Duration of Device-Based Fever Prevention after Cardiac Arrest.

BACKGROUND: Guidelines recommend active fever prevention for 72 hours after cardiac arrest. Data from randomized clinical trials of this intervention have been lacking. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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-Pressure Targets in Comatose Survivors of Cardiac Arrest.

BACKGROUND: Evidence to support the choice of blood-pressure targets for the treatment of comatose survivors of out-of-hospital cardiac arrest who are receiving intensive care is limited. METHODS: In a double-blind, randomized trial with a 2-by-2 factorial design, we evaluated a mean arterial blood-pressure target of 63 mm Hg as compared with 77 mm Hg in comatose adults who had been resuscitated after an out-of-hospital cardiac arrest of presumed cardiac cause; patients were also assigned to one of two oxygen targets (reported separately). The primary outcome was a composite of death from any cause or hospital discharge with a Cerebral Performance Category (CPC) of 3 or 4 within 90 days (range, 0 to 5, with higher categories indicating more severe disability; a category of 3 or 4 indicates severe disability or coma). Secondary outcomes included neuron-specific enolase levels at 48 hours, death from any cause, scores on the Montreal Cognitive Assessment (range, 0 to 30, with higher scores indicating better cognitive ability) and the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at 3 months, and the CPC at 3 months. RESULTS: A total of 789 patients were included in the analysis (393 in the high-target group and 396 in the low-target group). A primary-outcome event occurred in 133 patients (34%) in the high-target group and in 127 patients (32%) in the low-target group (hazard ratio, 1.08; 95% confidence interval [CI], 0.84 to 1.37; P = 0.56). At 90 days, 122 patients (31%) in the high-target group and 114 patients (29%) in the low-target group had died (hazard ratio, 1.13; 95% CI, 0.88 to 1.46). The median CPC was 1 (interquartile range, 1 to 5) in both the high-target group and the low-target group; the corresponding median modified Rankin scale scores were 1 (interquartile range, 0 to 6) and 1 (interquartile range, 0 to 6), and the corresponding median Montreal Cognitive Assessment scores were 27 (interquartile range, 24 to 29) and 26 (interquartile range, 24 to 29). The median neuron-specific enolase level at 48 hours was also similar in the two groups. The percentages of patients with adverse events did not differ significantly between the groups. CONCLUSIONS: Targeting a mean arterial blood pressure of 77 mm Hg or 63 mm Hg in patients who had been resuscitated from 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.).

Oxygen Targets in Comatose Survivors of Cardiac Arrest.

BACKGROUND: The appropriate oxygenation target for mechanical ventilation in comatose survivors of out-of-hospital cardiac arrest is unknown. METHODS: In this randomized trial with a 2-by-2 factorial design, we randomly assigned comatose adults with out-of-hospital cardiac arrest in a 1:1 ratio to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao2) of 9 to 10 kPa (68 to 75 mm Hg) or a liberal oxygen target of a Pao2 of 13 to 14 kPa (98 to 105 mm Hg); patients were also assigned to one of two blood-pressure targets (reported separately). The primary outcome was a composite of death from any cause or hospital discharge with severe disability or coma (Cerebral Performance Category [CPC] of 3 or 4; categories range from 1 to 5, with higher values indicating more severe disability), whichever occurred first within 90 days after randomization. Secondary outcomes were neuron-specific enolase levels at 48 hours, death from any cause, the score on the Montreal Cognitive Assessment (ranging from 0 to 30, with higher scores indicating better cognitive ability), the score on the modified Rankin scale (ranging from 0 to 6, with higher scores indicating greater disability), and the CPC at 90 days. RESULTS: A total of 789 patients underwent randomization. A primary-outcome event occurred in 126 of 394 patients (32.0%) in the restrictive-target group and in 134 of 395 patients (33.9%) in the liberal-target group (hazard ratio, 0.95; 95% confidence interval, 0.75 to 1.21; P = 0.69). At 90 days, death had occurred in 113 patients (28.7%) in the restrictive-target group and in 123 (31.1%) in the liberal-target group. On the CPC, the median category was 1 in the two groups; on the modified Rankin scale, the median score was 2 in the restrictive-target group and 1 in the liberal-target group; and on the Montreal Cognitive Assessment, the median score was 27 in the two groups. At 48 hours, the median neuron-specific enolase level was 17 µg per liter in the restrictive-target group and 18 µg per liter in the liberal-target group. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Targeting of a restrictive or liberal oxygenation strategy in comatose patients after resuscitation for cardiac arrest resulted in a similar incidence of death or severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).

