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Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

Systemic inflammation is a major feature of the post-cardiac arrest syndrome. The three monocyte subpopulations are thought to play an important role in this inflammatory state because they are endowed with numerous pattern recognition receptors, such as CD14, that have been associated with ischemia-reperfusion injury. By contrast, an exaggerated antiinflammatory response has also been described following cardiac arrest, which may be mediated by downregulation of antigen presentation receptor HLA-DR. We report the composition of monocyte subpopulations and the expression of CD14 and HLA-DR following cardiac arrest. Blood specimens were collected from 32 patients at three timepoints in the first 48 h after cardiac arrest. Monocyte subset composition was determined by flow cytometry based on the expression of CD14, CD16, and HLA-DR. Monocyte subset composition and the expression of CD14 and HLA-DR were correlated with patient outcomes. The results were compared to 19 patients with coronary artery disease. Cardiac arrest patients showed a significant decline in the percentage of nonclassical monocytes. Monocyte CD14 expression was upregulated after 24 h and correlated with the time to return of spontaneous circulation. Downregulation of HLA-DR expression was observed mainly among classical monocytes and significantly correlated with the dose of norepinephrine used to treat shock. Downregulation of HLA-DR among nonclassical and intermediate monocytes was significantly associated with disease severity. Our data demonstrate the disturbance of monocyte subset composition with a significant decline in nonclassical monocytes at an early stage following cardiac arrest. Our findings suggest the simultaneous presence of hyperinflammation, as evidenced by upregulation of CD14, and monocyte deactivation, characterized by downregulation of HLA-DR. The extent of monocyte deactivation was significantly correlated with disease severity.

Background Animal disease models represent the cornerstone in basic cardiac arrest (CA) research. However, current experimental models of CA and resuscitation in mice are limited. In this study, we aimed to develop a mouse model of asphyxial CA followed by cardiopulmonary resuscitation (CPR), and to characterize the immune response after asphyxial CA/CPR. Methods and Results CA was induced in mice by switching from an O 2 /N 2 mixture to 100% N 2 gas for mechanical ventilation under anesthesia. Real-time measurements of blood pressure, brain tissue oxygen, cerebral blood flow, and ECG confirmed asphyxia and ensuing CA. After a defined CA period, mice were resuscitated with intravenous epinephrine administration and chest compression. We subjected young adult and aged mice to this model, and found that after CA/CPR, mice from both groups exhibited significant neurologic deficits compared with sham mice. Analysis of post-CA brain confirmed neuroinflammation. Detailed characterization of the post-CA immune response in the peripheral organs of both young adult and aged mice revealed that at the subacute phase following asphyxial CA/CPR, the immune system was markedly suppressed as manifested by drastic atrophy of the spleen and thymus, and profound lymphopenia. Finally, our data showed that post-CA systemic lymphopenia was accompanied with impaired T and B lymphopoiesis in the thymus and bone marrow, respectively. Conclusions In this study, we established a novel validated asphyxial CA model in mice. Using this new model, we further demonstrated that asphyxial CA/CPR markedly affects both the nervous and immune systems, and notably impairs lymphopoiesis of T and B cells.

Biomarkers that reflect hemodynamic stress, inflammation, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction may improve risk stratification and add valuable pathobiological insight in patients with out-of-hospital cardiac arrest (OHCA). In total, 120 patients with OHCA who survived at least 48 h after return of spontaneous circulation were consecutively included in the present analysis. Concentrations of 30 biomarkers were measured simultaneously using a multi-panel biomarker assay. Cox regression models were adjusted for age, sex, estimated glomerular filtration rate, lactate concentration, bystander resuscitation, initial cardiac rhythm, and type of targeted temperature management. Overall, 57 patients (47.5%) had a favorable neurological outcome (Cerebral Performance Category ≤ 2) at 30 days, while palliative care was initiated in 49 patients (40.8%), and 52 patients (43.3%) died. After correction for multiple testing with Bonferroni-Holm, 8 biomarkers (including Angiopoietin-2, Procalcitonin, Resistin, IL-4Rα, MMP-8, TNFα, Renin, and IL-1α) were significantly associated with all-cause death. After multivariable adjustment, only angiopoietin-2 (Adjusted (Adj) hazard ratio (HR) per 1-unit increase in standardized biomarker concentrations 1.52 (95% CI 1.16-1.99)) and renin (Adj HR 1.32 (95% CI 1.06-1.65) remained independently associated with an increased risk of death. The discriminatory performance indicated good performance for angiopoietin-2 (area under the curve (AUC): 0.75 (95% CI 0.66-0.75) and was significantly higher (P = 0.011) as compared with renin (AUC: 0.60, 95% CI 0.50-0.60). In conclusion, angiopoietin-2 was significantly associated with all-cause mortality in patients with OHCA who survived the first 48 h and may prove to be useful for risk stratification of these patients.

