Comatose Out-of-hospital Cardiac Arrest Patients Research Articles

Oxygen targets following immediate percutaneous coronary intervention in comatose survivors of out-of-hospital cardiac arrest - a BOX sub-study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Novo Nordisk Foundation The Lundbeck Foundation. Background Treatment with supplemental oxygen in patients with acute myocardial infarction (AMI) has previously been associated with poorer outcomes. However, in patients with AMI resuscitated from out-of-hospital cardiac arrest (OHCA) and undergoing immediate revascularization, evidence regarding specific oxygen targets is sparse. Purpose To assess the impact of a restrictive versus a liberal oxygen target on infarct size in OHCA patients undergoing immediate percutaneous coronary intervention (PCI). Methods The current study is a sub-study of the BOX trial, a randomized trial with a 2-by-2 factorial design, in which comatose OHCA patients with a presumed cardiac cause of arrest were randomly assigned to either a restrictive oxygen target (partial pressure of arterial oxygen (Pao2) of 9 to 10 kPa) or a liberal oxygen target (Pao2 of 13 to 14 kPa). In this sub-study we included patients who underwent immediate revascularization with PCI. The primary outcome was myocardial infarct size as assessed by the cardiac enzyme troponin-T (TnT). TnT was measured repeatedly during the first 72 hours and analyzed with a repeated measures variance component model with baseline adjustment. Secondary outcome was one-year all-cause mortality assessed by Kaplan-Meier and Cox proportional hazards analyses. Results A total of 329 patients underwent immediate PCI, whereof 172 patients were randomized to the restrictive oxygen target and 157 to the liberal oxygen target. The oxygen intervention was successful with a significantly higher PaO2 in the liberal oxygen target group during the first 72 hours (p<0.0001). Baseline characteristics and findings on coronary angiography (CAG) were similar in the two oxygen target groups. Thus, median age was 63 (interquartile range (IQR) 55–71), 81% were male, and estimated left ventricular ejection fraction on arrival to hospital was 35% (IQR 25–45%). Further, 74% of the patients had an initial postresuscitation electrocardiogram with ST-segment elevations, and the left anterior descending artery was deemed as culprit lesion in 49% of the patients. There was no difference in peak TnT between the restrictive and liberal oxygen target group (median 2540 (IQR 925–6420) versus 3410 (792–8630), ng/l, p=0.23), nor did TnT differ between the groups during the first 72 hours after admission (Figure 1, p=1.00). Within one year from admission, 120 patients (36.5%) had died. There was no difference in mortality between the restrictive (34%) and liberal (39%) oxygen target group (hazard ratio, 0.80; 95% CI, 0.56-1.14; p=0.21) (Figure 2). Conclusion Targeting a restrictive versus a liberal oxygen level in comatose survivors of OHCA who underwent immediate revascularization did not affect infarct size nor did it result in a significant difference in one-year mortality rate.Figure 1:Troponin-T levelsFigure 2:Kaplan-Meier curves

Immediate Platelet Inhibition Strategy for Comatose Out-of-Hospital Cardiac Arrest Survivors Undergoing Percutaneous Coronary Intervention and Mild Therapeutic Hypothermia.

Background: Comatose survivors of out-of-hospital cardiac arrest (OHCA) undergoing percutaneous coronary intervention (PCI) and target temperature management (TTM) are at increased risk of stent thrombosis (ST), partly due to delayed platelet inhibition even with more potent P2Y12 agents. We hypothesized that periprocedural cangrelor would induce immediate platelet inhibition, bridging the "P2Y12 inhibition gap". Methods: In our pilot study, we randomized 30 comatose OHCA patients undergoing PCI and TTM (32-34 °C) into cangrelor and control groups. Both groups received unfractioned heparin, acetylsalicylic acid, and ticagrelor via enteral tube. The cangrelor group also received an intravenous bolus of cangrelor followed by a 4 h infusion. Platelet inhibition was measured using VerifyNow® and Multiplate® ADP at baseline and 1, 3, 5, and 8 h post PCI. Results: Patient characteristics did not differ between groups. VerifyNow® showed significantly decreased platelet reactivity with cangrelor at 1 h (30 vs. 221 PRU; p < 0.001) and 3 h (24 vs. 180 PRU; p < 0.001), with differences at 5 and 8 h. Similarly, the proportion of patients with high on-treatment platelet reactivity (HPR) in the cangrelor group was significantly lower at 1 h (0% vs. 67%; p < 0.001) and 3 h (0% vs. 47%; p = 0.007). Multiplate® ADP was also decreased at 1 h (14 vs. 48 U; p < 0.001) and 3 h (11 vs. 42 U; p = 0.001), with no difference at 5 and 8 h. The occurrence of bleeding events was similar in both groups. Conclusions: Cangrelor safely induced immediate and profound platelet inhibition. We observed no significant drug-drug interaction with ticagrelor.

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

BackgroundFollowing 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.MethodsThe 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.ResultsA 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.ConclusionsPrehospital 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.Graphic

Acute coronary occlusion and percutaneous coronary intervention after out-of-hospital cardiac arrest.

