Improving Outcomes After Post-Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation.

This scientific statement presents a conceptual framework for the pathophysiology of post-cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post-cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post-cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post-cardiac arrest brain injury.

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.

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

BACKGROUND: Following 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. METHODS: The 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. RESULTS: A 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. CONCLUSIONS: Prehospital 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.

Prediction of the neurological outcomes post-cardiac arrest: A prospective validation of the CAST and rCAST.

INTRODUCTION: The neurologic prognosis of out-of-hospital cardiac arrest (OHCA) patients in whom return of spontaneous circulation (ROSC) is achieved remains poor. The aim of this study was to externally and prospectively validate two scoring systems developed by us: the CAST score, a scoring system to predict the neurological prognosis of OHCA patients undergoing targeted temperature management (TTM), and a simplified version of the same score developed for improved ease of use in clinical settings, the revised CAST (rCAST) score. METHODS: This study was a prospective, multicenter, observational study conducted using the SOS KANTO 2017 registry, an OHCA registry involving hospitals in the Kanto region (including Tokyo) of Japan. The primary outcome was favorable neurological outcome (defined as Cerebral Performance Category score of 1 or 2) at 30 days and the secondary outcomes were favorable neurological outcome at 90 days and survival at 30 and 90 days. The predictive accuracies of the original CAST (oCAST) and rCAST scores were evaluated by using area under the receiver operating characteristic curve (AUC). RESULTS: Of 9909 OHCA patients, 565 showed ROSC and received TTM. Of these, we analyzed the data of 259 patients in this study. The areas under the receiver operating characteristic curve (AUCs) of the oCAST and rCAST scores for predicting a favorable neurological outcome at 30 days were 0.86 and 0.87, respectively, and those for predicting a favorable neurological outcome at 90 days were 0.87 and 0.88, respectively. The rCAST showed a higher predictive accuracy for the neurological outcome as compared with the NULL-PLEASE score. The patients with a favorable neurological outcome who had been classified into the high severity group based on the rCAST tended to have hypothermia at hospital arrival and to not show any signs of loss of gray-white matter differentiation on brain CT. Neurological function at 90 days was correlated with the rCAST (r = 0.63, p < 0.001). CONCLUSIONS: rCAST showed high predictive accuracy for the neurological prognosis of OHCA patients managed by TTM, comparable to that of the oCAST score. The scores on the rCAST were strongly correlated with the neurological functions at 90 days, implying that the rCAST is a useful scale for assessing the severity of brain injury after cardiac arrest.

Cytokine hemoadsorption with CytoSorb® in post-cardiac arrest syndrome, a pilot randomized controlled trial.

BACKGROUND: Hemoadsorption (HA) might mitigate the systemic inflammatory response associated with post-cardiac arrest syndrome (PCAS) and improve outcomes. Here, we investigated the feasibility, safety and efficacy of HA with CytoSorb® in cardiac arrest (CA) survivors at risk of PCAS. METHODS: In this pilot randomized controlled trial, we included patients admitted to our intensive care unit following CA and likely to develop PCAS: required norepinephrine (> 0.2 µg/kg/min), and/or had serum lactate > 6 mmol/l and/or a time-to-return of spontaneous circulation (ROSC) > 25 min. Those requiring ECMO or renal replacement therapy were excluded. Eligible patients were randomly allocated to either receive standard of care (SOC) or SOC plus HA. Hemoadsorption was performed as stand-alone therapy for 24 h, using CytoSorb® and regional heparin-protamine anticoagulation. We collected feasibility, safety and clinical data as well as serial plasma cytokines levels within 72 h of randomization. RESULTS: We enrolled 21 patients, of whom 16 (76%) had out-of-hospital CA. Median (IQR) time-to-ROSC was 30 (20, 45) minutes. Ten were assigned to the HA group and 11 to the SOC group. Hemoadsorption was initiated in all patients allocated to the HA group within 18 (11, 23) h of ICU admission and conducted for a median duration of 21 (14, 24) h. The intervention was well tolerated except for a trend for a higher rate of aPTT elevation (5 (50%) vs 2 (18%) p = 0.18) and mild (100-150 G/L) thrombocytopenia at day 1 (5 (50%) vs 2 (18%) p = 0.18). Interleukin (IL)-6 plasma levels at randomization were low (< 100 pg/mL) in 10 (48%) patients and elevated (> 1000 pg/mL) in 6 (29%). The median relative reduction in IL-6 at 48 h was 75% (60, 94) in the HA group versus 5% (- 47, 70) in the SOC group (p = 0.06). CONCLUSIONS: In CA survivors at risk of PCAS, HA was feasible, safe and was associated with a nonsignificant reduction in cytokine plasma levels. Future trials are needed to further define the role of HA after CA. Those studies should include cytokine assessment to enrich the study population. TRIAL REGISTRATION: NCT03523039, registered 14 May 2018.

