)), and that hypertension was independently associated with higher pro-CNP (4.5, 95% CI 0.6 to 8.4 pmol/L, p=0.03).ConclusionsIn female but not male patients presenting with STEMI, high concentrations of pro-CNP (≥median) at admission independently indicate a higher risk of all-cause mortality. The findings are remarkably specific for female patients, suggesting a different vascular phenotype beyond traditional measures of coronary artery flow compared with male patients.
N-terminal pro-B-type natriuretic (NT-proBNP) is expressed in the heart and brain, and serum levels are elevated in acute heart and brain diseases. We aimed to assess the possible association between ...serum levels and neurological outcome and death in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Of the 939 comatose OHCA patients enrolled and randomized in the Targeted Temperature Management (TTM) trial to TTM at 33°C or 36°C for 24 hours, 700 were included in the biomarker substudy. Of these, 647 (92%) had serum levels of NT-proBNP measured 24, 48, and 72 hours after return of spontaneous circulation (ROSC). Neurological outcome was evaluated by the Cerebral Performance Category (CPC) score and modified Rankin Scale (mRS) at 6 months. Six hundred thirty-eight patients (99%) had serum NT-proBNP levels ≥125 pg/ml. Patients with TTM at 33°C had significantly lower NT-proBNP serum levels (median 1,472 pg/ml) than those in the 36°C group (1,914 pg/ml) at 24 hours after ROSC, p <0.01 but not at 48 and 72 hours. At 24 hours, an increase in NT-proBNP quartile was associated with death (Plogrank <0.0001). In addition, NT-proBNP serum levels > median were independently associated with poor neurological outcome (odds ratio, ORCPC 2.02, CI 1.34 to 3.05, p <0.001; ORmRS 2.28, CI 1.50 to 3.46, p <0.001) adjusted for potential confounders. The association was diminished at 48 and 72 hours after ROSC. In conclusion, NT-proBNP serum levels are increased in comatose OHCA patients. Furthermore, serum NT-proBNP levels are affected by level of TTM and are associated with death and poor neurological outcome.
Background
Midregional proadrenomedullin (MR‐proADM) has demonstrated prognostic potential after myocardial infarction (MI). Yet, the prognostic value of MR‐proADM at admission has not been examined ...in patients with ST‐segment–elevation MI (STEMI).
Methods and Results
The aim of this substudy, DANAMI‐3 (The Danish Study of Optimal Acute Treatment of Patients with ST‐segment–elevation myocardial infarction), was to examine the associations of admission concentrations of MR‐proADM with short‐ and long‐term mortality and hospital admission for heart failure in patients with ST‐segment–elevation myocardial infarction. Outcomes were assessed using Cox proportional hazard models and area under the curve using receiver operating characteristics. In total, 1122 patients were included. The median concentration of MR‐proADM was 0.64 nmol/L (25th–75th percentiles, 0.53–0.79). Within 30 days 23 patients (2.0%) died and during a 3‐year follow‐up 80 (7.1%) died and 38 (3.4%) were admitted for heart failure. A doubling of MR‐proADM was, in adjusted models, associated with an increased risk of 30‐day mortality (hazard ratio, 2.67; 95% confidence interval, 1.01–7.11; P=0.049), long‐term mortality (hazard ratio, 3.23; 95% confidence interval, 1.97–5.29; P<0.0001), and heart failure (hazard ratio, 2.71; 95% confidence interval, 1.32–5.58; P=0.007). For 30‐day and 3‐year mortality, the area under the curve for MR‐proADM was 0.77 and 0.78, respectively. For 3‐year mortality, area under the curve (0.84) of the adjusted model marginally changed (0.85; P=0.02) after addition of MR‐proADM.
Conclusions
Elevation of admission MR‐proADM was associated with long‐term mortality and heart failure, whereas the association with short‐term mortality was borderline significant. MR‐proADM may be a marker of prognosis after ST‐segment–elevation myocardial infarction but does not seem to add substantial prognostic information to established clinical models.
Clinical Trial Registration
URL: http:/www.ClinicalTrials.gov/. Unique identifiers: NCT01435408 and NCT01960933.
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