Background: Cerebral ischemia-reperfusion injury (CIRI) is the leading cause of poor neurological prognosis after cardiopulmonary resuscitation (CPR). We previously reported that the extracellular signal-regulated kinase (ERK) activation mediates CIRI. Here, we explored the potential ERK/calpain-2 pathway role in CIRI using a rat model of cardiac arrest (CA)., Methods: Adult male Sprague-Dawley rats suffered from CA/CPR-induced CIRI, received saline, DMSO, PD98059 (ERK1/2 inhibitor, 0.3 mg/kg), or MDL28170 (calpain inhibitor, 3.0 mg/kg) after spontaneous circulation recovery. The survival rate and the neurological deficit score (NDS) were utilized to assess the brain function. Hematoxylin stain, Nissl staining, and transmission electron microscopy were used to evaluate the neuron injury. The expression levels of p-ERK, ERK, calpain-2, neuroinflammation-related markers (GFAP, Iba1, IL-1β, TNF-α), and necroptosis proteins (TNFR1, RIPK1, RIPK3, p-MLKL, and MLKL) in the brain tissues were determined by western blotting and immunohistochemistry. Fluorescent multiplex immunohistochemistry was used to analyze the p-ERK, calpain-2, and RIPK3 co-expression in neurons, and RIPK3 expression levels in microglia or astrocytes., Results: At 24 h after CA/CPR, the rats in the saline-treated and DMSO groups presented with injury tissue morphology, low NDS, ERK/calpain-2 pathway activation, and inflammatory cytokine and necroptosis protein over-expression in the brain tissue. After PD98059 and MDL28170 treatment, the brain function was improved, while inflammatory response and necroptosis were suppressed by ERK/calpain-2 pathway inhibition., Conclusion: Inflammation activation and necroptosis involved in CA/CPR-induced CIRI were regulated by the ERK/calpain-2 signaling pathway. Inhibition of that pathway can reduce neuroinflammation and necroptosis after CIRI in the CA model rats., (Copyright © 2021. Published by Elsevier B.V.)

Purpose of Review: The purpose of this review is to provide an update on how best to manage the investigation of suspected perioperative hypersensitivity reactions based on recent literature and key publications., Recent Findings: In the past two years, several very important initiatives have been taken in the field of perioperative hypersensitivity. The 6th national audit project in the United Kingdom has provided new knowledge through a series of studies, including a nationwide prospective study, and the European Academy of Allergy and Clinical Immunology has commissioned a position paper with updated recommendations for investigations. Lastly, a large international working group comprising experts in anesthesiology, allergology, and immunology, the International Suspected Perioperative Allergic Reactions group, has published a series of articles providing updates and new insights into several different key areas of perioperative hypersensitivity., Summary: The investigation of perioperative hypersensitivity reactions is highly complex and aims to identify the correct culprit to ensure future avoidance but also to disprove allergy to other suspected culprits, making them available for subsequent anesthesia. To achieve this, close collaboration between anesthesiologists and allergists is called upon to ensure the best possible outcome for the patient.

Background: Brain injury is the leading cause of death and disability in survivors of cardiac arrest, where neuroinflammation is believed to play a pivotal role, but the underlying mechanism remains unclear. Pyroptosis is a pro-inflammatory form of programmed cell death that triggers inflammatory response upon infection or other stimuli. This study aims to understand the role of microglial pyroptosis in post-cardiac arrest brain injury., Methods: Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. Flow cytometry analysis, Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), co-immunoprecipitation, and immunofluorescence were used to evaluate activated microglia and CD11b-positive leukocytes after cardiac arrest and assess inflammasome activation and pyroptosis of specific cellular populations. To further explore the underlying mechanism, MCC950 or Ac-YVAD-cmk was administered to block nod-like receptor family protein 3 (NLRP3) or caspase-1, respectively., Results: Our results showed that, in a rat model, successful resuscitation from cardiac arrest resulted in microglial pyroptosis and consequential inflammatory infiltration which was mediated by the activation of NLRP3 inflammasome. Targeting NLRP3 and caspase-1, the executor of pyroptosis, with selective inhibitors MCC950 and Ac-YVAD-cmk treatment significantly prevented microglial pyroptosis, reduced infiltration of leukocytes, improved neurologic outcome, and alleviated neuro-pathological damages after cardiac arrest in modeling rats., Conclusions: This study demonstrates that microglial pyroptosis mediated by NLRP3 inflammasome is critically involved in the pathogenesis of post-cardiac arrest brain injury and provides a new therapeutic strategy.

Background: Cardiac arrest is a tragic event that causes 1 death roughly every 90 seconds worldwide. Survivors generally undergo a workup to identify the cause of arrest. However, 5% to 10% of cardiac arrests remain unexplained. Because cardiac arrhythmias underlie most cardiac arrests and increasing evidence strongly supports the involvement of autoantibodies in arrhythmogenesis, a large-panel autoantibody screening was performed in patients with cardiac arrest., Methods: This is an observational, cross-sectional study of patients from the Montreal Heart Institute hospital cohort, a single-center registry of participants. A peptide microarray was designed to screen for immunoglobulin G targeting epitopes from all known cardiac ion channels with extracellular domains. Plasma samples from 23 patients with unexplained cardiac arrest were compared with those from 22 patients with cardiac arrest cases of ischemic origin and a group of 29 age-, sex-, and body mass index-matched healthy subjects. The false discovery rate, least absolute shrinkage and selection operator logistic regression, and random forest methods were carried out jointly to find significant differential immunoglobulin G responses., Results: The autoantibody against the pore domain of the L-type voltage-gated calcium channel was consistently identified as a biomarker of idiopathic cardiac arrest ( P =0.002; false discovery rate, 0.007; classification accuracies ≥0.83). Functional studies on human induced pluripotent stem cell-derived cardiomyocytes demonstrated that the anti-L-type voltage-gated calcium channel immunoglobulin G purified from patients with idiopathic cardiac arrest is proarrhythmogenic by reducing the action potential duration through calcium channel inhibition., Conclusions: The present report addresses the concept of autoimmunity and cardiac arrest. Hitherto unknown autoantibodies targeting extracellular sequences of cardiac ion channels were detected. Moreover, the study identified an autoantibody signature specific to patients with cardiac arrest.