Prevalence, reasons, and timing of decisions to withhold/withdraw life-sustaining therapy for out-of-hospital cardiac arrest patients with extracorporeal cardiopulmonary resuscitation.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is rapidly becoming a common treatment strategy for patients with refractory cardiac arrest. Despite its benefits, ECPR raises a variety of ethical concerns when the treatment is discontinued. There is little information about the decision to withhold/withdraw life-sustaining therapy (WLST) for out-of-hospital cardiac arrest (OHCA) patients after ECPR. METHODS: We conducted a secondary analysis of data from the SAVE-J II study, a retrospective, multicenter study of ECPR in Japan. Adult patients who underwent ECPR for OHCA with medical causes were included. The prevalence, reasons, and timing of WLST decisions were recorded. Outcomes of patients with or without WLST decisions were compared. Further, factors associated with WLST decisions were examined. RESULTS: We included 1660 patients in the analysis; 510 (30.7%) had WLST decisions. The number of WLST decisions was the highest on the first day and WSLT decisions were made a median of two days after ICU admission. Reasons for WLST were perceived unfavorable neurological prognosis (300/510 [58.8%]), perceived unfavorable cardiac/pulmonary prognosis (105/510 [20.5%]), inability to maintain extracorporeal cardiopulmonary support (71/510 [13.9%]), complications (10/510 [1.9%]), exacerbation of comorbidity before cardiac arrest (7/510 [1.3%]), and others. Patients with WLST had lower 30-day survival (WLST vs. no-WLST: 36/506 [7.1%] vs. 386/1140 [33.8%], p < 0.001). Primary cerebral disorders as cause of cardiac arrest and higher severity of illness at intensive care unit admission were associated with WLST decisions. CONCLUSION: For approximately one-third of ECPR/OHCA patients, WLST was decided during admission, mainly because of perceived unfavorable neurological prognoses. Decisions and neurological assessments for ECPR/OHCA patients need further analysis.

Serial assessments of cardiac output and mixed venous oxygen saturation in comatose patients after out-of-hospital cardiac arrest.

AIM: To assess the association with outcomes of cardiac index (CI) and mixed venous oxygen saturation (SvO2) in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: In the cohort study of 789 patients included in the "BOX"-trial, 565 (77%) patients were included in this hemodynamic substudy (age 62 ± 13 years, male sex 81%). Pulmonary artery catheters were inserted shortly after ICU admission. CI and SvO2 were measured as soon as possible in the ICU and until awakening or death. The endpoints were all-cause mortality at 1 year and renal failure defined as need for renal replacement therapy. RESULTS: First measured CI was median 1.7 (1.4-2.1) l/min/m2, and first measured SvO2 was median 67 (61-73) %. CI < median with SvO2 > median was present in 222 (39%), and low SvO2 with CI < median was present in 59 (11%). Spline analysis indicated that SvO2 value < 55% was associated with poor outcome. Low CI at admission was not significantly associated with mortality in multivariable analysis (p = 0.14). SvO2 was significantly inversely associated with mortality (hazard ratioadjusted: 0.91 (0.84-0.98) per 5% increase in SvO2, p = 0.01). SvO2 was significantly inversely associated with renal failure after adjusting for confounders (ORadjusted: 0.73 [0.62-0.86] per 5% increase in SvO2, p = 0.001). The combination of lower CI and lower SvO2 was associated with higher risk of mortality (hazard ratioadjusted: 1.54 (1.06-2.23) and renal failure (ORadjusted: 5.87 [2.34-14.73]. CONCLUSION: First measured SvO2 after resuscitation from OHCA was inversely associated with mortality and renal failure. If SvO2 and CI were below median, the risk of poor outcomes increased significantly. REGISTRATION: The BOX-trial is registered at clinicaltrials.gov (NCT03141099, date 2017-30-04, retrospectively registered).