Early coronary angiography (CAG) has been recommended in selected patients following out-of-hospital-cardiac-arrest (OHCA). We aimed to identify clinical features associated with acute coronary occlusion (ACO) and evaluate the associations between ACO, successful percutaneous coronary intervention (PCI) and outcomes in this population. We included comatose OHCA patients treated with targeted temperature management (TTM) between December 2005 and September 2016 who underwent early CAG within 24 hours. The co-primary outcomes were all-cause 30-day mortality and good neurological outcome (modified Rankin Score [mRS] ≤2) at hospital discharge. Among 155 patients (93% shockable arrest rhythm, 55% with ST elevation), 133 (86%) had coronary artery stenosis ≥50% and 65 (42%) had ACO. ST elevation (sensitivity 74%, specificity 59%, OR 4.0, 95% CI 2.0-8.1) and elevated first troponin (sensitivity 88%, specificity 26%, OR 2.5, 95% CI 1.1-6.1) had limited sensitivity and specificity for ACO. Unadjusted 30-day mortality did not differ significantly by coronary disease severity or ACO. Successful PCI was associated with a lower risk of 30-day mortality (adjusted HR 0.5, 95% CI 0.2-0.9, P=.03), especially among patients with ACO (adjusted HR 0.4, 95% CI 0.1-0.9, P=0.03). After adjustment, ACO and PCI were not associated with the probability of good neurological outcome. In this select cohort of resuscitated OHCA patients undergoing CAG, unstable coronary disease is highly prevalent and successful PCI was associated with a higher probability of 30-day survival, especially among those with ACO. Neither ACO nor successful PCI were independently associated with good neurological outcome.

Prehospital high-dose methylprednisolone in resuscitated out-of-hospital cardiac arrest patients (STEROHCA): a randomized clinical trial

PurposePatients who are successfully resuscitated following out-of-hospital cardiac arrest (OHCA) are still at a high risk of neurological damage and death. Inflammation and brain injury are components of the post-cardiac arrest syndrome, and can be assessed by systemic interleukin 6 (IL-6) and neuron-specific enolase (NSE). Anti-inflammatory treatment with methylprednisolone may dampen inflammation, thereby improving outcome. This study aimed to determine if prehospital high-dose methylprednisolone could reduce IL-6 and NSE in comatose OHCA patients.MethodsThe STEROHCA trial was a randomized, blinded, placebo-controlled, phase II prehospital trial performed at two cardiac arrest centers in Denmark. Resuscitated comatose patients with suspected cardiac etiology were randomly assigned 1:1 to a single intravenous injection of 250 mg methylprednisolone or placebo. The co-primary outcome was reduction of IL-6 and NSE-blood levels measured daily for 72 h from admission. The main secondary outcome was survival at 180 days follow-up.ResultsWe randomized 137 patients to methylprednisolone (n = 68) or placebo (n = 69). We found reduced IL-6 levels (p < 0.0001) in the intervention group, with median (interquartile range, IQR) levels at 24 h of 2.1 pg/ml (1.0; 7.1) and 30.7 pg/ml (14.2; 59) in the placebo group. We observed no difference between groups in NSE levels (p = 0.22), with levels at 48 h of 18.8 ug/L (14.4; 24.6) and 14.8 ug/L (11.2; 19.4) in the intervention and placebo group, respectively. In the intervention group, 51 (75%) patients survived and 44 (64%) in the placebo group.ConclusionPrehospital treatment with high-dose methylprednisolone to resuscitated comatose OHCA patients, resulted in reduced IL-6 levels after 24 h, but did not reduce NSE levels.

Abstract 100: Blood Pressure Targets and Hemodynamics According to Initial Blood Lactate Levels in Patients With Comatose Out-of-Hospital Cardiac Arrest - A Substudy of the BOX Trial

Out-of-hospital cardiac arrest (OHCA) patients are often circulatory unstable and have high mortality in the first days following resuscitation. An increase in lactate will reflect the severity and duration of hypoperfusion in out-of-hospital cardiac arrest (OHCA). Further, the severity of hypoperfusion could modify the effect on survival and neurological injury of different mean arterial blood pressure (MAP) targets. In this sub-study of the BOX trial, adults successfully resuscitated comatose OHCA patients (n=789) with a presumed cardiac cause were randomized to a MAP 63 mmHg vs. 77 mmHg. Patients were arbitrarily grouped in low-lactate: &lt;25%, medium-lactate: 25%-75%, and high &gt;75 % according to blood lactate levels at hospital arrival as a surrogate of severity of hypoperfusion. Invasive evaluations were performed using an arterial line and pulmonary artery catheter (PAC). Logistic regression analysis evaluated whether lactate levels (as continuous and categorical) modify the effect of MAP targets on 1-year mortality. The three lactate groups were: low-lactate: &lt;2.9 mmol/L, medium-lactate: 2.9-7.9 mmol/L, and high-lactate &gt;7.9 mmol/L. The vasoactive inotropic score was higher with increasing initial lactate level with the largest difference at 6 hours (low-lactate: 7.8 (95%CI: 5.7 - 10.1) vs. high-lactate: 16.4 (95%CI: 13.4 - 19.6). No difference in the cardiac index or systemic vascular resistance was observed between lactate groups. The initial lactate level modified the effect of the two MAP targets (p=0.044), with a tendency to higher mortality for high-lactate patients if the MAP target were 77 mmHg (odds ratio: 1.7 (95%CI: 0.9-3.0, p=0.08). Comatose OHCA patients with high initial lactate levels required more vasoactive drugs on the first two days of ICU admission to meet the blood pressure target and have a poorer prognosis. The results do not support a higher MAP target benefit for patients with an initial high lactate level in the first 48 hours.