Acute cardiorenal syndrome is a common complication of acute cardiovascular disease. Studies of acute kidney injury (AKI) to chronic kidney disease (CKD) transition, including patients suffering acute cardiovascular disease, report high rates of CKD development. Therefore, acute cardiorenal syndrome associates with CKD, but no study has established causation. To define this we used a murine cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) model or sham procedure on male mice. CA was induced with potassium chloride while CPR consisted of chest compressions and epinephrine eight minutes later. Two weeks after AKI was induced by CA/CPR, the measured glomerular filtration rate (GFR) was not different from sham. However, after seven weeks the mice developed CKD, recapitulating clinical observations. One day, and one, two, and seven weeks after CA/CPR, the GFR was measured, and renal tissue sections were evaluated for various indices of injury and inflammation. One day after CA/CPR, acute cardiorenal syndrome was indicated by a significant reduction of the mean GFR (649 in sham, vs. 25 μL/min/100g in CA/CPR animals), KIM-1 positive tubules, and acute tubular necrosis. Renal inflammation developed, with F4/80 positive and CD3-positive cells infiltrating the kidney one day and one week after CA/CPR, respectively. Although there was functional recovery with normalization of GFR two weeks after CA/CPR, deposition of tubulointerstitial matrix proteins α-smooth muscle actin and fibrillin-1 progressed, along with a significantly reduced mean GFR (623 in sham vs. 409 μL/min/100g in CA/CPR animals), proteinuria, increased tissue transforming growth factor-β, and fibrosis establishing the development of CKD seven weeks after CA/CPR. Thus, murine CA/CPR, a model of acute cardiorenal syndrome, causes an AKI-CKD transition likely due to prolonged renal inflammation., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background Patients resuscitated from cardiac arrest ( CA ) have highly variable neurological, circulatory, and systemic ischemia-reperfusion injuries. After the initial hypoxic-ischemic insult, a cascade of immune and inflammatory responses develops and is often fatal. The role of the immune response in pathophysiological characteristics and recovery is not well understood. We studied immune cell activity and its association with outcomes in a cohort of CA survivors. Methods and Results After informed consent, we collected blood samples at intervals over a week after resuscitation from CA . We examined the expression of CD 39 and CD 73 (alias 5'-nucleotidase), production of tumor necrosis factor-α, generation of reactive oxygen species, and secretion of vascular endothelial growth factor by circulating myeloid and lymphoid cells, in comparison to cells obtained from control subjects before coronary artery bypass grafting surgery. The number of circulating total and CD 73-expressing lymphocytes correlated with survival after CA . Incubation of immune cells, obtained from post- CA subjects, with AMP , a substrate for CD 73, resulted in inhibition of tumor necrosis factor-α production and generation of reactive oxygen species. This effect was blocked by adenosine 5'-(α, β-methylene) diphosphate, a specific inhibitor of CD 73 and ZM 241385, an A2 adenosine receptor antagonist. We also found that AMP -dependent activation of CD 73 induces production of vascular endothelial growth factor. Conclusions CD 73-expressing lymphocytes mediate cellular protection from inflammation after CA through inhibition of proinflammatory activation of myeloid cells and promotion of vascular endothelial growth factor secretion. The contribution of CD 73 lymphocytes in the regulation of acute inflammation and tissue injury after CA warrants further study.

Background: Gamma-aminobutyric acid-B receptor autoantibodies are becoming an increasingly recognized contributor to the spectrum of autoimmune limbic encephalitis. They are classically associated with seizures and behavioral disturbance, and may coexist with other autoantibodies. Many are paraneoplastic, most commonly associated with small cell lung cancer. Until now there have been no reports of cardiac dysrhythmias in these patients., Case Presentation: A 65-year-old Caucasian man presented with multiple seizures, dysarthria and behavioral disturbance of unclear etiology, with associated asystolic cardiac arrest. Antibody testing showed anti-Gamma-aminobutyric acid-B receptor and anti-Hu antibodies in serum and Gamma-aminobutyric acid-B receptor autoantibodies in cerebrospinal fluid. The diagnosis of small cell lung cancer was subsequently made after lung biopsy, and the patient showed improvement with chemotherapy and intravenous immunoglobulin., Conclusions: We present the case of a patient with Gamma-aminobutyric acid-B receptor limbic encephalitis associated with asystolic cardiac arrest, an association not previously described. This case illustrates how difficult it is to make the diagnosis on clinical grounds alone. We therefore propose more routine antibody testing in patients with similar symptomatology who remain undifferentiated after initial workup. We also recommend that in the acute setting, patients with Gamma-aminobutyric acid-B receptor encephalitis should receive cardiac monitoring, as further research is required to clarify its possible link with cardiac dysrhythmias.

