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

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

Survival and neurological outcome after bystander versus lay responder defibrillation in out-of-hospital cardiac arrest: A sub-study of the BOX trial.

BACKGROUND AND AIM: Bystander defibrillation is associated with increased survival with good neurological outcome after out-of-hospital cardiac arrest (OHCA). Dispatch of lay responders could increase defibrillation rates, however, survival with good neurological outcome in these remain unknown. The aim was to compare long-term survival with good neurological outcome in bystander versus lay responder defibrillated OHCAs. METHODS: This is a sub-study of the BOX trial, which included OHCA patients from two Danish tertiary cardiac intensive care units from March 2017 to December 2021. The main outcome was defined as 3-month survival with good neurological performance (Cerebral Performance Category of 1or 2, on a scale from 1 (good cerebral performance) to 5 (death or brain death)). For this study EMS witnessed OHCAs were excluded. RESULTS: Of the 715 patients, a lay responder arrived before EMS in 125 cases (16%). In total, 81 patients were defibrillated by a lay responder (11%), 69 patients by a bystander (10%) and 565 patients by the EMS staff (79%). The 3-month survival with good neurological outcome was 65% and 81% in the lay responder and bystander defibrillated groups, respectively (P = 0.03). CONCLUSION: In patients with OHCA, 3-month survival with good neurological outcome was higher in bystander defibrillated patients compared with lay responder defibrillated patients.

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.

Blood Pressure and Oxygen Targets on Kidney Injury After Cardiac Arrest.

BACKGROUND: Acute kidney injury (AKI) represents a common and serious complication to out-of-hospital cardiac arrest. The importance of post-resuscitation care targets for blood pressure and oxygenation for the development of AKI is unknown. METHODS: This is a substudy of a randomized 2-by-2 factorial trial, in which 789 comatose adult patients who had out-of-hospital cardiac arrest with presumed cardiac cause and sustained return of spontaneous circulation were randomly assigned to a target mean arterial blood pressure of either 63 or 77 mm Hg. Patients were simultaneously randomly assigned to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao2) of 9 to 10 kPa or a liberal oxygenation target of a Pao2 of 13 to 14 kPa. The primary outcome for this study was AKI according to KDIGO (Kidney Disease: Improving Global Outcomes) classification in patients surviving at least 48 hours (N=759). Adjusted logistic regression was performed for patients allocated to high blood pressure and liberal oxygen target as reference. RESULTS: The main population characteristics at admission were: age, 64 (54-73) years; 80% male; 90% shockable rhythm; and time to return of spontaneous circulation, 18 (12-26) minutes. Patients allocated to a low blood pressure and liberal oxygen target had an increased risk of developing AKI compared with patients with high blood pressure and liberal oxygen target (84/193 [44%] versus 56/187 [30%]; adjusted odds ratio, 1.87 [95% CI, 1.21-2.89]). Multinomial logistic regression revealed that the increased risk of AKI was only related to mild-stage AKI (KDIGO stage 1). There was no difference in risk of AKI in the other groups. Plasma creatinine remained high during hospitalization in the low blood pressure and liberal oxygen target group but did not differ between groups at 6- and 12-month follow-up. CONCLUSIONS: In comatose patients who had been resuscitated after out-of-hospital cardiac arrest, patients allocated to a combination of a low mean arterial blood pressure and a liberal oxygen target had a significantly increased risk of mild-stage AKI. No difference was found in terms of more severe AKI stages or other kidney-related adverse outcomes, and creatinine had normalized at 1 year after discharge. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03141099.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Patients with ST-Elevation Myocardial Infarction and Its Association with Acute Kidney Injury and Mortality.

Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory biomarker related to acute kidney injury (AKI). Including 1892 consecutive patients with ST-elevation myocardial infarction (STEMI), in which NGAL was measured in 1624 (86%) on admission and in a consecutive subgroup at 6-12 h (n = 163) and 12-24 h (n = 222) after admission, this study aimed to evaluate the prognostic value of NGAL in predicting AKI and mortality. Patients were stratified based on whether their admission NGAL plasma concentration was greater than or equal to/less than the median. The primary endpoint was a composite of the first occurrence of AKI or all-cause death within 30 days. AKI was classified by the maximal plasma creatinine increase from baseline during index admission as KDIGO1 (<200% increase) or KDIGO23 (≥200% increase) according to the Kidney Disease Improving Global Outcomes (KDIGO) system. Admission NGAL > the median was independently associated with a higher risk of severe AKI (KDIGO2-3) and 30-day all-cause mortality when adjusted for age, admission systolic blood pressure and high-sensitivity C-reactive protein, left-ventricular ejection fraction, known kidney dysfunction, and cardiogenic shock with an odds ratio (95% confidence interval) of 2.26 (1.18-4.51), p = 0.014. Finally, we observed increasing predictive values in a subgroup during the first day of hospitalization suggesting that assessment of NGAL should be delayed for optimal prognostic purposes.

