Effects of mild hypercapnia on myocardial injury after out-of-hospital cardiac arrest. A sub-study of the TAME trial.

PURPOSE: Mild hypercapnia did not improve neurological outcomes for resuscitated out-of-hospital cardiac arrest (OHCA) patients in the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. However, the effects of hypercapnic acidosis on myocardial injury in patients with cardiac arrest is unexplored. We investigated whether mild hypercapnia compared to normocapnia, following emergency coronary intervention, increased myocardial injury in comatose OHCA-patients with AMI. METHODS: Single-centre, prospective, pre-planned sub-study of the TAME trial. Patients were randomised to targeted mild hypercapnia (PaCO2 = 6.7-7.3 kPa) or normocapnia (PaCO2 = 4.7-6.0 kPa) for 24 h. Myocardial injury was assessed with high-sensitive cardiac troponin T (hs-cTnT) measured at baseline, 24, 48 and 72 h. Haemodynamics were assessed with right heart catheterisation and blood-gas analyses every 4th hour for 48 h. RESULTS: We included 125 OHCA-patients. 57 (46%) had an AMI, with 31 and 26 patients randomised to hypercapnia and normocapnia, respectively. Median peak hs-cTnT in AMI-patients was 58% lower in the hypercapnia-group: 2136 (IQR: 861-4462) versus 5165 ng/L (IQR: 2773-7519), p = 0.007. Lower average area under the hs-cTnT curve was observed in the hypercapnia-group: 2353 (95% CI 1388-3319) versus 4953 ng/L (95% CI 3566-6341), P-group = 0.002. Hypercapnia was associated with increased cardiac power output (CPO) and lower lactate levels in patients with AMI (P-group < 0.05). hs-cTnT, lactate and CPO were not significantly different between intervention groups in OHCA-patients without AMI (p > 0.05). CONCLUSIONS: Mild hypercapnia was not associated with increased myocardial injury in resuscitated OHCA-patients. In AMI-patients, mild hypercapnia was associated with lower hs-cTnT and lactate, and improved cardiac performance. TRIAL REGISTRATION NUMBER: NCT03114033.

Novel cardiac extracellular matrix biomarkers in STEMI: Associations with ischemic injury and long-term mortality.

BACKGROUND: We aimed to determine whether serum levels of proteins related to changes in cardiac extracellular matrix (ECM) were associated with ischemic injury assessed by cardiac magnetic resonance (CMR) and mortality in patients with ST-elevation myocardial infarction (STEMI). METHODS: The concentrations of six ECM-related proteins (periostin, osteopontin, syndecan-1, syndecan-4, bone morphogenetic protein 7, and growth differentiation factor (GDF)-15) were measured in serum samples from patients on Day 1 and Month 4 after STEMI (n = 239). Ischemic injury was assessed by myocardial salvage index, microvascular obstruction, infarct size, and left ventricular function measured by CMR conducted during the initial admission (median 2 days after admission) and after 4 months. All-cause mortality was recorded after a median follow-up time of 70 months. RESULTS: Levels of periostin increased from Day 1 to Month 4 after hospitalization, while the levels of GDF-15, osteopontin, syndecan-1, and syndecan-4 declined. At both time points, high levels of syndecan-1 were associated with microvascular obstruction, large infarct size, and reduced left ventricular ejection fraction, whereas high levels of syndecan-4 at Month 4 were associated with a higher myocardial salvage index and less dilatation of the left ventricle. Higher mortality rates were associated with periostin levels at both time points, low syndecan-4 levels at Month 4, or high GDF-15 levels at Month 4. CONCLUSIONS: In patients with STEMI, we found an association between serum levels of ECM biomarkers and ischemic injury and mortality. The results provide new insight into the role ECM components play in ischemic injury following STEMI and suggests a potential for these biomarkers in prognostication after STEMI.

Outcome prediction in comatose cardiac arrest patients with initial shockable and non-shockable rhythms.