Toll-like receptor 4 (TLR4) activation mediates renal injury in regional ischemia and reperfusion (I/R) models generated by clamping renal pedicles. However, it remains unclear whether TLR4 is causal in the kidney injury following global I/R induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The present study used wild‑type (C3H/HeN) and TLR4‑mutant (C3H/HeJ) mice to produce the CA/CPR model. CA was induced by injection of cold KCl and left untreated for different time periods. After resuscitation (72 h), the level of blood urea nitrogen (BUN) and serum creatinine (Scr), as well as histological changes in renal tissue were assessed to evaluate the severity of acute kidney injury (AKI). The expression of TLR4, intercellular adhesion molecule‑1 (ICAM‑1), myeloperoxidase (MPO) and growth‑regulated oncogene‑β (GRO‑β) in kidney tissues was detected. The results demonstrated that the levels of Scr and BUN increased significantly in C3H/HeN and C3H/HeJ mice after CPR. CPR also resulted in increased expression of TLR4, ICAM‑1, GRO‑β and MPO in a CA‑duration dependent manner. However, there was decreased expression of ICAM‑1, GRO‑β and MPO in C3H/HeJ mice compared with that in C3H/HeN mice. C3H/HeJ mice were resistant to AKI as demonstrated by the minor changes in renal histology and function following CPR. In conclusion, mice suffered from AKI after successful CPR and severe AKI occurred in mice with prolonged CA duration. TLR4 and its downstream signaling events that promote neutrophil infiltration via ICAM‑1 and GRO‑β may be important in mediating inflammatory responses to renal injury after CPR.

Objective: To investigate whether Shen-Fu Injection (, SFI) reduces post-resuscitation immune dysfunction in a porcine model of cardiac arrest by modulating apoptosis of regulatory T lymphocytes (Treg) in the spleen., Methods: After 8-min untreated ventricular fibrillation and 2-min basic life support, 24 pigs were divided into 3 groups with a random number table, i.e. SFI group, epinephrine (EP) group, and saline (SA) group (8 in each group), which received central venous injection of SFI (1.0 mL/kg), EP (0.02 mg/kg) and SA, respectively. The same procedure without CA initiation was achieved in the sham-operated (sham) group (n=6). After successful return of spontaneous circulation (ROSC), apoptosis rate of splenic Treg was detected by flow cytometry; and the mRNA expression of forkhead/winged helix transcription factor (Foxp3) of splenic Treg was detected by real time-polymerase chain reaction; and the levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in porcine splenic Treg were detected by using enzyme-linked immunosorbent assay (ELISA)., Results: Compared with the sham group, the apoptosis rate of Treg was significantly decreased, and the levels of Foxp3 mRNA expression, IFN-γ, IL-4 and IFN-γ/IL-4 were increased in the SA group (P<0.05 or P<0.01). Compared with the EP and SA groups, SFI treatment increased the apoptosis rate of Treg and reduced the levels of Foxp3 mRNA expression, IFN-γ and IFN-γ/IL-4 (P<0.05)., Conclusions: SFI has signifificant effects in attenuating post-resuscitation immune dysfunction by modulating apoptosis of Treg in the spleen.

Background: Postresuscitation immune dysfunction contributes to the low survival rate after successful resuscitation, but its mechanism remains poorly understood. The purpose of this study was to investigate whether splenic regulatory T-cell (Treg) apoptosis was involved in the postresuscitation immune dysfunction., Methods: Thirty-eight pigs were randomly divided into sham-operated group (SHAM group, n = 8), 12 h post return of spontaneous circulation (ROSC) group, 24 h post-ROSC group, and 48 h post-ROSC group (n = 10 per group). A Wuzhishan miniature porcine model of 8-min ventricular fibrillation cardiac arrest (CA) was established. The apoptosis rates of Treg in the spleen were tested by flow cytometry; the expressions of forkhead/winged helix transcription factor (Foxp3) of Treg in the spleen were detected by real-time polymerase chain reaction; and the levels of interleukin-4 (IL-4), IL-10, and interferon gamma (IFN-γ) of Treg in the spleen were detected by enzyme-linked immunosorbent assay., Results: The apoptosis rates of Treg in all post-ROSC groups were significantly lower than that of SHAM group (7.7% ± 1.9%, 7.1% ± 1.8%, 6.2% ± 0.4% vs. 13.1% ± 1.6%; P < 0.05); the expression levels of Foxp3 and IL-10 were also decreased with the increase of apoptosis rates of Treg. Helper T-cells CD4+ lymphocyte subsets were significantly lower in the post-ROSC groups compared with SHAM group (29.1% ± 2.2%, 24.3% ± 2.2%, 24.1% ± 2.5% vs. 43.8% ± 4.5%; P < 0.01) at 12, 24, and 48 h after ROSC. Compared with SHAM group, the levels of IFN-γ (161.0 ± 12.9, 167.7 ± 10.5, 191.2 ± 7.7 vs. 7.6 ± 0.9 ng/L) and IL-4 (27.7 ± 6.2, 35.9 ± 3.5, 50.6 ± 6.1 vs. 13.3 ± 2.3 ng/L) and the ratio of IFN-γ/IL-4 (8.6 ± 2.3, 4.9 ± 0.4, 4.5 ± 0.9 vs. 0.8 ± 0.2) were all greatly elevated in all post-ROSC groups (P < 0.05)., Conclusions: Apoptosis rate of Treg was significantly decreased after CA, and thus the proportion of Treg was increased and the inhibitory effects were enhanced, which further led to the decrease of the amount of CD4+ T-cells. In addition, the T helper type 2/T helper type 1 (Th2/Th1) cell drift of Treg in the spleen caused postresuscitation immune dysfunction.