Inflammatory response after out-of-hospital cardiac arrest-Impact on outcome and organ failure development.

BACKGROUND: Post-cardiac arrest syndrome that occurs in out-of-hospital cardiac arrest (OHCA) patients is characterized by inflammatory response. We conducted a scoping review of current evidence regarding several inflammatory markers' usefulness for assessment of patient outcome and illness severity. We also discuss the proposed underlying mechanisms leading to inflammatory response after OHCA. METHODS: We searched the MEDLINE, PubMed Central, Cochrane CENTRAL and Web of Science Core Collection databases with the following search terms: ("inflammation" OR "cytokines") AND "out-of-hospital cardiac arrest." Each inflammatory marker found was combined with "out-of-hospital cardiac arrest" using "AND" to find further relevant studies. We included original studies measuring inflammatory markers in adult OHCA patients that assessed their prognostic capabilities for mortality, neurological outcome, or organ failure severity. RESULTS: Fifty-nine studies met the inclusion criteria, covering in total 65 different markers. Interleukin-6 (IL-6), procalcitonin (PCT) and C-reactive protein (CRP) were the most studied markers, and they were associated with poor outcomes in 13/15, 13/14 and 11/17 studies, respectively. Based on area under the receiver operating characteristic curve (AUC) value, the time point of best discriminatory capacity for poor outcome was ICU admission for IL-6 (median AUC 0.78, range 0.71-0.98) and day one after OHCA for PCT (median AUC 0.84, range 0.61-0.98). Seven studies reported AUCs for CRP (range 0.52-0.76) with no measurement time point being superior to others. The association of IL-6 and PCT with outcome appeared stronger in studies with more severely ill patients. Studies reported conflicting results regarding each marker's association with organ failure severity. CONCLUSION: Inflammatory markers are potentially useful for early risk stratification after OHCA. PCT and IL-6 have moderate prognostic value during the first 24 h of the ICU stay. Predictive accuracy appears to be associated with the study overall event rate.

Post-Cardiac Arrest Syndrome Is Not Associated With an Early Bacterial Translocation.

BACKGROUND: The aim of this study was to investigate bacterial translocation and its possible role in the development of post-resuscitation inflammatory response following Cardio-Pulmonary Resuscitation (CPR) after cardiac arrest. METHODS: Munich female swine were employed for a model of cardiac arrest via application of electrical current. After 7 min, CPR was initiated, and animals were either successfully return to spontaneous circulation (ROSC) within 40 min or not (no-ROSC). At the end of experimental period and prior to sacrifice, samples from the intestine, mesenteric lymph nodes (MLN), liver and portal vein blood were obtained. Evaluation of inflammation and gut permeability was performed; MLN, liver and portal vein samples were analyzed for 16 s rRNA detection and cytokine mRNA expression. RESULTS: A decreased expression of the tight junction protein Occludin, with higher levels of inflammation, greater epithelial disintegration, ulceration, loss of crypts and villi height were found in the intestines of the ROSC swine in comparison to no-ROSC. The macrophage surface antigen CD-14 staining was relatively more intense in the ROSC than in no-ROSC. Higher levels of TNF-α mRNA expression were present in the liver of the ROSC group. Finally, despite the inflammatory response and the gut mucosal alterations in ROSC group, no bacterial translocation was detected in liver, MLN and portal vein. CONCLUSIONS: We show that resuscitation from cardiac arrest induces inflammatory response and intestinal permeability in swine 4h after resuscitation, but not a bacterial translocation. Bacterial translocation is not an early phase phenomenon but probably part of the pathophysiologic sequelae.

Association between short-term neurological outcomes and extreme hyperoxia in patients with out-of-hospital cardiac arrest who underwent extracorporeal cardiopulmonary resuscitation: a retrospective observational study from a multicenter registry.