Coronary features across the spectrum of out-of-hospital cardiac arrest with ST-elevation myocardial infarction (CAD-OHCA study)

AimWe hypothesized that adult patients with out-of-hospital cardiac arrest (OHCA) and ST-elevation myocardial infarction (STEMI) requiring prolonged resuscitation have more severe coronary artery disease (CAD) than those responding rapidly, and more severe CAD than patients with STEMI without OHCA. MethodsConsecutive conscious and comatose OHCA patients with STEMI after reestablishment of spontaneous circulation (ROSC), and patients with refractory OHCA undergoing veno-arterial extracorporeal membrane oxygenation (E-CPR OHCA) were compared to STEMI without OHCA (STEMI no OHCA). CAD severity was assessed by a single physician blinded to the resuscitation method, time to ROSC and level of consciousness. ResultsBetween 2016 and 2022, 71 conscious OHCA, 157 comatose OHCA, 50 E-CPR OHCA and 101 STEMI no OHCA underwent immediate coronary angiography. Acute culprit lesion was documented less often in OHCA (88.1% vs 97%; p = 0.009) but complete occlusion was more frequent (68.8% vs 58.4%; p = 0.038) than in STEMI no OHCA. SYNTAX score was 5.6 in STEMI no OHCA, 10.2 in conscious OHCA, 13.4 in comatose OHCA and 26.8 in E-CPR OHCA (p < 0.001). There was a linear correlation between SYNTAX score and delay to ROSC/ECMO initiation (r2 = 0.61; p < 0.001). Post PCI culprit TIMI 3 flow was comparable between the groups (≥86%). SYNTAX score was among independent predictors of 5-year survival which was significantly decreased in comatose OHCA (56.1%) and E-CPR OHCA (36.0%) compared to conscious OHCA (83.1%) and STEMI no OHCA (88.1%). ConclusionCompared to STEMI no OHCA, OHCA was associated with increased incidence of acute coronary occlusion and more complex non culprit CAD which progressively increased from conscious OHCA to E-CPR OHCA. Severity of CAD was associated with increased delays to ROSC/ECMO initiation and decreased long term survival.

Predicting poor neurological outcomes following out-of-hospital cardiac arrest using neuron-specific enolase and neurofilament light chain in patients with and without haemolysis.

Hypoxic-ischaemic brain injury following out-of-hospital cardiac arrest (OHCA) is a common complication and a major cause of death. Neuron-specific enolase (NSE) and neurofilament light chain (NfL) are released after brain injury and elevated concentrations of both are associated with poor neurological outcome. We explored the influence of haemolysis on the prognostic performance of NSE and NfL. The study is based on post hoc analyses of a randomized, single-centre, double-blinded, controlled trial (IMICA), where comatose OHCA patients of presumed cardiac cause were included. Free-haemoglobin was measured at admission to quantify haemolysis. NSE and NfL were measured after 48 h to estimate the extent of brain injury. Montreal Cognitive Assessment score (MoCA) was assessed to evaluate neurocognitive impairments. Seventy-three patients were included and divided into two groups by the median free-haemoglobin at admission. No group differences in mortality or poor neurological outcome were observed. The high-admission free-haemoglobin group had a significantly higher concentration of NSE compared to the low-admission free-haemoglobin group (27.4 µmol/L vs. 19.6 µmol/L, P = 0.03), but no differences in NfL. The performance of NSE and NfL in predicting poor neurological outcome were high for both, but NfL was numerically higher [area under the ROC (AUROC) 0.90 vs. 0.96, P = 0.09]. Furthermore, NfL, but not NSE, was inversely correlated with MoCA score, R2 = 0.21, P = 0.006. High free-haemoglobin at admission was associated with higher NSE concentration after 48 h, but, the performance of NSE and NfL in predicting poor neurological outcome among OHCA patients were good regardless of early haemolysis. Only elevated NfL concentrations were associated with cognitive impairments.