Background: Compared to many other cardiovascular diseases, there is a paucity of data on the characteristics of successfully resuscitated cardiac arrest (CA) patients with human immunodeficiency virus (HIV) infection. We investigated causes, clinical features and outcome of these patients, and assessed the specific burden of HIV on outcome., Methods: Retrospective analysis of HIV-infected patients admitted to 20 French ICUs for successfully resuscitated CA (2000-2012). Characteristics and outcome of HIV-infected patients were compared to those of a large cohort of HIV-uninfected patients admitted after CA in the Cochin Hospital ICU during the same period., Results: 99 patients were included (median CD4 lymphocyte count 233/mm(3), viral load 43 copies/ml). When compared with the control cohort of 1701 patients, HIV-infected patients were younger, with a predominance of male, a majority of in-hospital CA (52%), and non-shockable initial rhythm (80.8%). CA was mostly related to respiratory cause (n=36, including 23 pneumonia), cardiac cause (n=33, including 16 acute myocardial infarction), neurologic cause (n=8) and toxic cause (n=5). CA was deemed directly related to HIV infection in 18 cases. Seventy-one patients died in the ICU, mostly for care withdrawal after post-anoxic encephalopathy. After propensity score matching, ICU mortality was not significantly affected by HIV infection. Similarly, HIV disease characteristics had no impact on ICU outcome., Conclusions: Etiologies of CA in HIV-infected patients are miscellaneous and mostly not related to HIV infection. Outcome remains bleak but is similar to outcome of HIV-negative patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Although inflammatory mechanisms have been linked to neuronal injury following global cerebral ischemia, the presence of infiltrating peripheral immune cells remains understudied. We performed flow cytometry of single cell suspensions obtained from the brains of mice at varying time points after global cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation (CA/CPR) to characterize the influx of lymphocytes into the injured brain. We observed that CA/CPR caused a large influx of lymphocytes within 3h of resuscitation that was maintained for the 3day duration of our experiments. Using cell staining flow cytometry we observed that the large majority of infiltrating lymphocytes were CD4(+) T cells. Intracellular stains revealed a large proportion of pro-inflammatory T cells expressing either TNFα or INFγ. Importantly, the lack of functional T cells in TCRα knockout mice reduced neuronal injury following CA/CPR, implicating pro-inflammatory T cells in the progression of ischemic neuronal injury. Finally, we made the remarkable observation that the novel CD4(+)CD40(+) (Th40) population of pro-inflammatory T cells that are strongly associated with autoimmunity are present in large numbers in the injured brain. These data indicate that studies investigating the neuro-immune response after global cerebral ischemia should consider the role of infiltrating T cells in orchestrating the acute and sustained immune response., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Postresuscitation immunologic dysfunction contributes to the low survival rate after successful resuscitation, but its mechanism remains poorly understood. The mitochondrial apoptosis pathway is initiated by the Bcl-2/Bax-controlled and caspase-3-mediated pathway, this study investigated whether mitochondrial pathway-mediated splenic lymphocyte apoptosis is involved in the postresuscitation immunosuppression in a porcine model of cardiac arrest., Methods: Twenty-eight Wuzhishan miniature pigs were randomly divided into 2 groups: return of spontaneous circulation (ROSC; n = 22) and sham-operated (n = 6). Return of spontaneous circulation was initiated after 8 minutes of untreated ventricular fibrillation. After successful ROSC, CD4(+) and CD8(+) lymphocyte subsets were determined by flow cytometry. Surviving pigs were randomly assigned to be humanely killed at 24 and 72 hours after ROSC (n = 8 per group). Spleens were removed for histopathologic analysis, Western blotting, quantitative real-time polymerase chain reaction, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay., Results: A high degree of splenic lymphocyte apoptosis was observed in the ROSC group. Expression of Bax and activated caspase-3 was markedly increased in splenic tissue, whereas Bcl-2 was significantly decreased in the post-ROSC group compared with the sham-operated group (P < .05) at 24 and 72 hours after ROSC. The messenger RNA levels of activated caspase-3 of splenic tissue were significantly elevated at 24 and 72 hours after ROSC., Conclusion: These results demonstrates that Bcl-2/Bax and caspase-3-mediated mitochondrial apoptosis signaling pathway may contribute to abnormal splenic lymphocyte apoptosis, which may be one of the main pathologic mechanisms of postresuscitation disturbance of immunologic function in a porcine model of cardiac arrest., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Induced hypothermia is increasingly applied as a therapeutic intervention in ICUs. One of the underlying mechanisms of the beneficial effects of hypothermia is proposed to be reduction of the inflammatory response. However, a fear of reducing the inflammatory response is an increased infection risk. Therefore, we studied the effect of induced hypothermia on immune response after cardiac arrest., Methods: A prospective observational cohort study in a mixed surgical-medical ICU. Patients admitted at the ICU after surviving cardiac arrest were included and during 24 hours body temperature was strictly regulated at 33°C or 36°C. Blood was drawn at three time points: after reaching target temperature, at the end of the target temperature protocol and after rewarming to 37°C. Plasma cytokine levels and response of blood leucocytes to stimulation with toll-like receptor (TLR) ligands lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteicoic acid (LTA) from Gram-positive bacteria were measured. Also, monocyte HLA-DR expression was determined., Results: In total, 20 patients were enrolled in the study. Compared to healthy controls, cardiac arrest patients kept at 36°C (n = 9) had increased plasma cytokines levels, which was not apparent in patients kept at 33°C (n = 11). Immune response to TLR ligands in patients after cardiac arrest was generally reduced and associated with lower HLA-DR expression. Patients kept at 33°C had preserved ability of immune cells to respond to LPS and LTA compared to patients kept at 36°C. These differences disappeared over time. HLA-DR expression did not differ between 33°C and 36°C., Conclusions: Patients after cardiac arrest have a modest systemic inflammatory response compared to healthy controls, associated with lower HLA-DR expression and attenuated immune response to Gram-negative and Gram-positive antigens, the latter indicative of an impaired immune response to bacteria. Patients with a body temperature of 33°C did not differ from patients with a body temperature of 36°C, suggesting induced hypothermia does not affect immune response in patients with cardiac arrest., Trial Registration: ClinicalTrials.gov NCT01020916, registered 25 November 2009.