BACKGROUND: To investigate the impact of hyperoxia that developed immediately after extracorporeal membrane oxygenation (ECMO)-assisted cardiopulmonary resuscitation (ECPR) on patients' short-term neurological outcomes after out-of-hospital cardiac arrest (OHCA). METHODS: This study retrospectively analyzed data from the Japanese OHCA registry from June 2014 to December 2017. We analyzed adult patients (≥ 18 years) who had undergone ECPR. Eligible patients were divided into the following three groups based on their initial partial pressure of oxygen in arterial blood (PaO2) levels after ECMO pump-on: normoxia group, PaO2 ≤ 200 mm Hg; moderate hyperoxia group, 200 mm Hg < PaO2 ≤ 400 mm Hg; and extreme hyperoxia group, PaO2 > 400 mm Hg. The primary and secondary outcomes were 30-day favorable neurological outcomes. Logistic regression statistical analysis model of 30-day favorable neurological outcomes was performed after adjusting for multiple propensity scores calculated using pre-ECPR covariates and for confounding factors post-ECPR. RESULTS: Of the 34,754 patients with OHCA enrolled in the registry, 847 were included. The median PaO2 level was 300 mm Hg (interquartile range: 148-427 mm Hg). Among the eligible patients, 277, 313, and 257 were categorized as normoxic, moderately hyperoxic, and extremely hyperoxic, respectively. Moderate hyperoxia was not significantly associated with 30-day neurologically favorable outcomes compared with normoxia as a reference (adjusted odds ratio, 0.86; 95% confidence interval: 0.55-1.35; p = 0.51). However, extreme hyperoxia was associated with less 30-day neurologically favorable outcomes when compared with normoxia (adjusted odds ratio, 0.48; 95% confidence interval: 0.29-0.82; p = 0.007). CONCLUSIONS: For patients with OHCA who received ECPR, extreme hyperoxia (PaO2 > 400 mm Hg) was associated with 30-day poor neurological outcomes. Avoidance of extreme hyperoxia may improve neurological outcomes in patients with OHCA treated with ECPR.

Hypernatremia is associated with poor long-term neurological outcomes in out-of-hospital cardiac arrest survivors.

BACKGROUND: Brain oedema after cardiac arrest is strongly associated with poor neurological outcomes. Excessive sodium supplementation may increase serum osmolarity and facilitate brain oedema development in cardiac arrest survivors. We aimed to investigate the association of serum sodium levels with long-term neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors. METHODS: This retrospective observational study used a multicentre prospective cohort registry of OHCA survivors collected between December 2013 and February 2018. We analyzed the association of serum sodium levels at the return of spontaneous circulation (ROSC) (Sodium 0H) and at 24 h after ROSC (Sodium 24H) with 1-year neurological outcomes in OHCA survivors. Patients with 1-year cerebral performance categories (CPC) 1 and 2 were included in the good outcome group while those with CPC 3, 4, and 5 were included in the poor outcome group. RESULTS: Among 277 patients, 84 (30.3%) and 193 (69.7%) were in the good and poor outcome groups, respectively. Compared with the good outcome group, the poor outcome group showed significantly higher Sodium 24H levels (140 mEq/L vs. 137.4 mEq/L, p < 0.001). Increased serum sodium levels per 1 mEq/L increased the risk of poor 1-year CPC by 13% (adjusted odds ratio = 1.13; 95% CI, 1.04⎼1.23; p = 0.004). CONCLUSIONS: Relatively high Sodium 24H levels showed a strong and independent association with poor long-term neurological outcomes in OHCA survivors. These findings may be applied in therapeutic strategies for improving neurological outcomes in OHCA survivors.

Mid-term (30- to 90-day) neurological changes in out-of-hospital cardiac arrest patients: A nationwide retrospective study (the JAAM-OHCA registry).