Sex differences in outcome after targeting mean arterial blood-pressures and oxygenation in comatose patients after out-of-hospital cardiac arrest

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Background Previous studies have found lower survival rate and neurological outcomes for female patients with out-of-hospital cardiac arrest (OHCA) compared to males. Recently, the effect of liberal or restrictive oxygenation and lower or higher mean arterial blood-pressures (MAP) on outcome in comatose OHCA patients were investigated; showing no differences between the target groups. Evidence concerning sex differences in outcome after appropriate oxygenation and different MAP levels in comatose OHCA patients is limited. Purpose The aim of this study was to investigate whether female sex was associated with higher rates of unfavourable outcome after treatment with oxygenation and MAP in comatose patients after OHCA related to outcome. Methods Adult comatose OHCA patients (age ≥18 years) of presumed cardiac cause were included in a dual-center, double-blind, randomized trial with a 2-by-2 factorial design. Patients were allocated by a 1:1:1:1 ratio into a MAP target of 63 mm Hg or 77 mm Hg and arterial oxygen concentration during mechanical ventilation of 9–10 kPa (restrictive) or 13–14 kPa (liberal). The primary outcome was a composite of all causes of death within a year or hospital discharge with a cerebral performance category (CPC) of 3 or 4. Results Of the 789 included comatose OHCA patients, 152 (19%) were women. Mean age of women and men were similar, 61±14 years and 63±13 years, respectively. Comorbidities and characteristics of the cardiac arrest were comparable between sexes except for ischemic heart disease, which was more frequent in men (12% women, 24% men) and pulseless electrical activity, which was more frequent in women (8% women, 4% men). CPC 3 or 4 occurred equally in women and men (both 3%). Women had a higher, but non-significant one-year all-cause mortality (women: 42%, men: 35%), Figure 1. In a univariate Cox regression model, the difference in all-cause mortality was not significant (HR: 1.25, CI: 0.95-1.63), but showed significance after adjustment for age (HR: 1.31, CI: 1.004-1.72). Conclusion Men and women in comatose after OHCA had similar unfavourable outcome when treated in the same manner with oxygenation and MAP.

Sex differences in acute hemodynamic response in comatose survivors of OHCA

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Fonden Background In critically ill patients with cardiogenic shock, neurohormonal activation is higher in females compared with males. Whether this is the case in patients resuscitated from out of hospital cardiac arrest (OHCA) is not known and whether sex-based differences relate to achieving mean-arterial-pressure (MAP)-target has not previously been described. Methods This was an investigator-initiated, randomized, controlled study of targeted MAP (63 vs 77 mmHg) and PaO2 (9-10 vs 13-14 kPa) interventions in 789 comatose OHCA (of presumed cardiac origin) patients. Patients underwent serial hemodynamic assessments with pulmonary artery catheter at time of insertion, 6 h, 12 h, 24 h, 36 h and 48 h. Among parameters recorded were heart rate (HR), cardiac output (CO) and central venous pressure (CVP), from which cardiac index (CI) and systemic vascular resistance index (SVRI) were derived. Patient characteristics included sex for stratification, age, time to return of spontaneous circulation (ROSC) and initial electrocardiographic (ECG) rhythm. Results Hemodynamic parameters from 729 patients were analysed, of which 138 (19%) were female and 591 (81%) were male. Both groups had a median age of 64 years, with median time-to-ROSC of 19 minutes in females versus 18 minutes in males. In females versus in males, SVRI and HR were higher (fig.1,2). There were no differences among sexes with regards to CI, MAP, or dose of noradrenaline. At 12 hours, median SVRI in females was 755 dyn·s/cm5·m2 (inter-quartile ratio, IQR 569-931) versus 554 dyn·s/cm5·m2 (IQR 441-684) in males (P&amp;lt;0.0001). At the same point in time, median HR was 71 beats/minute (bpm) in females (IQR 59-82) versus 62 bpm (IQR 54-74) in males (P&amp;lt;0.0001). Lastly, 12-hour median CI was 1.82 L/min/m2 (IQR 1.54-2.40) in females versus 1.95 L/min/m2 (IQR 1.63-2.43) in males (P=0.1303). Conclusions Female comatose OHCA patients had higher SVRI and HR during the first 48 hours of ICU admission, without difference in MAP or vasopressor requirement. Sex specific physiological mechanisms may be involved in maintaining vascular resistance.

Blood pressure targets in out-of-hospital cardiac arrest according to the time to return of spontaneous circulation