Treatment Effects of Interleukin-6 Receptor Antibodies for Modulating the Systemic Inflammatory Response After Out-of-Hospital Cardiac Arrest (The IMICA Trial): A Double-Blinded, Placebo-Controlled, Single-Center, Randomized, Clinical Trial.

BACKGROUND: Patients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury. METHODS: Eighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis. RESULTS: The primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P<0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both P<0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both P<0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], P<0.001. There were no differences in survival or neurological outcome. CONCLUSIONS: Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.

Interventional treatment of acute myocardial infarction-related cardiogenic shock.

PURPOSE OF REVIEW: Acute revascularization is with some evidence the only intervention proven to improve the prognosis in myocardial infarction-related cardiogenic shock but several interventions are continuously being investigated in order to increase survival among these patients. In this review, several aspects related to the interventional treatment of cardiogenic shock are discussed chronologically from symptom debut to leaving the cardiac catheterization laboratory. RECENT FINDINGS: In the randomized CULPRIT-SHOCK trial, a culprit-only revascularization strategy was reported superior to immediate complete revascularization among patients with multivessel disease. Recent large-scale observational data underline the marked prognostic importance of time from medical contact to revascularization in acute myocardial infarction-related cardiogenic shock. Moreover, studies suggest a potential beneficial effect of a transradial vascular access as well as early initialization of mechanical circulatory support in carefully selected patients. This, however, needs further validation. SUMMARY: Acute revascularization remains a crucial part of the initial management of acute myocardial infarction-related cardiogenic shock. Among cardiogenic shock patients presenting with multivessel disease, a culprit-only approach should be the routine strategy. Time to revascularization plays a crucial role in the setting of cardiogenic shock, why prehospital optimization and triaging may be the most important factors in order to improve prognosis in AMI-related cardiogenic shock.

Admission biomarkers among patients with acute myocardial-infarction related cardiogenic shock with or without out-of-hospital cardiac arrest an exploratory study.

BACKGROUND: Acute myocardial infarction complicated by cardiogenic shock (AMICS) with or without out-of-hospital cardiac arrest (OHCA) have some pathophysiological differences and could potentially be considered as two individual clinical entities. Thus, there may also be differences in terms of blood borne biomarkers. PURPOSE: To explore potential differences in concentrations of the biomarkers lactate, mid-regional proadrenomedullin (MRproADM), Copeptin, pro-atrial natriuretic peptide (proANP), Syndecan-1, soluble thrombomodulin (sTM), soluble suppression of tumorigenicity 2 (sST2) and neutrophil gelatinase-associated lipocalin (NGAL), in patients with AMICS with or without OHCA. METHOD: Patients admitted for acute coronary angiography due to suspected ST-elevation myocardial infarction were enrolled during a 1-year period. In the present study 86 patients with confirmed AMICS at admission were included. RESULTS: In the adjusted analysis OHCA patients had higher levels of lactate (p = 0.008), NGAL (p = 0.03) and sTM (p = 0.011) while the level of sST2 was lower (p = 0.029). There was little difference in 30-day mortality between the OHCA and non-OHCA groups (OHCA 37% vs. non-OHCA 38%). CONCLUSION: AMICS patients with or without OHCA had similar 30-day mortality but differed in terms of Lactate, NGAL, sTM and sST2 levels. These findings support that non-OHCA and OHCA patients with CS could be considered as two individual clinical entities.

Association of Body Mass Index with Mortality in Patients with Cardiogenic Shock following Acute Myocardial Infarction: A Contemporary Danish Cohort Analysis.