Cardiac arrest causes generalized ischaemia/hypoxia, and subsequent resuscitation inflicts reperfusion injury, the pathology of which is not fully understood. Moreover, predicting the prognosis of comatose, post-cardiac arrest patients is a complex clinical challenge. We hypothesized that the extent of complement activation might be a reliable predictor of mortality in this population. Forty-six comatose cardiac arrest patients were enrolled into our prospective cohort study, conducted in a tertiary care university clinic. All subjects were cooled to 32-34 °C body temperature for 24 h and then allowed to rewarm to normothermia. All patients underwent diagnostic coronary angiography. On admission, at 6 and 24 h, blood samples were taken from the arterial catheter. In these, complement products (C3a, C3, C4d, C4, SC5b9 and Bb) were measured by ELISA in blood samples. Patients were followed up for 30 days; 22 patients (47.8%) died by the end of this period. We observed that complement activation (determined as the C3a to C3 ratio) was higher in non-survivors than in survivors at each time point. In the multivariate Cox regression analysis, the C3a/C3 ratio determined 24 h after the initiation of therapeutic hypothermia predicted 30-day mortality regardless of age, sex and the APACHE II score. Complement activation occurs in post-cardiac arrest patients, and its extent correlates with 30-day survival. The C3a/C3 ratio might prove useful for estimating the prognosis of comatose post-cardiac arrest patients., (© 2014 John Wiley & Sons Ltd.)

A 54-year-old male entered the emergency room in cardiorespiratory arrest after syncope at home. Resuscitation was attempted, but the patient died a few hours later. At necropsy, aneurysms were found at the right and left anterior descending coronary arteries. At microscopic examination, there was no significant coronary atherosclerosis, and a dense inflammatory infiltrate was detected, with a high number of igG4-positive cells (94.0 positive cells/hpf). The case illustrates that IgG4-related disease can cause coronary disease and sudden cardiac death., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cardiac arrest (CA) causes hippocampal neuronal death that frequently leads to severe loss of memory function in survivors. No specific treatment is available to reduce neuronal death and improve functional outcome. The brain's inflammatory response to ischemia can exacerbate injury and provides a potential treatment target. We hypothesized that microglia are activated by CA and contribute to neuronal loss. We used a mouse model to determine whether pharmacologic inhibition of the proinflammatory microglial enzyme soluble epoxide hydrolase (sEH) after CA alters microglial activation and neuronal death. The sEH inhibitor 4-phenylchalcone oxide (4-PCO) was administered after successful cardiopulmonary resuscitation (CPR). The 4-PCO treatment significantly reduced neuronal death and improved memory function after CA/CPR. We found early activation of microglia and increased expression of inflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the hippocampus after CA/CPR, which was unchanged after 4-PCO treatment, while expression of antiinflammatory IL-10 increased significantly. We conclude that sEH inhibition after CA/CPR can alter the transcription profile in activated microglia to selectively induce antiinflammatory and neuroprotective IL-10 and reduce subsequent neuronal death. Switching microglial gene expression toward a neuroprotective phenotype is a promising new therapeutic approach for ischemic brain injury.

Anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a recently identified autoimmune disorder that is increasingly recognized in children. Most cases occur in girls and women and may be paraneoplastic with an associated ovarian teratoma. Characteristic clinical features include neuropsychiatric symptoms, dyskinesias, decreased consciousness, and autonomic instability. We report the first case of asystole associated with temporal lobe seizures in this disorder and highlight the need for careful monitoring for this potentially fatal complication. A 15-year-old previously healthy girl presented with focal seizures and personality changes that progressed to periods of agitation and confusion alternating with catatonia. Anti-NMDAR antibodies were detected in the cerebrospinal fluid and serum. Twenty-six days after initial presentation, new seizures developed characterized by bradycardia and oxygen desaturation. Continuous video-electroencephalogram monitoring captured 3 seizures with left-temporal onset and associated asystole. An ovarian teratoma was diagnosed by pelvic ultrasound and computed tomography, and surgical resection was followed by gradual improvement in her neuropsychiatric symptoms. Treatment with phenobarbital beginning on day 26 lead to the cessation of seizures. However, asymptomatic bradycardia and pauses of 3 seconds continued. After insertion of a demand pacemaker on day 46, there were no further cardiac events. The patient was also treated with 2 courses of intravenous immunoglobulin. Outpatient follow-up at 4 months revealed near-complete neurologic recovery and no cardiac events. To our knowledge, ictal asystole has not previously been described as a complication of anti-NMDAR encephalitis; it is a preventable cause of death in this emerging pediatric disorder, which presents with protean symptoms and is easily misdiagnosed.

The present study evaluates the role of the inflammatory status and apoptosis activation in the development of organ dysfunction after brain death using plasma assays and macroarray analysis on skeletal muscle biopsies to look for evidence of remote tissue damage in two intensive care units in France and one in Belgium. As controls, we used patients undergoing hip surgery and healthy volunteers. Causes of brain death in the 85 consecutive patients included in the study were cardiac arrest (n = 29; 34%), stroke (n = 42; 49%, with 38 patients having hemorrhagic stroke), and head injury (n = 14; 17%). Of the 85 patients, 45 donated 117 organs. Plasma endotoxin and cytokine levels indicated a marked systemic inflammatory response in brain-dead patients, which was strongest in the cardiac arrest group. Leukocyte dysfunction, as assessed by cytokines production in response to various stimuli, was noted in a subgroup of patients with brain death after stroke. Interestingly, skeletal muscle biopsies showed no increase in mRNAs for genes related to inflammation, whereas mRNAs for both antiapoptotic and proapoptotic genes were increased, the balance being in favor of apoptosis induction. The increased activation of the proapoptotic caspase 9 was further confirmed by Western blot. In conclusion, the presence of inflammation and apoptosis induction may explain the rapid organ dysfunction seen after brain death. Both abnormalities may play a role in organ dysfunction associated with brain death. However, the level of systemic inflammation or the presence of circulating endotoxin was not associated with lower graft survival.

Increased levels of cytokines have been reported after resuscitation from cardiac arrest. We hypothesized that proinflammatory cytokines, released in response to ischemia/reperfusion, increase following resuscitation and play a role in post-cardiac arrest myocardial dysfunction. Ventricular fibrillation (VF) was induced by coronary occlusion in 20 swine. After 7 min of VF, resuscitation was performed as per guidelines. Plasma levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were measured 15 min after the start of resuscitation in all animals and at intervals of 6 h in resuscitated animals. Intravascular pressures and cardiac output (CO) were also recorded. TNF-alpha abruptly increased after resuscitation, peaking at 15 min following return of spontaneous circulation, and declined to baseline levels after 3 h. IL-1beta increased more slowly, reaching a maximum 2 h after reperfusion. IL-6 concentrations were not significantly different from control values at any time point. Males demonstrated greater elevations of TNF-alpha and IL-1beta than females. Stroke work was significantly depressed at all time points with a nadir at 15-30 min after reperfusion, corresponding to the peak TNF-alpha values. The anti-TNF-alpha antibody infliximab attenuated the decrease in myocardial function observed 30 min after reperfusion. TNF-alpha increases during recovery from cardiac arrest are associated with depression of left ventricle (LV) function. The effect of TNF-alpha can be attenuated by anti-TNF-alpha antibodies.

Purpose: Although animal studies document conflicting data on the influence of hypothermia on cytokine release in various settings, no data exist if hypothermia affects the inflammatory response after successful cardiopulmonary resuscitation., Materials and Methods: Arrest- and treatment-related variables of 71 patients were documented, and serum samples were analyzed for levels of interleukin 6, tumor necrosis factor-alpha, C-reactive protein, and procalcitonin immediately after hospital admission and after 6, 24, and 120 hours. At day 14, patients were dichotomized in those with good and bad neurological outcome., Results: Regardless of outcomes, interleukin 6 levels were significantly elevated by the use of hypothermia (n = 39). The rate of bacterial colonization was significantly higher in hypothermic patients (64.1 vs 12.5 %; P < .001). On the contrary, procalcitonin levels were, independent of the use of hypothermia, only significantly elevated in patients with bad neurological outcome. Hypothermic patients showed a strong trend to reduced mortality. However, there was no influence on neurological recovery., Conclusions: In this observational study, hypothermia influenced the inflammatory response after cardiopulmonary resuscitation and lead to a higher rate of bacterial colonization without altering ultimate neurologic recovery.