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation and Lundbeck Foundation. Introduction Time to return of spontaneous circulation (ROSC) in patients resuscitated after out-of-hospital cardiac arrest (OHCA) is associated with the severity of brain damage and is an important predictor of mortality. We have recently shown no difference in mortality or neurological outcome with different mean arterial blood pressure targets (63 or 77 mmHg) in the initial phase of post-cardiac arrest management in resuscitated OHCA patients who remained comatose. Accordingly, in this post-hoc analysis, we explored whether time to ROSC modifies the effect of different blood pressure targets on mortality and neurological outcome. Method In a double-blind, randomized trial, a mean arterial blood-pressure target of 63 mm Hg vs. 77 mm Hg in comatose adults who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause was investigated (BOX-trial, N Engl J Med 2022). Primary outcome for the present analysis was a composite of discharge from hospital severe brain damage or death from any cause within 365 days from randomization for the blood pressure target intervention was analyzed in a proportional hazard model with time to ROSC (tertiles: short, medium, and long) as a subgroup following testing for interaction. The analysis was conducted in the intention to treat the population. Results A total of 789 patients were included in the analysis. The time to ROSC in the three tertiles was: Short [0 min - 13 min], medium [14 min - 22 min], and long [23 min - 117 min]. The three groups were well balanced in the two blood pressure target groups (In the high group (77 mmHg): Short, n=124 (49%); medium, n= 133 (50%), long, n=136 (51%). Age (short: 62.7 (± 14), medium 62.4 (± 13), and 62.6 (± 13) and sex (short: 19.5% female, medium: 19.0% female, long: 19.4% female) were similar in the three groups. The first monitored rhythm did not differ in the three groups (shockable in 82.6%, 86.2%, and 85.3% of patients, respectively). Time to the first defibrillation did, however, differ between the three groups ((short 6.2 min (± 3.3), medium 9.0 min (± 3.8), and long 11.0 min (± 6.6), p&amp;lt;0.0001). The primary outcome occurred in 44 (17.3%), 92 (34.3%), and 153 (57.5%) in the short, medium, and long groups, respectively (p&amp;lt;0.0001). No interaction of time to ROSC and blood pressure target was found (p=0.62). Hazard ratios in the high (77 mmHg) group for the three tertiles were: short: HR 1.34 (95% CI: 0.75 – 2.40), medium: HR: 0.99 (95% CI: 0.68 – 1.45) and long: HR 0.97 (95% CI: 0.71 – 1.32). Conclusion Longer time to ROSC is associated with an adverse outcome, but it does not modify the effect of different blood pressure targets in comatose OHCA patients.

Quantitative pupillometry thresholds for early neuroprognostication after cardiac arrest: A BOX-trial substudy

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Novo Nordisk Foundation Background Quantitative pupillometry as part of multimodal prognostication in comatose out-of-hospital cardiac arrest (OHCA) patients is promising, but the lack of validated thresholds for outcome presents a challenge for clinical use. Studies have suggested that a percentage reduction of pupillary size (qPLR, %) ≤3.8% and a neurological pupil index (NPi, 0-5) ≤2 is 100% specific for poor neurological outcome. However, this remains to be validated in a large consecutive population. Purpose To assess the proposed thresholds for qPLR and NPi for early identification of poor neurological outcome, defined as Cerebral Performance Category (CPC) 3–5 at 3-months follow-up after OHCA. Methods This predefined, prospective substudy from a large multicenter, randomized trial, obtained quantitative pupillometry measurements from consecutively enrolled patients at 0, 24, 48, 72, 96, and 120 hours after OHCA (t0-t120). However, pupillometry was not used to guide clinical decision-making. Specificity and sensitivity were calculated for the proposed thresholds of qPLR and NPi. Overall prognostic performances were assessed with logistic regression and area under the receiver operating characteristic (ROC) curves (AUC). Models were further adjusted for potential confounders. Results Of the 789 patients comprising the BOX-trial population, serial measurements of quantitative pupillometry were performed in a total of 710 (90%) patients. Patients had a mean age of 63±14 (range 18-93) years, predominantly of male sex (82%), with primary outcome occurring in 266 (37%) patients. For all time points, both median values of qPLR and NPi were significantly lower in patients with poor neurological outcome. The highest AUC was found at t48 for both qPLR and NPi. In the unadjusted model, AUC was 0.80 [95%CI 0.76-0.84] for qPLR and 0.79 [95%CI 0.75-0.83] for NPi (Fig 1). In the adjusted model AUC was 0.92 [95%CI: 0.87-0.96] for qPLR and 0.92 [95%CI: 0.88-0.97] for NPi (Fig 2). Both parameters had a significant contribution to the AUC in the adjusted model, with no significant difference in performance between qPLR and NPi in either model. At t48, specificity for CPC 3-5 was 99% [95%CI 97-100] with sensitivity at 20% [95%CI 15-26] for qPLR≤3.8% and 100% [95%CI 99-100] with sensitivity at 10% [95%CI 6-14] for NPi ≤2. At time points t0, t24, t72, t96, and t120 specificity was 91%, 96%, 99%, 100%, and 100%, respectively for qPLR≤3.8%, and 100% for all time points for NPi ≤2. Conclusion The predictive performance of qPLR and NPi was equally good with optimal timing of measurements at 48 hours after admission. The BOX-trial validates thresholds of NPi ≤2 with 100% specificity for outcome at all time points and of qPLR≤3.8% with 99-100% specificity at t48-t120. These findings support the clinical usefulness of quantitative pupillometry for multimodal neuroprognostication of comatose OHCA patients.