AIMS: The obesity paradox suggests a better prognosis in overweight or obese patients with heart failure and acute myocardial infarction (AMI) than patients with normal weight. Few studies have investigated the association between BMI and mortality in patients with AMI complicated by cardiogenic shock (AMICS). The aim of this study was to evaluate the association between BMI and 30-day mortality in patients with AMICS. METHODS AND RESULTS: A retrospective study of 1,716 patients with AMICS treated at 2 tertiary centers in south-eastern Denmark between 2010 and 2017. Patients undergoing revascularization and who were admitted to the intensive care unit were included (n = 1,216). BMI was available in 1,017 patients (83.6%). Patients were divided according to the WHO classification as normal weight BMI <24.9 kg/m2 (n = 453), overweight BMI 25-29.9 kg/m2 (n = 391), obese class 1 BMI 30-34.9 kg/m2 (n = 131), and obese class 2 + 3 BMI >35 kg/m2 (n = 42). Differences in baseline characteristics, in-hospital treatment, and the primary outcome of all-cause mortality at 30 days were examined. Obese patients had more comorbidities such as diabetes, hypertension, and dyslipidemia than patients with normal weight. Need for renal replacement therapy was higher among obese patients (normal weight, 19% vs. obese class 2 + 3, 35%, p = 0.02); otherwise, no difference in management was found. No difference in 30-day mortality was observed between groups (normal weight 44%, overweight 38%, obese class 1 41%, and obese class 2 + 3 45% at 30 days; ns). CONCLUSIONS: Thirty-day mortality in patients with AMICS was not associated with the BMI category. Thus, evidence of an "obesity paradox" was not observed in this contemporary cohort of patients with AMICS in Denmark.

Mortality in cardiogenic shock is stronger associated to clinical factors than contemporary biomarkers reflecting neurohormonal stress and inflammatory activation.

PURPOSE: To validate the IABP-SHOCK II risk score in a Danish cohort and assess the association between the IABP-SHOCK II risk score and admission concentration of biomarkers reflecting neurohormonal - (Copeptin, Pro-atrial natriuretic peptide (proANP), Mid-regional pro-adrenomedullin (MRproADM)) and inflammatory (ST2) activation in patients with CS complicating ST segment elevation myocardial infarction (STEMI). METHODS: A total of 137 consecutive patients admitted with STEMI and CS at two tertiary heart centres were stratified according to the IABP-SHOCK II risk score (0-2; 3/4; 5-9), and had blood sampled upon admission. RESULTS: Plasma concentrations of Copeptin (median (pmol/L) score 0-2: 313; score 3/4: 682; score 5-9: 632 p < 0.0001), proANP (pmol/L) (1459; 2225; 2876 p = 0.0009) and MRproADM (nmol/L) (0.86; 1.2; 1.4 p = 0.04) were significantly associated with the risk score, whereas ST2 (ng/mL) was not (44; 60; 45 p = 0.23). The IABP-SHOCK II risk score predicted 30-day mortality (score 0-2: 22%; score 4/3: 51%; score 5-9: 72%, area under the curve (AUC): 0.73, plogrank < 0.0001), while the tested biomarkers did not (AUC: 0.51

Impact of concomitant vasoactive treatment and mechanical left ventricular unloading in a porcine model of profound cardiogenic shock.

BACKGROUND: Concomitant vasoactive drugs are often required to maintain adequate perfusion pressure in patients with acute myocardial infarction (AMI) and cardiogenic shock (CS) receiving hemodynamic support with an axial flow pump (Impella CP). OBJECTIVE: To compare the effect of equipotent dosages of epinephrine, dopamine, norepinephrine, and phenylephrine on cardiac work and end-organ perfusion in a porcine model of profound ischemic CS supported with an Impella CP. METHODS: CS was induced in 10 pigs by stepwise intracoronary injection of polyvinyl microspheres. Hemodynamic support with Impella CP was initiated followed by blinded crossover to vasoactive treatment with norepinephrine (0.10 µg/kg/min), epinephrine (0.10 µg/kg/min), or dopamine (10 µg/kg/min) for 30 min each. At the end of the study, phenylephrine (10 µg/kg/min) was administered for 20 min. The primary outcome was cardiac workload, a product of pressure-volume area (PVA) and heart rate (HR), measured using the conductance catheter technique. End-organ perfusion was assessed by measuring venous oxygen saturation from the pulmonary artery (SvO2), jugular bulb, and renal vein. Treatment effects were evaluated using multilevel mixed-effects linear regression. RESULTS: All catecholamines significantly increased LV stroke work and cardiac work, dopamine to the greatest extend by 341.8 × 103 (mmHg × mL)/min [95% CI (174.1, 509.5), p < 0.0001], and SvO2 significantly improved during all catecholamines. Phenylephrine, a vasoconstrictor, caused a significant increase in cardiac work by 437.8 × 103 (mmHg × mL)/min [95% CI (297.9, 577.6), p < 0.0001] due to increase in potential energy (p = 0.001), but no significant change in LV stroke work. Also, phenylephrine tended to decrease SvO2 (p = 0.063) and increased arterial lactate levels (p = 0.002). CONCLUSION: Catecholamines increased end-organ perfusion at the expense of increased cardiac work, most by dopamine. However, phenylephrine increased cardiac work with no increase in end-organ perfusion.