Global myocardial oedema in resuscitated out-of-hospital cardiac arrest patients assessed by cardiac magnetic resonance: a pilot study.

AIMS: Myocardial dysfunction is well described after out-of-hospital cardiac arrest (OHCA); however, the underlying mechanisms are not yet understood. We hypothesized that this dysfunction is associated to a global myocardial oedema. Using cardiac magnetic resonance (CMR), we assessed the presence of such oedema early after successful resuscitation from OHCA. METHODS AND RESULTS: Comatose patients resuscitated from OHCA and admitted to the cardiac intensive care unit were consecutively included and underwent CMR in general anaesthesia within 36 h after cardiac arrest with anaesthetic support. To assess global myocardial oedema, T1 and T2 segmented maps were generated from three representative short-axis slices, and values from each segment were then used to determine a mean global T1 and T2 time for each patient. Healthy subjects were used as controls. CMR was obtained in 16 patients and compared with nine controls. The OHCA patients were 60 ± 9 years old, and acute myocardial infarction (MI) was diagnosed in six cases. On admission, left ventricular ejection fraction assessed by transthoracic echocardiography was 35 ± 15%, and this improved significantly to 43 ± 14% during hospitalization (P < 0.05). Mean global T1 and T2 time was significantly higher in OHCA patients compared with the control group (1071 ms vs. 999 ms, P = 0.002, and 52 ms vs. 46 ms, P < 0.001, respectively), and this difference remained significant when segments involved in the MI were excluded. CONCLUSION: Assessed with CMR, we for the first time document an early global myocardial oedema in patients successfully resuscitated from OHCA.

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.

Hypothermic versus Normothermic Temperature Control after Cardiac Arrest.

BACKGROUND: The evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics. METHODS: An individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence). RESULTS: The primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups. CONCLUSIONS: Hypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)

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.

Trauma-induced coagulopathy: standard coagulation tests, biomarkers of coagulopathy, and endothelial damage in patients with traumatic brain injury.

It remains to be debated whether traumatic brain injury (TBI) induces a different coagulopathy than does non-TBI. This study investigated traditional coagulation tests, biomarkers of coagulopathy, and endothelial damage in trauma patients with and without TBI. Blood from 80 adult trauma patients was sampled (median of 68 min [IQR 48-88] post-injury) upon admission to our trauma center. Plasma/serum were retrospectively analyzed for biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), coagulation activation/inhibition and fibrinolysis (protein C, activated protein C, tissue factor pathway inhibitor, antithrombin, prothrombin fragment 1+2, thrombin/antithrombin complex, von Willebrand factor, factor XIII, d-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1), immunology (interleukin [IL]6), endothelial cell/glycocalyx damage (soluble thrombomodulin, syndecan-1), and vasculogenesis (angiopoietin-1, -2). Patients were stratified according to: (1) isolated severe head/neck injuries (Abbreviated injury score [AIS]-head/neck ≥ 3, AIS-other<3) (isoTBI); (2) severe head/neck and extracranial injuries (AIS-head/neck ≥ 3, AIS-other>3) (sTBI+other); and (3) injuries without significant head/neck injuries (AIS-head/neck<3, including all AIS-other scores) (non-TBI). Twenty-three patients presented with isoTBI, 15 with sTBI+other and 42 with non-TBI. Acute coagulopathy of trauma shock, defined as activated partial thromboplastin time (APTT) and/or international normalized ratio (INR)>35 sec and>1.2, was found in 13%, 47%, and 5%, respectively (p=0.000). sTBI+other had significantly higher plasma levels of adrenaline, noradrenaline, annexin V, d-dimer, IL-6, syndecan-1, soluble thrombomodulin, and reduced protein C and factor XIII levels (all p<0.05). No significant biomarker differences were found between isoTBI and non-TBI patients. Injury severity scale (ISS) rather than the presence or absence of head/neck injuries determined the hemostatic and biomarker response to the injury. The coagulopathy identified thus reflected the severity of injury rather than its localization.