High Level of Endotoxemia Following Out-of-Hospital Cardiac Arrest Is Associated With Severity and Duration of Postcardiac Arrest Shock*

Grimaldi, David; Sauneuf, Bertrand; Guivarch, Elise; Ricome, Sylvie; Géri, Guillaume; Charpentier, Julien; Zuber, Benjamin; Dumas, Florence; Spaulding, Christian; Mira, Jean‐Paul; Cariou, Alain

doi:10.1097/ccm.0000000000001303

Cited by 40 publications

(38 citation statements)

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“…That said, it is important to consider that acute brain injury also induces gut dysbiosis and the associated release of bacterial endotoxin. 39,40 Given studies from our group and others demonstrating the combined effects of damage-associated molecular pattern and pathogen-associated molecular pattern priming postischemic brain injury, 9,41 it will be interesting to test whether fluctuations in systemic arterial SOD3 levels exert similar effects on the enteric microvasculature with attendant effects on associated bacterial translocation and endotoxin leak. The selectivity of the surfactant protein-C promoter and the immunologically distinct human form of SOD3 provided additional insight regarding potential mechanisms leading to neurovascular protection in our model.…”

Section: Discussionmentioning

confidence: 99%

Lung‐Derived SOD3 Attenuates Neurovascular Injury After Transient Global Cerebral Ischemia

Mai

Miller-Rhodes

Prifti

et al. 2019

JAHA

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Background-Systemic innate immune priming is a recognized sequela of post-ischemic neuroinflammation and contributor to delayed neurodegeneration. Given mounting evidence linking acute stroke with reactive lung inflammation, we asked whether enhanced expression of the endogenous antioxidant extracellular superoxide dismutase 3 (SOD3) produced by alveolar type II pneumocytes would protect the lung from transient global cerebral ischemia and the brain from the delayed effects of ischemiareperfusion. Methods and Results-Following 15 minutes of global cerebral ischemia or sham conditions, transgenic SOD3 and wild-type mice were followed daily for changes in weight, core temperature, and neurological function. Three days after reperfusion, arterial and venous samples were collected for complete blood counts, flow cytometry, and SOD3 protein blotting, and immunohistochemistry was performed on lung and brain tissue to assess tissue injury, blood-brain barrier permeability, and neutrophil transmigration. Relative to ischemic controls, transgenic SOD3 mice performed better on functional testing and exhibited reduced peripheral neutrophil activation, lung inflammation, and blood-brain barrier leak. Once released from the lung, SOD3 was predominantly not cell associated and depleted in the venous phase of circulation. Conclusions-In addition to reducing the local inflammatory response to cerebral ischemia, targeted enrichment of SOD3 within the lung confers distal neuroprotection against ischemia-reperfusion injury. These data suggest that therapies geared toward enhancing adaptive lung-neurovascular coupling may improve outcomes following acute stroke and cardiac arrest.

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Section: Discussionmentioning

confidence: 99%

Lung‐Derived SOD3 Attenuates Neurovascular Injury After Transient Global Cerebral Ischemia

Mai

Miller-Rhodes

Prifti

et al. 2019

JAHA

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“…The use of low-dose endotoxin as a driver of PCAS pathology is a unique feature of this work and is based on reports from the clinical literature citing the association between serum endotoxin and the duration of post cardiac arrest shock (Grimaldi, et al 2013, Grimaldi, et al 2015). Mesenteric ischemia stimulates the growth of gram-negative bacteria in situ and induces villous blunting with mucosal degeneration (Karhausen, et al 2013, L’Her, et al 2005, Wang, et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In our initial dose ranging studies, we found the delivery of LPS above 1 mg/kg after the 3VO procedure caused a high rate of perioperative mortality (data not shown). We, therefore, adjusted our dosing strategy reducing the amount of LPS (50 μg/kg) to a point where serum endotoxin was undetectable, such as has been described for a significant number of patients (Grimaldi, et al 2015). Although low-dose endotoxin challenge was not detected in serum using the limulus amebocyte lysate assay, which is sensitive to levels as low as 0.1 EU/ml (or approximately 0.01 ng endotoxin/ml), its use in our paradigm resulted in the activation of brain endothelium, damage to the BBB with the accumulation of serum proteins in the parenchyma, microglial activation, and the accumulation of PMNs in areas of cortical ischemia.…”

Section: Discussionmentioning

confidence: 99%

“…Ischemic damage also induces a sterile inflammatory response through the release of damage-associated molecular patterns (DAMPs) from the brain and other tissues (Pittman and Kubes 2013, Tadie, et al 2013, Wang, et al 2015). More recently, studies have revealed detectable levels of endotoxin in the serum of up to 86% of patients within 24–48 hours following return of spontaneous circulation (Adrie, et al 2002, Grimaldi, et al 2013, Grimaldi, et al 2015, L’Her, et al 2005). The presence of endotoxin and other pathogen-associated molecular patterns (PAMPs) has been linked with ischemia-induced growth of gram-negative intestinal flora and loss of mucosal barrier function with secondary bacteremia (Adrie, et al 2002, Karhausen, et al 2013, Wang, et al 2012).…”