Oral Midodrine Hydrochloride for Prevention of Orthostatic Hypotension during Early Mobilization after Hip Arthroplasty: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Early postoperative mobilization is essential for rapid recovery but may be impaired by orthostatic intolerance (OI) and orthostatic hypotension (OH), which are highly prevalent after major surgery. Pathogenic mechanisms include an insufficient postoperative vasopressor response. The oral α-1 agonist midodrine hydrochloride increases vascular resistance, and the authors hypothesized that midodrine would reduce the prevalence of OH during mobilization 6 h after total hip arthroplasty relative to placebo. METHODS: This double-blind, randomized trial allocated 120 patients 18 yr or older and scheduled for total hip arthroplasty under spinal anesthesia to either 5 mg midodrine hydrochloride or placebo orally 1 h before mobilization at 6 and 24 h postoperatively. The primary outcome was the prevalence of OH (decrease in systolic or diastolic arterial pressures of > 20 or 10 mmHg, respectively) during mobilization 6 h after surgery. Secondary outcomes were OI and hemodynamic responses to mobilization at 6 and 24 h. RESULTS: At 6 h, 14 (25%; 95% CI, 14 to 38%) versus 23 (39.7%; 95% CI, 27 to 53%) patients had OH in the midodrine and placebo group, respectively, relative risk 0.63 (0.36 to 1.10; P = 0.095), whereas OI was present in 15 (25.0%; 15 to 38%) versus 22 (37.3%; 25 to 51%) patients, relative risk 0.68 (0.39 to 1.18; P = 0.165). At 24 h, OI and OH prevalence did not differ between groups. CONCLUSIONS: Preemptive use of oral 5 mg midodrine did not significantly reduce the prevalence of OH during early postoperative mobilization compared with placebo. However, further studies on dose and timing are warranted since midodrine is effective in chronic OH conditions.

DIFFERENCES IN MANAGEMENT AND PROGNOSTICATION OF CARDIOGENIC SHOCK PATIENTS IN THE PRESENCE AND ABSENCE OF OUT-OF-HOSPITAL CARDIAC ARREST.

ABSTRACT: Background: The clinical spectrum of acute myocardial infarction complicated by cardiogenic shock (AMICS) varies. Out-of-hospital cardiac arrest (OHCA) can be the first sign of cardiac failure, whereas others present with various degrees of hemodynamic instability (non-OHCA). The aim of the present study was to explore differences in prehospital management and characteristics of survivors and nonsurvivors in AMICS patients with OHCA or non-OHCA. Methods: Data analysis was based on patient data from the RETROSHOCK cohort comprising consecutive AMICS patients admitted to two tertiary cardiac centers between 2010 and 2017. Results: 1,716 AMICS patients were included and 42% presented with OHCA. Mortality in OHCA patients was 47% versus 57% in the non-OHCA group. Almost all OHCA patients were intubated before admission (96%). In the non-OHCA group, prehospital intubation (25%) was associated with a better survival ( P < 0.001). Lactate level on admission demonstrated a linear relationship with mortality in OHCA patients. In non-OHCA, probability of death was higher for any given lactate level <12 mmol/L compared with OHCA. However, a lactate level >7 mmol/L in non-OHCA did not increase mortality odds any further. Conclusion: Mortality was almost doubled for any admission lactate level up to 7 mmol/L in non-OHCA patients. Above this level, mortality remained unchanged in non-OHCA patients but continued to increase in OHCA patients. Prehospital intubation was performed in almost all OHCA patients but only in one of four patients without OHCA. Early intubation in non-OHCA patients was associated with a better outcome.

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

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

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

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

Impact of blood pressure targets on central hemodynamics during intensive care after out-of-hospital cardiac arrest.