Sex difference in neurological outcome and post-cardiac arrest care in out-of-hospital cardiac arrest patients treated with targeted temperature management

Abstract Funding Acknowledgements Type of funding sources: None. Objectives Conflicting results regarding sex-based differences in the outcomes of out-of-hospital cardiac arrest (OHCA) patients have been reported. Furthermore, no study has examined whether differences in in-hospital interventions and courses are driven by sex differences. This study evaluated the effect of sex on the in-hospital course of these patients as well as the survival rates and long-term neurological outcomes of comatose OHCA patients treated with targeted temperature management (TTM). Methods We retrospectively analyzed the Korean Hypothermia Network prospective registry composed of data collected from 22 hospitals in Korea between October 2015 and December 2018. To evaluate the effect of sex on patient outcomes, we created various multivariate logistic regression models including baseline characteristics, resuscitation, and in-hospital care variables with an interaction term (age × sex). We also performed a stratified analysis of different age groups (less than 50 years of age and older). Regarding the difference in in-hospital courses, we compared daily total and SOFA sub-scores between the sexes and analyzed whether the decision regarding early cardiac interventions and limitations in in-hospital care were associated with sex. Results Among 1339 patients included in the study, 952 were men and 387 were women. There were no differences in age or modified comorbidity index values between the gender groups. Women were more likely to experience cardiac arrest at home and unwitnessed arrests, whereas men were more likely to have shockable initial rhythm, cardiac cause arrest, and ST-segment elevation myocardial infarction (STEMI) on initial electrocardiography and undergo early coronary interventions. The rate of survival to discharge was similar, but men showed better 6-month neurological outcomes. After adjusting for confounders, the male sex was not associated with survival to discharge or good 6-month neurological outcomes. There was no association between sex and outcome in patients of reproductive age and no interaction between age and sex. Regarding the in-hospital course, the daily total and SOFA sub-scores were similar in both sexes. The adjusted effect of sex was not associated with the clinician’s decision to perform early cardiac interventions. The decision to discontinue life-sustaining treatment was determined by poor prognostic factors, not by sex. Conclusions The findings suggested that men had more favorable 6-month survivals and good neurological outcomes compared to women since they had more favorable resuscitation variables. However, after adjusting for confounders, there was no difference between the sexes. This result was consistent with the data in patients of reproductive age. The results regarding in-hospital course showed that daily patient severity scores, early cardiac interventions, resource consumption, and the rates of withdrawal/withholding of in-hospital care were similar in men and women.

Modulation of inflammation by treatment with tocilizumab after out-of-hospital cardiac arrest and associations with clinical status, myocardial- and brain injury

AimTo investigate how the inflammatory response after out-of-hospital cardiac arrest (OHCA) is modulated by blocking IL-6-mediated signalling with tocilizumab, and to relate induced changes to clinical status, myocardial- and brain injury. MethodsThis is a preplanned substudy of the IMICA trial (ClinicalTrials.gov, NCT03863015). Upon admission 80 comatose OHCA patients were randomized to infusion of tocilizumab or placebo. Inflammation was characterized by a cytokine assay, CRP, and leukocyte differential count; myocardial injury by TnT and NT-proBNP; brain injury by neuron-specific enolase (NSE) and Neurofilament Light chain (NFL), while sequential organ assessment (SOFA) score and Vasoactive-Inotropic Score (VIS) represented overall clinical status. ResultsResponses for IL-5, IL-6, IL-17, neutrophil as well as monocyte counts, and VIS were affected by tocilizumab treatment (all p < 0.05), while there was no effect on levels of NFL. IL-5 and IL-6 were substantially increased by tocilizumab, while IL-17 was lowered. Neutrophils and monocytes were lower at 24 and 48 hours, and VIS was lower at 24 hours, for the tocilizumab group compared to placebo. Multiple correlations were identified for markers of organ injury and clinical status versus inflammatory markers; this included correlations of neutrophils and monocytes with TnT, NSE, NFL, SOFA- and VIS score for the tocilizumab but not the placebo group. NT-proBNP, NFL and SOFA score correlated with CRP in both groups. ConclusionsTreatment with tocilizumab after OHCA modulated the inflammatory response with notable increases for IL-5, IL-6, and decreases for neutrophils and monocytes, as well as reduced vasopressor and inotropy requirements.

Comparison of the prognostic value of early-phase proton magnetic resonance spectroscopy and diffusion tensor imaging with serum neuron-specific enolase at 72 h in comatose survivors of out-of-hospital cardiac arrest—a substudy of the XeHypotheca trial