Section: Introductionmentioning

confidence: 99%

“…While endotoxemia has been associated with durable neurocognitive deficits in patients surviving Escherichia coli sepsis (Annane and Sharshar 2015), the levels of lipopolysaccharide (LPS) detected in cases of sepsis are typically higher than those reported following cardiac arrest (2.6 vs . <0.6 EU/ml) (Casey, et al 1993, Grimaldi, et al 2015). And while linked to increased risk of shock and organ failure (Grimaldi, et al 2013), the effects and consequences of serologically undetectable endotoxemia on cerebral ischemia-reperfusion injury remain unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion

Mai

Prifti

Rininger

et al. 2017

Experimental Neurology

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Post-ischemic neurodegeneration remains the principal cause of mortality following cardiac resuscitation. Recent studies have implicated gastrointestinal ischemia in the sepsis-like response associated with the post-cardiac arrest syndrome (PCAS). However, the extent to which the resulting low-grade endotoxemia present in up to 86% of resuscitated patients affects cerebral ischemia-reperfusion injury has not been investigated. Here we report that a single injection of low-dose lipopolysaccharide (50 μg/kg, IP) delivered after global cerebral ischemia (GCI) induces blood-brain barrier permeability, microglial activation, cortical injury, and functional decline in vivo, compared to ischemia alone. And while GCI was sufficient to induce neutrophil (PMN) activation and recruitment to the post-ischemic CNS, minimal endotoxemia exhibited synergistic effects on markers of systemic inflammation including PMN priming, lung damage, and PMN burden within the lung and other non-ischemic organs including the kidney and liver. Our findings predict that acute interventions geared towards blocking the effects of serologically occult endotoxemia in survivors of cardiac arrest will limit delayed neurodegeneration, multi-organ dysfunction and potentially other features of PCAS. This work also introduces lung-brain coupling as a novel therapeutic target with broad effects on innate immune priming and post-ischemic neurodegeneration following cardiac arrest and related cerebrovascular conditions.

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Nutrition During Targeted Temperature Management After Cardiac Arrest: Observational Study of Neurological Outcomes and Nutrition Tolerance

Martin

Reignier

Thuaut

et al. 2019

J Parenter Enteral Nutr

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Background: Whether providing nutrition support is beneficial or deleterious during targeted temperature management (TTM) after cardiac arrest is unclear. We therefore performed a retrospective observational study to determine whether early nutrition was beneficial or deleterious during TTM. Methods: We retrospectively studied patients admitted to our intensive care unit (ICU) between 2008 and 2014 after successfully resuscitated cardiac arrest. We compared the group given nutrition within 48 hours after ICU admission (E+ group) to the group given nutrition later on or not at all (E-group). Results: Of the 203 included patients, 143 were in the E+ group and 60 in the E-group. The E+ group had a significantly higher proportion of patients with a good 3-month neurological outcome (42.7% vs 16.7%, P < 0.001). The difference remained significant after adjustment on a propensity score (odds ratio, 3.47; 95% confidence interval, 1.48-8.14; P = 0.004). The cumulative energy deficit for an energy goal of 20 kcal/kg/d from admission to day 7 was significantly lower in the E+ group (3304 ± 2863 kcal vs 5017 ± 2655 kcal, P < 0.001). Within the E+ group, the subgroups with nutrition initiation when body temperature was <36°C vs ࣙ36°C were not significantly different regarding the frequencies of early-onset pneumonia, ventilator-associated pneumonia, vomiting, and prokinetic drug use (all P-values > 0.05). Conclusions: Early nutrition after cardiac arrest during TTM appears safe and may be associated with better neurological outcomes. These findings warrant a randomized controlled trial to resolve the remaining issues. (JPEN J Parenter Enteral Nutr. 2020;44:138-145) Keywords cardiac arrest; induced hypothermia; nutrition; pneumonia; targeted temperature management Clinical Relevancy StatementPatients comatose after cardiac arrest are admitted to the intensive care unit (ICU) for targeted temperature management and neurological prognostication. Whether providing From the

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High Level of Endotoxemia Following Out-of-Hospital Cardiac Arrest Is Associated With Severity and Duration of Postcardiac Arrest Shock*

Cited by 40 publications

References 38 publications

Lung‐Derived SOD3 Attenuates Neurovascular Injury After Transient Global Cerebral Ischemia

Lung‐Derived SOD3 Attenuates Neurovascular Injury After Transient Global Cerebral Ischemia

Endotoxemia induces lung-brain coupling and multi-organ injury following cerebral ischemia-reperfusion

Nutrition During Targeted Temperature Management After Cardiac Arrest: Observational Study of Neurological Outcomes and Nutrition Tolerance

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