OBJECTIVES: The aim was to investigate the advanced hemodynamic effects of the two MAP-targets during intensive care on systemic hemodynamics in comatose patients after cardiac arrest. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Primary vasopressor used was per protocol norepinephrine. Hemodynamic monitoring was done with pulmonary artery catheters (PAC) and measurements were made on predefined time points. The primary endpoint of this substudy was the difference in cardiac index within 48 h from a repeated measurements-mixed model. Secondary endpoints included systemic vascular resistance index (SVRI), heart rate, and stroke volume index. PATIENTS: Comatose survivors after out-of-hospital cardiac arrest. INTERVENTIONS: The "Blood pressure and oxygenations targets after out-of-hospital cardiac arrest (BOX)"-trial was a randomized, controlled, double-blinded, multicenter-study comparing targeted mean arterial pressure (MAP) of 63 mmHg (MAP63) vs 77 mmHg (MAP77). MEASUREMENTS AND MAIN RESULTS: Among 789 randomized patients, 730 (93%) patients were included in the hemodynamic substudy. From PAC-insertion (median 1 hours after ICU-admission) and the next 48 hours, the MAP77-group received significantly higher doses of norepinephrine (mean difference 0.09 µg/kg/min, 95% confidence interval (CI) 0.07-0.11, pgroup < 0.0001). Cardiac index was significantly increased (0.20 L/min/m2 (CI 0.12-0.28), pgroup < 0.0001) as was SVRI with an overall difference of (43 dynes m2/s/cm5 (CI 7-79); pgroup = 0.02). Heart rate was increased in the MAP77-group (4 beats/minute; CI 2-6, pgroup < 0.003), but stroke volume index was not (pgroup = 0.10). CONCLUSIONS: Targeted MAP at 77 mmHg compared to 63 mmHg resulted in a higher dose of norepinephrine, increased cardiac index and SVRI. Heart rate was also increased, but stroke volume index was not affected by a higher blood pressure target.

Impact of Impella RP Versus Vasoactive Treatment on Right and Left Ventricular Strain in a Porcine Model of Acute Cardiogenic Shock Induced by Right Coronary Artery Embolization.

Background The response of the left ventricle to cardiogenic shock (CS) caused by right ventricular (RV) infarction and the effect of treatment with either vasoactive treatment or Impella RP are not well described. We sought to determine RV and left ventricular longitudinal strain (LS) by echocardiography after initiation of either Impella RP or vasoactive treatment for CS induced by right coronary artery embolization. Methods and Results CS was induced with microsphere embolization in the right coronary artery in 20 pigs. Shock was defined as a reduction in cardiac output of ≥50% and/or an SvO2 <30%. At the time of CS either Impella RP or vasoactive treatment (norepinephrine and milrinone) was initiated. Echocardiography and conductance measures were obtained at baseline, when CS was present, and 30, 90, and 180 minutes after induction of CS. Of 20 animals, 14 completed the protocol and were treated with either vasoactive treatment (n=7) or Impella RP (n=7); 6 animals died (3 in each group). In the RV there was a significantly higher LS with the vasoactive treatment compared with Impella RP (-7.6% [4.5] to -6.0% [5.2] vs -4.5% [6.6] to -14.2% [10.6]; P<0.006). Left ventricular LS improved with both treatments compared with shock, but with a larger effect (-9.4% [3.2] to -17.9% [3.6]) on LS with vasoactive treatment than Impella RP (-9.8% [3.1] to -12.3% [4.6]; P<0.001). We found a significant correlation between stroke work and RV LS (r=-0.60, P<0.001) and left ventricular LS (r=-0.62, P<0.001). Conclusions We found significantly higher hemodynamic effects with vasoactive treatment compared with Impella RP in both the RV and left ventricular but at a cost of increased stroke work.

Inflammatory response by 48 h after admission and mortality in patients with acute myocardial infarction complicated by cardiogenic shock.

AIMS: Cardiogenic shock (CS) is known to induce an inflammatory response. The prognostic utility of this remains unclear. To investigate the association between C-reactive protein (CRP) levels and leucocyte count and mortality in patients with acute myocardial infarction complicated by CS (AMICS). METHODS AND RESULTS: Consecutive patients (N = 1716) admitted between 2010 and 2017 with an individually validated diagnosis of AMICS were included. The analysis was restricted to patients alive at 48 h after first medical contact and a valid CRP and leucocyte measurement at 48 ± 12 h from the first medical contact. A combined inflammatory score for each patient was computed by summing the CRP and leucocyte count z-scores to normalize the response on a standard deviation scale. Associations with mortality were analysed using a multivariable Cox proportional hazards model stratified by inflammatory response quartiles: Of the 1716 patients in the cohort, 1111 (64.7%) fulfilled inclusion criteria. The median CRP level at 48 h was 145 mg/dL [interquartile range (IQR) 96-211]. The median leucocyte count was 12.6 × 10-9/L (IQR 10.1-16.4). Patients with the highest inflammatory response (Q4) had lower median left ventricular ejection fractions and higher lactate levels at the time of diagnosis. The 30-day all-cause mortality rates were 46% in Q4 and 21% in Q1 (P < 0.001). In multivariable models, the inflammatory response remained associated with mortality [hazard ratio (HR)Q4 2.32, 95% confidence interval (CI) 1.59-3.39, P < 0.001]. The finding was also significant in AMICS patients presenting with out-of-hospital cardiac arrest following multivariable adjustment (HRQ4 3.37, 95% CI 2.02-4.64, P < 0.001). CONCLUSION: Cardiogenic shock induces an acute inflammatory response, the severity of which is associated with mortality.