PurposeWe compared the predictive accuracy of early-phase brain diffusion tensor imaging (DTI), proton magnetic resonance spectroscopy (1H-MRS), and serum neuron-specific enolase (NSE) against the motor score and epileptic seizures (ES) for poor neurological outcome after out-of-hospital cardiac arrest (OHCA).MethodsThe predictive accuracy of DTI, 1H-MRS, and NSE along with motor score at 72 h and ES for the poor neurological outcome (modified Rankin Scale, mRS, 3 − 6) in 92 comatose OHCA patients at 6 months was assessed by area under the receiver operating characteristic curve (AUROC). Combined models of the variables were included as exploratory.ResultsThe predictive accuracy of fractional anisotropy (FA) of DTI (AUROC 0.73, 95% CI 0.62–0.84), total N-acetyl aspartate/total creatine (tNAA/tCr) of 1H-MRS (0.78 (0.68 − 0.88)), or NSE at 72 h (0.85 (0.76 − 0.93)) was not significantly better than motor score at 72 h (0.88 (95% CI 0.80–0.96)). The addition of FA and tNAA/tCr to a combination of NSE, motor score, and ES provided a small but statistically significant improvement in predictive accuracy (AUROC 0.92 (0.85–0.98) vs 0.98 (0.96–1.00), p = 0.037).ConclusionNone of the variables (FA, tNAA/tCr, ES, NSE at 72 h, and motor score at 72 h) differed significantly in predicting poor outcomes in this patient group. Early-phase quantitative neuroimaging provided a statistically significant improvement for the predictive value when combined with ES and motor score with or without NSE. However, in clinical practice, the additional value is small, and considering the costs and challenges of imaging in this patient group, early-phase DTI/MRS cannot be recommended for routine use.Trial registrationClinicalTrials.gov NCT00879892, April 13, 2009.

The influence of hemolysis upon admission on the performance of neuron-specific enolase in predicting death after resuscitated out-of-hospital cardiac arrest – a substudy of the IMICA trial

Abstract Background The predominant cause of mortality among out-of-hospital cardiac arrest (OHCA) patients admitted to the intensive care unit in a comatose state is hypoxic-ischemic brain injury and consequent withdrawal of life sustaining therapies. Current guideline for post-resuscitation care suggests a multimodal approach for neuroprognostication including measuring a blood-born biomarker of neuronal injury termed neuron-specific enolase (NSE). However, NSE is also present in erythrocytes and therefore hemolysis – which frequently occurs immediately after resuscitation – must be assessed by measuring free-hemoglobin (free-hgb), and samples discarded if the threshold index is surpassed to minimize false positive results. In addition, the plasma half-life of NSE is much longer than free-hgb, and hemolysis occurring prior to the sampling point of NSE measurement, may cause elevated NSE levels due to destruction of erythrocytes rather than neurons, although free-hgb is no longer detectable in plasma. Purpose To investigate the relationship between hemolysis at hospital admission and NSE measured at 48 hours, and to determine the influence of hemolysis on the clinical performance of NSE in predicting all-cause mortality in comatose OHCA patients. Methods Free-hgb was measured at admission (0h) to quantify hemolysis. NSE was measured at 48 hours after admission. In each NSE sample hemolysis index was measured and mathematically corrected according to standard laboratory procedure. The relationship between free-hgb at 0h and NSE at 48h was investigated by Pearson's correlation analysis. The area under the receiver operating characteristic curves (AUROC) for prediction of all-cause mortality at 30 days were determined for both NSE and free-hgb, and the difference in AUROC between the two was calculated. Further, the positive and negative predictive values (PPV and NPV respectively) of NSE with a cut-off value at &amp;gt;60 μg/l (as recommended by guidelines) in predicting all-cause mortality were calculated. Results Admission free-hgb and NSE at 48 hours were available for 64 consecutive patients surviving beyond 48 hours. The 30-day mortality in this population was 33%. There was no correlation between free-hgb at 0h and NSE at 48h (r=0.13, p=0.30; Figure 1). The AUROC for NSE was 0.92 (Figure 2), and 0.59 for free-hgb at 0h. The PPV for NSE&amp;gt;60 μg/l was 1.0 (1.0–1.0) and NPV 0.84 (0.74–0.94). Conclusions The performance of NSE at 48 hours for predicting all-cause mortality among out-of-hospital cardiac arrest patients was not influenced by the degree of hemolysis at the time of admission, and NSE at 48 hours had both high positive and negative predictive values irrespectively of early hemolysis. Funding Acknowledgement Type of funding sources: None.

15-year survival of comatose OHCA patients according to initial rhythm

Abstract Introduction Long-term outcome of comatose survivors of out-of-hospital cardiac arrest (OHCA) is largely unknown. We therefore investigated 15-year survival of consecutive patients who were admitted to our hospital after reestablishment of spontaneous circulation (ROSC) on the field. Methods and results Between January 2003 and January 2022, 851 patients with shockable and 247 patients with non-shockable rhythms were admitted. Patients with shockable rhythm were significantly younger (61.5±13,3 versus 66.8±14.8 years), had more often bystander life support (64% versus 35%), shorter delay to emergency team arrival (7.3±5.1 versus 8.3±5.9 minutes), shorter time from advanced life support to ROSC (16.6±15.27 versus 18.5±14.3) and more aggressive hospital treatment including hypothermia (89% versus 74%), coronary angiography/PCI strategy (81% versus 52%) and more IABP/ECMO support (18% versus 10%). Survival with good neurological outcome in patients with shockable rhythm decreased from 51% at hospital discharge to 35% at 15 years (Figure 1). In patients with non-shockable rhythm, survival decreased from 14% at hospital discharge to 8% at 15 years. Conclusion If comatose OHCA patient survives to hospital discharge, annual death rate during the following 15 years is 1.07% for shockable and 0.40 for non-shockable rhythms indicating good long-term outcome. Funding Acknowledgement Type of funding sources: None.