Immune system activation has implications for cerebrovascular health, but little is known about the function of the immune system after a major cerebrovascular event, such as cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Cardiac arrest and cardiopulmonary resuscitation damages the hippocampus, an important component of the hypothalamic-pituitary-adrenal (HPA) axis, and alterations in HPA axis activity can affect immune function. We tested the hypothesis that CA/CPR (approximately 8 mins) would cause HPA axis dysregulation and alter the delayed type hypersensitivity (DTH) response to antigenic challenge. We also assessed the primary and secondary antibody response of mice exposed to CA/CPR. Of the mice exposed to CA/CPR, half had brains protected by hypothermia to isolate the effects of the CA/CPR procedure from the effects of CA/CPR-induced neuronal damage. Cardiac arrest and cardiopulmonary resuscitation-induced neuronal damage resulted in a persistent elevation of blood corticosterone concentration and a concomitant augmentation of the DTH response to antigenic challenge. Furthermore, immune activation before CA/CPR decreased survival after global ischemia. These data highlight the potential impact of neuronal damage on cell-mediated immune function and the role of humoral immune activation in outcome after global ischemia.

In animal models, immune activation is often difficult to assess because of the limited availability of specific assays to detect cytokine activities. In human monocytes/macrophages, interferon-gamma induces increased production of neopterin and an enhanced activity of indoleamine 2,3-dioxygenase, which degrades tryptophan via the kynurenine pathway. Therefore, monitoring of neopterin concentrations and of tryptophan degradation can serve to detect the extent of T helper cell 1-type immune activation during cellular immune response in humans. In a porcine model of cardiac arrest, we examined the potential use of neopterin measurements and determination of the tryptophan degradation rate as a means of estimating the extent of immune activation. Urinary neopterin concentrations were measured with high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA) (BRAHMS Diagnostica, Berlin, Germany). Serum and plasma tryptophan and kynurenine concentrations were also determined using HPLC. Serum and urine neopterin concentrations were not detectable with HPLC in these specimens, whereas RIA gave weakly (presumably false) positive results. The mean serum tryptophan concentration was 39.0 +/- 6.2 micromol/l, and the mean kynurenine concentration was 0.85 +/- 0.33 micromol/l. The average kynurenine-per-tryptophan quotient in serum was 21.7 +/- 8.4 nmol/micromol, and that in plasma was 20.7 +/- 9.5 nmol/micromol (n = 7), which corresponds well to normal values in humans. This study provides preliminary data to support the monitoring of tryptophan degradation but not neopterin concentrations as a potential means of detecting immune activation in a porcine model. The kynurenine-per-tryptophan quotient may serve as a short-term measurement of immune activation and hence permit an estimate of the extent of immune activation.

We have previously reported that fresh frozen plasma (FFP) may induce a rapid irreversible shock when repeatedly infused in pigs challenged with Gram-negative sepsis. The aims of the present study were to elucidate the cardiovascular nature of the shock and determine the aetiologic role of tumour necrosis factor (TNF), complement activation and halothane anaesthesia. Three groups of anaesthetized piglets were inoculated with a lethal dose of live E. coli bacteria. Groups I (n = 8) and III (n = 8) were anaesthetized with halothane and group II (n = 8) with ketamine. Animals in groups I and II received repeated infusions of FFP, whereas animals in group III received repeated infusions of 7% albumin. Six animals in group I and four animals in group II died during the first plasma infusion. Survival time was significantly longer in group II (P = 0.04) compared to group I. No animals in group III died during the albumin infusions, and no adverse effects were observed during the infusions. In group I the plasma induced shock was characterized by abruptly falling mean arterial pressure, cardiac index, systemic vascular resistance index and left ventricular contractility. Concomitant increases were recorded in left ventricular filling pressure and central venous pressure. Group II demonstrated a similar, but delayed response. Plasma infusion was associated with a significant increase in terminal complement complex (TCC) (P < 0.03 in group I, P < 0.05 in group II) and depletion of serum ionized calcium. We conclude that FFP may induce fatal myocardial depression and circulatory collapse in severe sepsis. Complement activation may be of aetiologic importance.

A case control study of congenital complete heart block (CHB) was undertaken to determine the degree of association of this condition with maternal connective tissue disease and with maternal autoantibodies, in particular those to Ro(SS-A). Mothers of cases (n = 18) and controls (n = 72) completed a self-administered questionnaire and donated 10 ml of blood. The odds of giving birth to a child with CHB were increased by a factor of 22 for women with antibodies to Ro(SS-A) and/or La(SS-B) compared with women who did not have these antibodies. Thus the association between CHB and both anti-Ro(SS-A) and anti-La(SS-B) antibodies has been demonstrated in an Australian population and indicates that anti-La(SS-B), as well as anti-Ro(SS-A) antibodies may be a risk factor for the development of CHB.

Immune complexes were detected in the sera of ten of 22 patients with acute pancreatitis using a Clq deviation assay. Five of these were positive using a second technique. There was no correlation between immune complexes and clinical or aetiological features of the pancreatitis. Two patients with immune complexes developed a benign and transient pancreatic polyarthritis. Immune complexes may provide one common path in the sequence of pathogenic events that lead to pancreatitis.