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

AIM: To 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. METHODS: This 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. RESULTS: Responses 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. CONCLUSIONS: Treatment 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.

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

PURPOSE: Patients 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. METHODS: The 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. RESULTS: We 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. CONCLUSION: Prehospital 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.

Outcome in Elderly Patients With Cardiogenic Shock Complicating Acute Myocardial Infarction.

INTRODUCTION: Despite advances in treatment of patients with cardiogenic shock following acute myocardial infarction (AMICS) in-hospital mortality remains around 50%. Outcome varies among patient subsets and the elderly often have a poor a priori prognosis. We sought to investigate outcome among elderly AMICS patients referred to evaluation and treatment at a tertiary university hospital. METHODS: Current analysis was based on the RETROSHOCK registry comprising consecutive AMICS patients admitted to tertiary care. Patients in the registry were individually identified and validated. RESULTS: Of 1,716 admitted patients, 496 (28.9%) patients were ≥75 years old. Older patients were less likely to be admitted directly to a tertiary centre (59.4% vs. 69.9%, P = 0.003), receive mechanical support devices (i.e., Impella® (8.9% vs. 15.0%, P = 0.003), and undergo revascularization attempt (76.8% vs. 90.2%, P < 0.001). Thirty-day survivors ≥75 years were characterized by having higher left ventricular ejection fraction (30.2% ±â€Š12.5% vs. 26.5% ±â€Š11.8%, P = 0.004) and lower arterial lactate (3.2[2.2-5.2] mmol/L vs. 5.5[3.3-8.2] mmol/L, P < 0.001) at admission. In a multivariable analysis of patients ≥75 years, higher age (HR 1.09, 95% CI 1.05-1.14, P < 0.001), higher heart rate (HR 1.01, 95% CI 1.001-1.014, P = 0.03), and higher lactate (HR 1.11, 95% CI 1.07-1.16, P < 0.001) at admission were associated with an increased risk of 30-day mortality. CONCLUSION: Among patients ≥75 years with AMICS referred for tertiary specialized treatment, 30-day mortality was 73.4%. Survivors were characterized by lower arterial lactate and heart rate at admission.

Biventricular Compared to Left Ventricular Impella and Norepinephrine Support in a Porcine Model of Severe Cardiogenic Shock.

Contemporary management of cardiogenic shock (CS) with vasopressors is associated with increased cardiac workload and despite the use of unloading devices such as the Impella pump, concomitant vasopressors are often necessary. Therefore, we compared if cardiac workload could be reduced and end-organ perfusion preserved with biventricular support (Bipella) compared to ImpellaCP and norepinephrine in pigs with left ventricular (LV) CS caused by left main coronary microembolization. Cardiac workload was calculated from heart rate × ventricular pressure-volume area obtained from conductance catheters placed in the LV and right ventricle (RV), whereas organ perfusion was measured from venous oxygen saturation in the pulmonary artery (SvO 2 ) and the kidney- and the cerebral vein. A cross-over design was used to access the difference after 30 minutes of ImpellaCP and norepinephrine 0.1 µg/kg/min versus Bipella for 60 minutes. Bipella treatment reduced LV workload ( p = 0.0078) without significant difference in RV workload from ImpellaCP and norepinephrine, however a decrease in SvO 2 (49[44-58] vs . 66[63-73]%, p = 0.01) and cerebral venous oxygen saturations (62[48-66] vs . 71[63-77]%, p = 0.016) was observed during Bipella compared to ImpellaCP and norepinephrine. We conclude that Bipella reduced LV workload but did not preserve end-organ perfusion compared to ImpellaCP and norepinephrine in short-term LV CS.