OBJECTIVE: Few studies have focused on mid/long-term neurological changes in out-of- hospital cardiac arrest (OHCA) survivors. Some studies suggest that there is still a slow, small, progressive improvement in cognitive function and quality of life for this population, even in the mid/long term. However, clinical data focused on mid/long-term outcomes for OHCA patients are still lacking. This study aimed to assess mid-term neurological changes in OHCA patients. We summarized patients' improved or worsened neurological changes between 30 and 90 days. Then we identified the relationship between clinical variables and 30- to 90-day neurological improvement. METHODS: A retrospective review of data (Jun 2014 - Dec 2017) from a Japanese nationwide OHCA registry was conducted. Inclusion criteria were OHCA patients ≥18 years old. Exclusion criteria were death within 30 days and missing Cerebral Performance Category (CPC) score at 30 and 90 days. We described the distributions of 30-day and 90-day CPC scores as well as the number and portion of patients whose CPC scores improved and worsened between 30 and 90 days. Additionally, factors affecting improved neurological changes over the time period were examined using multivariable logistic regression. RESULTS: Of the registry's 34,745 patients, 1868 were analyzed. Favorable neurological outcomes (CPC scores of 1 and 2) were seen in 1020/1868 patients at 90 days. CPC scores at 90 days were: CPC 1: 866 (46%), CPC 2: 154 (8.2%), CPC 3: 224 (12%), and CPC 4: 392 (20%), respectively. A total of 232 patients (CPC 5: 12%) died between 30 and 90 days. In 133 patients (7%), 90-day CPC scores improved compared to their 30-day scores. In 260 patients (14%), 90-day CPC scores worsened compared with their 30-day scores. Application of target temperature management was an independent factor for 30- to 90-day neurological improvement (adjusted odds ratio: 1.69, 95% confidence interval: 1.07-2.68). CONCLUSIONS: In our nationwide registry, 7% of resuscitated patients had improved neurological changes in the 30- to 90-day period; most of the improvements were CPC scores improving from 2 to 1. Target temperature management was an independent factor associated with CPC improvement over the 30- to 90-day period.

Status Myoclonus with Post-cardiac-arrest Syndrome: Implications for Prognostication.

BACKGROUND: Status myoclonus (SM) after cardiac arrest (CA) may signify devastating brain injury. We hypothesized that SM correlates with severe neurologic and systemic post-cardiac-arrest syndrome (PCAS). METHODS: Charts of patients admitted with CA to Mayo Clinic Saint Marys Hospital between 2005 and 2019 were retrospectively reviewed. Data included the neurologic examination, ancillary neurologic tests, and systemic markers of PCAS. Nonsustained myoclonus was clinically differentiated from SM. The cerebral performance category score at discharge was assessed; poor outcome was a cerebral performance category score > 2 prior to withdrawal of life-sustaining therapies or death. RESULTS: Of 296 patients included, 276 (93.2%) had out-of-hospital arrest and 202 (68.5%) had a shockable rhythm; the mean time to return of spontaneous circulation was 32 ± 19 min. One hundred seventy-six (59.5%) patients had a poor outcome. One hundred one (34.1%) patients had myoclonus, and 74 (73.2%) had SM. Neurologic predictors of poor outcome were extensor or absent motor response to noxious stimulus (p = 0.02, odds ratio [OR] 3.8, confidence interval [CI] 1.2-12.4), SM (p = 0.01, OR 10.3, CI 1.5-205.4), and burst suppression on EEG (p = 0.01, OR 4.6, CI 1.4-17.4). Of 74 patients with SM, 73 (98.6%) had a poor outcome. A nonshockable rhythm (p < 0.001, OR 4.5, CI 2.6-7.9), respiratory arrest (p < 0.001, OR 3.5, CI 1.7-7.2), chronic kidney disease (p < 0.001, OR 3.1, CI 1.6-6.0), and a pressor requirement (p < 0.001, OR 4.4, CI 1.8-10.6) were associated with SM. No patients with SM, anoxic-ischemic magnetic resonance imaging findings, and absent electroencephalographic reactivity had a good outcome. CONCLUSIONS: Sustained status myoclonus after CPR is observed in patients with other reliable indicators of severe acute brain injury and systemic PCAS. These clinical determinants should be incorporated as part of a comprehensive approach to prognostication after CA.

Pre Versus Post Implementation of a Pharmacologic Antishivering Protocol During Targeted Temperature Management Following Cardiac Arrest.