Early risk stratification for progression to death by neurological criteria following out-of-hospital cardiac arrest

BackgroundSome patients resuscitated from out-of-hospital cardiac arrest (OHCA) progress to death by neurological criteria (DNC). We hypothesized that initial brain imaging, electroencephalography (EEG), and arrest characteristics predict progression to DNC. MethodsWe identified comatose OHCA patients from January 2010 to February 2020 treated at a single quaternary care facility in Western Pennsylvania. We abstracted demographics and arrest characteristics; Pittsburgh Cardiac Arrest Category, initial motor exam and pupillary light reflex; initial brain computed tomography (CT) grey-to-white ratio (GWR), sulcal or basal cistern effacement; initial EEG background and suppression ratio. We used two modeling approaches: fast and frugal tree (FFT) analysis to create an interpretable clinical risk stratification tool and ridge regression for comparison. We used bootstrapping to randomly partition cases into 80% training and 20% test sets and evaluated test set sensitivity and specificity. ResultsWe included 1,569 patients, of whom 147 (9%) had diagnosed DNC. Across bootstrap samples, >99% of FFTs included three predictors: sulcal effacement, and in cases without sulcal effacement, the combination of EEG background suppression and GWR ≤ 1.23. This tree had mean sensitivity and specificity of 87% and 81%. Ridge regression with all available predictors had mean sensitivity 91 % and mean specificity 83%. Subjects falsely predicted as likely to progress to DNC generally died of rearrest or withdrawal of life sustaining therapies due to poor neurological prognosis. Two of these cases awakened from coma during the index hospitalization. ConclusionsSulcal effacement on presenting brain CT or EEG suppression with GWR ≤ 1.23 predict progression to DNC after OHCA.

MicroRNA-9-3p: a novel predictor of neurological outcome after cardiac arrest

Resuscitated out-of-hospital cardiac arrest (OHCA) patients who remain comatose after hospital arrival are at high risk of mortality due to anoxic brain injury. MicroRNA are small-non-coding RNA molecules ultimately involved in gene-silencing. They show promise as biomarkers, as they are stable in body fluids. The microRNA 9-3p (miR-9-3p) is associated with neurological injury in trauma and subarachnoid haemorrhage. This post hoc analysis considered all 171 comatose OHCA patients from a single centre in the target temperature management (TTM) trial. Patients were randomized to TTM at either 33°C or 36°C for 24 h. MicroRNA-9-3p (miR-9-3p) was measured in plasma sampled at admission and at 28, 48, and 72 h. There were no significant differences in age, gender, and pre-hospital data, including lactate level at admission, between miR-9-3p level quartiles. miR-9-3p levels changed markedly following OHCA with a peak at 48 h. Median miR-9-3p levels between TTM 33°C vs. 36°C were not different at any of the four time points. Elevated miR-9-3p levels at 48 h were strongly associated with an unfavourable neurological outcome [OR: 2.21, 95% confidence interval (CI): 1.64-3.15, P < 0.0001). MiR-9-3p was inferior to neuron-specific enolase in predicting functional neurological outcome [area under the curve: 0.79 (95% CI: 0.71-0.87) vs. 0.91 (95% CI: 0.85-0.97)]. MiR-9-3p is strongly associated with neurological outcome following OHCA, and the levels of miR-9-3p are peaking 48 hours following cardiac arrest.

Clinical Outcomes with Targeted Temperature Management (TTM) in Comatose Out-of-Hospital Cardiac Arrest Patients-A Retrospective Cohort Study.

Purpose: we evaluated the effects of the shift of a targeted temperature management (TTM) strategy from 33 °C to 36 °C in comatose out-of-hospital cardiac arrest (OHCA) patients admitted to the Intensive Care Unit (ICU). Methods: we performed a retrospective study of all comatose (GCS < 8) OHCA patients treated with TTM from 2010 to 2018 (n = 798) from a single-center academic hospital. We analyzed 90-day mortality, and neurological outcome (CPC score) at ICU discharge and ICU length of stay, as primary and secondary outcomes, respectively. Results: we included 798 OHCA patients (583 in the TTM33 group and 215 in the TTM36 group). We found no association between the TTM strategy (TTM33 and TTM36) and 90-day mortality (hazard ratio (HR)] 0.877, 95% CI 0.677–1.135, with TTM36 as reference). Also, no association was found between TTM strategy and favorable neurological outcome at ICU discharge (odds ratio (OR) 1.330, 95% CI 0.941–1.879). Patients in the TTM33 group had on average a longer ICU LOS (beta 1.180, 95% CI 0.222–2.138). Conclusion: no differences in clinical outcomes—both 90-day mortality and favorable neurological outcome at ICU discharge—were found between targeted temperature at 33 °C and 36 °C. These results may help to corroborate previous trial findings and assist in implementation of TTM.