BACKGROUND: Prognosis after out-of-hospital cardiac arrest (OHCA) is presumed poorer in patients with non-shockable than shockable rhythms, frequently leading to treatment withdrawal. Multimodal outcome prediction is recommended 72 h post-arrest in still comatose patients, not considering initial rhythms. We investigated accuracy of outcome predictors in all comatose OHCA survivors, with a particular focus on shockable vs. non-shockable rhythms. METHODS: In this observational NORCAST sub-study, patients still comatose 72 h post-arrest were stratified by shockable vs. non-shockable rhythms for outcome prediction analyzes. Good outcome was defined as cerebral performance category 1-2 within 6 months. False positive rate (FPR) was used for poor and sensitivity for good outcome prediction accuracy. RESULTS: Overall, 72/128 (56%) patients with shockable and 12/50 (24%) with non-shockable rhythms had good outcome (p < .001). For poor outcome prediction, absent pupillary light reflexes (PLR) and corneal reflexes (clinical predictors) 72 h after sedation withdrawal, PLR 96 h post-arrest, and somatosensory evoked potentials (SSEP), all had FPR <0.1% in both groups. Unreactive EEG and neuron-specific enolase (NSE) >60 µg/L 24-72 h post-arrest had better precision in shockable patients. For good outcome, the clinical predictors, SSEP and CT, had 86%-100% sensitivity in both groups. For NSE, sensitivity varied from 22% to 69% 24-72 h post-arrest. The outcome predictors indicated severe brain injury proportionally more often in patients with non-shockable than with shockable rhythms. For all patients, clinical predictors, CT, and SSEP, predicted poor and good outcome with high accuracy. CONCLUSION: Outcome prediction accuracy was comparable for shockable and non-shockable rhythms. PLR and corneal reflexes had best precision 72 h after sedation withdrawal and 96 h post-arrest.

Transcranial Doppler during the first week after cardiac arrest and association with 6-month outcomes.

Background: Early prediction of outcomes in comatose patients after out-of-hospital cardiac arrest is challenging. Prognostication tools include clinical examination, biomarkers, and neuroradiological and neurophysiological tests. We studied the association between transcranial Doppler (TCD) and the outcome. Methods: This was a pre-defined sub-study of the prospective observational Norwegian Cardiorespiratory Arrest Study. Patients underwent standardized post-resuscitation care, including target temperature management (TTM) to 33°C for 24 h. TCD was performed at days 1, 3, and 5-7. The primary endpoint was cerebral performance category (CPC) at 6 months, dichotomized into good (CPC 1-2) and poor (CPC 3-5) outcomes. We used linear mixed modeling time-series analysis. Results: Of 139 TCD-examined patients, 81 (58%) had good outcomes. Peak systolic velocity in the middle cerebral artery (PSV) was low during TTM (Day 1) and elevated after rewarming (Day 3). Thereafter, it continued to rise in patients with poor, but normalized in patients with good, outcomes. At days 5-7, PSV was 1.0 m/s (95% CI 0.9; 1.0) in patients with good outcomes and 1.3 m/s (95% CI 1.1; 1.4) in patients with poor outcomes (p < 0.001). Conclusion: Elevated PSV at days 5-7 indicated poor outcomes. Our findings suggest that serial TCD examinations during the first week after cardiorespiratory arrest may improve our understanding of serious brain injury.

Cardiovascular changes induced by targeted mild hypercapnia after out of hospital cardiac arrest. A sub-study of the TAME cardiac arrest trial.

AIM: Hypercapnia may elicit detrimental haemodynamic effects in critically ill patients. We aimed to investigate the consequences of targeted mild hypercapnia versus targeted normocapnia on pulmonary vascular resistance and right ventricular function in patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: Pre-planned, single-centre, prospective, sub-study of the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. Patients were randomised to mild hypercapnia (PaCO2 = 6.7-7.3 kPa) or normocapnia (PaCO2 = 4.7-6.0 kPa) for 24 hours. Haemodynamic assessment was performed with right heart catheterisation and serial blood-gas analyses every4th hour for 48 hours. RESULTS: We studied 84 patients. Mean pH was 7.24 (95% CI 7.22-7.30) and 7.32 (95% CI 7.31-7.34) with hypercapnia and normocapnia, respectively (P-group < 0.001). Pulmonary vascular resistance index (PVRI), pulmonary artery pulsatility index, and right atrial pressure did not differ between groups (P-group > 0.05). Mean cardiac index was higher with mild hypercapnia (P-group < 0.001): 2.0 (95% CI 1.85-2.1) vs 1.6 (95% CI 1.52-1.76) L/min/m2. Systemic vascular resistance index was 2579 dyne-sec/cm-5/ m2 (95% CI 2356-2830) with hypercapnia, and 3249 dyne-sec/cm-5/ m2 (95% CI 2930-3368) with normocapnia (P-group < 0.001). Stroke volumes (P-group = 0.013) and mixed venous oxygen saturation (P-group < 0.001) were higher in the hypercapnic group. CONCLUSION: In resuscitated OHCA patients, targeting mild hypercapnia did not increase PVRI or worsen right ventricular function compared to normocapnia. Mild hypercapnia comparatively improved cardiac performance and mixed venous oxygen saturation.

Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab.

BACKGROUND: Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. METHODS: STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24-36, 72-168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. RESULTS: Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=-0.29, -0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=-0.09,-0.14, respectively). CONCLUSIONS: Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients. TRIAL REGISTRATION NUMBER: NCT03004703.

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).

Blood Milieu in Acute Myocardial Infarction Reprograms Human Macrophages for Trauma Repair.

Acute myocardial infarction (AMI) is accompanied by a systemic trauma response that impacts the whole body, including blood. This study addresses whether macrophages, key players in trauma repair, sense and respond to these changes. For this, healthy human monocyte-derived macrophages are exposed to 20% human AMI (n = 50) or control (n = 20) serum and analyzed by transcriptional and multiparameter functional screening followed by network-guided data interpretation and drug repurposing. Results are validated in an independent cohort at functional level (n = 47 AMI, n = 25 control) and in a public dataset. AMI serum exposure results in an overt AMI signature, enriched in debris cleaning, mitosis, and immune pathways. Moreover, gene networks associated with AMI and with poor clinical prognosis in AMI are identified. Network-guided drug screening on the latter unveils prostaglandin E2 (PGE2) signaling as target for clinical intervention in detrimental macrophage imprinting during AMI trauma healing. The results demonstrate pronounced context-induced macrophage reprogramming by the AMI systemic environment, to a degree decisive for patient prognosis. This offers new opportunities for targeted intervention and optimized cardiovascular disease risk management.

Changes in health status and health related quality of life from six months to five years in out-of-hospital cardiac arrest survivors - A NORCAST sub study.

BACKGROUND: Brain injury in out-of-hospital cardiac arrest (OHCA) survivors affects health status and health-related quality of life (HRQoL). It is unknown how HRQoL evolves over time, and assessments at different time points may lead to different results. METHODS: In a NORCAST sub study, OHCA survivors eligible for health status (EQ-5D-3L) and HRQoL (SF-36) assessments were examinated six months and five years after OHCA. At five-year follow-up, survivors also retrospectively assessed their health status for each consecutive year following OHCA. The next of kin independently assessed health status and HRQoL of their respective OHCA survivors. RESULTS: Among 138 survivors alive after six months and 117 after five years, 80 (88% male) completed both follow-ups. Health status and HRQoL remained stable over time, except for increasing SF-36 mental summary score and decreasing physical functioning and physical component score. Anxiety and depression levels were generally low, although younger survivors stated more anxiety than older survivors. Retrospective assessment showed reduced health status for the first two years, which increased only from the third year. Explorative analyses revealed that younger age, longer time to return of spontaneous circulation (tROSC) and late awakening affected health status, particularly in the first two years post-arrest. CONCLUSIONS: OHCA survivors showed stable health status and HRQoL with only minor differences between six months and five years. Younger survivors with long tROSC, late awakening, and more anxiety and depression symptoms at six months, had reduced health status the first two years with significant improvements towards the fourth year.

Interleukin-6 inhibition in ST-elevation myocardial infarction: Immune cell profile in the randomised ASSAIL-MI trial.

BACKGROUND: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear. METHODS: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69). FINDINGS: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8+ count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset. INTERPRETATION: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage. FUNDING: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867).

Complement ratios C3bc/C3 and sC5b-9/C5 do not increase the sensitivity of detecting acute complement activation systemically.

BACKGROUND: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone. MATERIALS AND METHODS: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean. RESULTS: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio. CONCLUSION: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically.

Complement activation in association with clinical outcomes in ST-elevation myocardial infarction.