BACKGROUND: Targeted temperature management (TTM) is endorsed by various guidelines to improve neurologic outcomes following cardiac arrest. Shivering, a consequence of hypothermia, can counteract the benefits of TTM. Despite its frequent occurrence, consensus guidelines provide minimal guidance on the management of shivering. The purpose of this study was to evaluate the impact of a pharmacologic antishivering protocol in patients undergoing TTM following cardiac arrest on the incidence of shivering. METHODS: A retrospective observational cohort study at a large academic medical center of adult patients who underwent TTM targeting 33 °C following out-of-hospital (OHCA) or in-hospital cardiac arrest (IHCA) was conducted between January 2013 and January 2019. Patients were included in the preprotocol group if they received TTM prior to the initiation of a pharmacologic antishivering protocol in 2015. The primary outcome was incidence of shivering between pre- and postprotocol patients. Secondary outcomes included time from arrest (IHCA) or admission to the hospital (OHCA) to goal body temperature, total time spent at goal body temperature, and percentage of patients alive at discharge. All pharmacologic agents listed as part of the antishivering protocol were recorded. RESULTS: Fifty-one patients were included in the preprotocol group, and 80 patients were included in the postprotocol group. There were no significant differences in baseline characteristics between the groups, including percentage of patients experiencing OHCA (75% vs. 63%, p = 0.15) and time from arrest to return of spontaneous circulation (17.5 vs. 17.9 min, p = 0.96). Incidence of patients with shivering was significantly reduced in the postprotocol group (57% vs. 39%, p = 0.03). Time from arrest (IHCA) or admission to the hospital (OHCA) to goal body temperature was similar in both groups (5.1 vs. 5.3 h, p = 0.57), in addition to total time spent at goal body temperature (17.7 vs. 18 h, p = 0.93). The percentage of patients alive at discharge was significantly improved in the postprotocol group (35% vs. 55%, p = 0.02). Patients in the postprotocol group received significantly more buspirone (4% vs. 73%, p < 0.01), meperidine (8% vs. 34%, p < 0.01), and acetaminophen (12% vs. 65%, p < 0.01) as part of the pharmacologic antishivering protocol. Use of neuromuscular blockade significantly decreased post protocol (19% vs. 6%, p = 0.02). CONCLUSIONS: In patients undergoing TTM following cardiac arrest, the implementation of a pharmacologic antishivering protocol reduced the incidence of shivering and the use neuromuscular blocking agents. Prospective data are needed to validate the results and further evaluate the safety and efficacy of an antishivering protocol on clinical outcomes.

Cytokine Storm-Definition, Causes, and Implications.

The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators). Usually, a fragile equilibrium of pro- and anti-inflammation effects is maintained by complex regulatory mechanisms. Disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines. This may result in a drastic self-reinforcement of various feedback mechanisms, which can ultimately lead to systemic damage, multi-organ failure, or death. Not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies. Due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce.

Protocolized Post-Cardiac Arrest Care with Targeted Temperature Management.

Improvements in teamwork and resuscitation science have considerably increased the success rate of cardiopulmonary resuscitation. Cerebral injury, myocardial dysfunction, systemic ischemia and reperfusion response, and precipitating pathology after the return of spontaneous circulation (ROSC) constitute post-cardiac arrest syndrome. Because the entire body is involved in cardiac arrest and the early post-arrest period, protocolized post-arrest care consisting of cardiovascular optimization, ventilation and oxygenation adjustment, coronary revascularization, targeted temperature management (TTM), and control of seizures and blood sugar would benefit survival and neurological outcomes. Emergent coronary angiography is suggested for cardiac arrest survivors suspected of having ST-elevation myocardial infarction, however the superiority of culprit or complete revascularization in patients with multivessel coronary lesions remains undetermined. High-quality TTM should be considered for comatose patients who are successfully resuscitated from cardiac arrest, however the optimal target temperature may depend on the severity of their condition. The optimal timing for making prognostication should be no earlier than 72 h after rewarming in TTM patients, and 72 h following ROSC in non-TTM patients. To predict neurological recovery correctly may need the use of several prognostic tools together, including clinical neurological examinations, brain images, neurological studies and biomarkers.

Fast hypothermia induced by extracorporeal circuit cooling alleviates renal and intestinal injury after cardiac arrest in swine.