Introduction: The complement system and neutrophil extracellular traps (NETs) might contribute to ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI). We aimed to estimate associations between complement activation and NETs in STEMI, and their prognostic value on clinical endpoints. Methods: In this cohort study, 864 patients admitted for PCI during STEMI were included. Complement activation was analyzed by the terminal complement complex (TCC), while NETs were analyzed by myeloperoxidase-DNA, citrullinated histone 3 (CitH3) and dsDNA. The composite endpoint was reinfarction, unscheduled revascularization, stroke, hospitalization due to heart failure, or death, and the secondary endpoint was total mortality. The association between TCC and clinical endpoints was assessed by Cox regression and ROC curve analysis. Results: TCC was weakly correlated to dsDNA (r = 0.127, p < 0.001) and CitH3 (r = 0.102, p = 0.003). After a median follow-up time of 4.6 years, 184 (21.3 %) patients had reached a clinical endpoint. TCC was not associated with the composite endpoint, but with total mortality (HR: 1.673, 95 % CI: [1.014, 2.761], p = 0.044). The significant association was lost when adjusting for CRP, NT-proBNP, LVEF and time from symptoms to PCI. In ROC curve analysis of total mortality, the AUC for TCC alone was 0.549 (95 % CI: [0.472, 0.625]), AUC for dsDNA alone was 0.653 (95 % CI: [0.579, 0.720]), while AUC for TCC and dsDNA combined was 0.660 (95 % CI: [0.590, 0.730]). Conclusions: In this STEMI cohort, TCC was not associated with the composite endpoint, but somewhat with total mortality. Combining TCC and dsDNA did not increase the prognostic value compared to dsDNA alone.

High levels of interleukin-6 are associated with final infarct size and adverse clinical events in patients with STEMI.

OBJECTIVE: Inflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction (STEMI). We aimed to explore the role of acute and sustained interleukin 6 (IL-6) signalling, including soluble IL-6 receptor (IL-6R), with regard to infarct size, adverse remodelling and future cardiovascular events in patients with STEMI. METHODS: We included 269 patients with first-time STEMI, symptom duration <6 hours and treated with percutaneous coronary intervention. Blood sampling and cardiac MRI were performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12-month and 70-month follow-up, respectively. RESULTS: IL-6 levels above median at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF). IL-6 levels in the highest quartile were at all sampling points associated with an increased risk of having an adverse clinical event during the first 12 months and with long-term all-cause mortality. IL-6R was not associated with infarct size, LVEF, myocardial salvage or long-term all-cause mortality. CONCLUSION: Acute and sustained elevation of IL-6 measured 4 months after STEMI were associated with larger infarct size, reduced LVEF and adverse clinical events including all-cause mortality. The results add important information to the sustained role of inflammation in patients with STEMI and IL-6 as a potential target for long-term intervention. TRIAL REGISTRATION NUMBER: NCT00922675.

Complement activation is associated with poor outcome after out-of-hospital cardiac arrest.

BACKGROUND: Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death. METHODS: Outcome was assessed at six months and defined by cerebral performance category scale (1-2; good outcome, 3-5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule. RESULTS: Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p < 0.001 for both) and in patients with poor compared to good outcome (p = 0.03 and p < 0.001, respectively). Unadjusted, higher sC5b-9 at admission was associated with poor outcome (odds ratio 1.08 (95% CI 1.01-1.14), p = 0.024). Adjusted, sC5b-9 was still associated with outcome, but the association became non-significant when time to return-of-spontaneous-circulation above 25 min was included as a covariate. Endothelial cell activation markers increased from admission to day three, but only sE-selectin and thrombomodulin were significantly higher in patients with poor versus good outcome (p = 0.004 and p = 0.03, respectively) and correlated to sCD14 and sC5b-9/C3bc, respectively. CONCLUSION: Complement system activation, reflected by sC5b-9 at admission, leading to subsequent endothelial cell activation, was associated with poor outcome in out-of-hospital cardiac arrest patients.

Nanocosm: a well plate photobioreactor for environmental and biotechnological studies.