BACKGROUND: Continuous renal replacement therapy (CRRT) was currently demonstrated to be an effective way to induce fast hypothermia and had proective effects on cardiac dysfunction and brain damage after cardiac pulmonary resuscitation (CPR). In the present study, we aimed to investigate the influence of extracorporeal circuit cooling using CRRT on renal and intestinal damage after CPR based on a porcine model. METHODS: 32 pigs were subjected to ventricular fibrillation for 8 min, followed by CPR for 5 min before defibrillation. All were randomized to receive extracorporeal circuit cooling using CRRT (CRRT, n = 9), surface cooling (SC, n = 9), normothermia (NT, n = 9) or sham control (n = 5) at 5 min post resuscitation. Pigs in the CRRT group were cooled by 8-h CRRT cooling with the infusion line initially submerged in 4 °C of ice water and 16-h SC, while in the SC group by a 24-h SC. Temperatures were maintained at a normal range in the other two groups. Biomarkers in serum were measured at baseline and 1, 3, 6, 12, 24 and 30 h post resuscitation to assess organ functions. Additionally, tissues of kidney and intestine were harvested, from which the degree of tissue inflammation, oxidative stress, and apoptosis levels were analyzed. RESULTS: The blood temperature decreased faster by extracorporeal circuit cooling using CRRT than SC (9.8 ± 1.6 vs. 1.5 ± 0.4 °C/h, P < 0.01). Post-resuscitation renal and intestinal injury were significantly improved in the 2 hypothermic groups compared to the NT group. And the improvement was significantly greater in animals received extracorporeal circuit cooling than those received surface cooling, from both the results of biomarkers in serum and pathological evidence. CONCLUSION: Fast hypothermia induced by extracorporeal circuit cooling was superior to. surface cooling in mitigating renal and intestinal injury post resuscitation.

Circulatory trajectories after out-of-hospital cardiac arrest: a prospective cohort study.

BACKGROUND: Circulatory failure frequently occurs after out-of-hospital cardiac arrest (OHCA) and is part of post-cardiac arrest syndrome (PCAS). The aim of this study was to investigate circulatory disturbances in PCAS by assessing the circulatory trajectory during treatment in the intensive care unit (ICU). METHODS: This was a prospective single-center observational cohort study of patients after OHCA. Circulation was continuously and invasively monitored from the time of admission through the following five days. Every hour, patients were classified into one of three predefined circulatory states, yielding a longitudinal sequence of states for each patient. We used sequence analysis to describe the overall circulatory development and to identify clusters of patients with similar circulatory trajectories. We used ordered logistic regression to identify predictors for cluster membership. RESULTS: Among 71 patients admitted to the ICU after OHCA during the study period, 50 were included in the study. The overall circulatory development after OHCA was two-phased. Low cardiac output (CO) and high systemic vascular resistance (SVR) characterized the initial phase, whereas high CO and low SVR characterized the later phase. Most patients were stabilized with respect to circulatory state within 72 h after cardiac arrest. We identified four clusters of circulatory trajectories. Initial shockable cardiac rhythm was associated with a favorable circulatory trajectory, whereas low base excess at admission was associated with an unfavorable circulatory trajectory. CONCLUSION: Circulatory failure after OHCA exhibits time-dependent characteristics. We identified four distinct circulatory trajectories and their characteristics. These findings may guide clinical support for circulatory failure after OHCA. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02648061.

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience.

BACKGROUND: Systemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines (interleukin-17 [IL-8], IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post-cardiac arrest period. METHODS: This was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated "survivors". The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays. RESULTS: Plasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC. CONCLUSION: These results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients. TRIAL REGISTRATION: Clinicaltrial.govNCT02297776, 2014-11-21.

The Role of Inflammatory Cytokines in Cardiac Arrest.

INTRODUCTION: Post-cardiac arrest syndrome (PCAS) is characterized by systemic ischemia/reperfusion injury, anoxic brain injury, and post-arrest myocardial dysfunction superimposed on a precipitating pathology. The role of inflammatory cytokines in cardiac arrest remains unclear. AIMS: We aimed to describe, with an emphasis on clinical applications, what is known about the role of inflammatory cytokines in cardiac arrest. DATA SOURCES: A PubMed literature review was performed for relevant articles. Only articles in English that studied cytokines in patients with cardiac arrest were included. RESULTS: Cytokines play a crucial role in the pathogenesis of PCAS. Following cardiac arrest, the large release of circulating cytokines mediates the ischemia/reperfusion injury, brain dysfunction, and myocardial dysfunction seen. Interleukins, tumor necrosis factor, and matrix metalloproteinases all play a unique prognostic role in PCAS. High levels of inflammatory cytokines have been associated with mortality and/or poor neurologic outcomes. Interventions to modify the systemic inflammation seen in PCAS continue to be heavily studied. Currently, the only approved medical intervention for comatose patients following cardiac arrest is targeted temperature management. Medical agents, including minocycline and sodium sulfide, have demonstrated promise in animal models. CONCLUSIONS: The role of inflammatory cytokines for both short- and long-term outcomes is an important area for future investigation.