Phytoplankton are key primary producers at the bottom of the aquatic food chain. They are a highly diverse group of organisms essential for the functioning of our ecosystems and because of their characteristics, their biomass is considered for various commercial applications. A full appreciation of their abundance, diversity and potential is only feasible by using systems that enable simultaneous testing of strains and/or variables in a fast and easy way. A major bottleneck is the lack of a cost-effective method with the capacity for complex experimental set-ups that enable fast and reproducible screening and analysis. In this study, we present nanocosm, a versatile LED-based micro-scale photobioreactor (PBR) that allows simultaneous testing of multiple variables such as temperature and light within the same plate. Every well can be independently controlled for intensity, temporal variation and light type (RGB, white, UV). We show that our systems guarantee homogeneous conditions because of controlled temperature and evaporation and adjustments for light crosstalk. By ensuring controlled environmental conditions the nanocosm is suitable for running factorial experimental designs where each well can be used as an independent micro-PBR. To validate culture performances, we assess well-to-well reproducibility and our results show minimal well-to-well variability for all the conditions tested. Possible modes of operation and application are discussed together with future development of the system.

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. OBJECTIVES: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. METHODS: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. RESULTS: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. CONCLUSIONS: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).

Case report: a patient with thyroid storm, refractory cardiogenic shock, and cardiac arrest treated with Lugol's iodine solution and veno-arterial extra corporal membrane oxygenation support.

BACKGROUND: Thyroid storm is a life-threatening condition. Refractory cardiogenic shock and cardiac arrest are rare complications of thyroid storm and the treatment options are limited. CASE SUMMARY: A 35-year- old woman treated for Grave's disease was admitted with thyrotoxicosis complicated by infection and neutropenia caused by thionamide treatment. After treatment including beta-blockers, steroids, and Lugol's iodine solution, she went into cardiac arrest. Echocardiography after resuscitation demonstrated severe biventricular heart failure. The patient was in refractory cardiogenic shock with recurrent cardiac arrest and mechanical circulatory support with a veno-arterial extra corporal membrane oxygenation (V-A ECMO) circuit was established. After 2 days on V-A ECMO and supportive treatment with iodine solution, glucocorticosteroids, and levosimendan, her myocardial function recovered and thyroid hormone levels were normalized. Veno-arterial extra corporal membrane oxygenation was discontinued, and the patient was treated with early total thyroidectomy. The patient made a full recovery with no neurological/cognitive impairment, as assessed after 4 weeks. DISCUSSION: Adverse reactions to standard treatment of hyperthyroidism contributed to this patient's development of thyroid storm and the following refractory cardiogenic shock. When she was critically unstable, levosimendan improved myocardial function while inotropic support with dobutamine was ineffective, likely due to prolonged beta-antagonist administration. Temporary support with V-A ECMO, until effective lowering of thyroid hormone levels and improvement in myocardial function were obtained, was life-saving in this young patient and may be considered in refractory cardiogenic shock caused by thyroid storm.

Outcome in refractory out-of-hospital cardiac arrest before and after implementation of an ECPR protocol.

AIM: To compare the outcomes in patients with refractory out-of-hospital cardiac arrest (OHCA) fulfilling the criteria for extracorporeal cardiopulmonary resuscitation (ECPR) before and after implementation of an ECPR protocol, whether the patient received ECPR or not. METHODS: We compared cardiac arrest registry data before (2014-2015) and after (2016-2019) implementation of the ECPR protocol. The ECPR criteria were presumed cardiac origin, witnessed arrest with ventricular fibrillation, bystander CPR, age 18-65, advanced life support (ALS) within 15 min and ALS > 10 min without return of spontaneous circulation (ROSC). The primary outcome was 30-day survival; the secondary outcomes were sustained ROSC, neurological outcome and the proportion of patients transported with ongoing ALS. RESULTS: There were 1086 and 3135 patients in the pre- and post-implementation sample; 48 (4%) and 100 (3%) met the ECPR criteria, respectively. Of these, 21 (44%) vs. 37 (37%) were alive after 30 days, p = 0.4, and 30 (63%) vs. 50 (50%) achieved sustained ROSC, p = 0.2. All survivors in the pre-implementation sample had cerebral performance category 1-2 vs. 30 (81%) in the post-implementation sample, p = 0.03. Of the patients fulfilling the ECPR criteria, 7 (15%) and 26 (26%), p = 0.1, were transported with ongoing ALS in the pre- and post-implementation sample, respectively. CONCLUSIONS: There were no differences in 30-day survival or prehospital ROSC in patients with refractory OHCA before and after initiation of an ECPR protocol.