Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use.

Cardiac arrest survivors suffer the repercussions of anoxic brain injury, a critical factor influencing long-term prognosis. This injury is characterised by profound and enduring metabolic impairment. Ketone bodies, an alternative energetic resource in physiological states such as exercise, fasting, and extended starvation, are avidly taken up and used by the brain. Both the ketogenic diet and exogenous ketone supplementation have been associated with neuroprotective effects across a spectrum of conditions. These include refractory epilepsy, neurodegenerative disorders, cognitive impairment, focal cerebral ischemia, and traumatic brain injuries. Beyond this, ketone bodies possess a plethora of attributes that appear to be particularly favourable after cardiac arrest. These encompass anti-inflammatory effects, the attenuation of oxidative stress, the improvement of mitochondrial function, a glucose-sparing effect, and the enhancement of cardiac function. The aim of this manuscript is to appraise pertinent scientific literature on the topic through a narrative review. We aim to encapsulate the existing evidence and underscore the potential therapeutic value of ketone bodies in the context of cardiac arrest to provide a rationale for their use in forthcoming translational research efforts.

Neutralization of extracellular histones by sodium-Β-O-methyl cellobioside sulfate in septic shock.

BACKGROUND: Extracellular histones have been associated with severity and outcome in sepsis. The aim of the present study was to assess the effects of sodium-ß-O-Methyl cellobioside sulfate (mCBS), a histone-neutralizing polyanion, on the severity and outcome of sepsis in an experimental model. METHODS: This randomized placebo-controlled experimental study was performed in 24 mechanically ventilated female sheep. Sepsis was induced by fecal peritonitis. Animals were randomized to three groups: control, early treatment, and late treatment (n = 8 each). mCBS was given as a bolus (1 mg/kg) followed by a continuous infusion (1 mg/kg/h) just after sepsis induction in the early treatment group, and 4 h later in the late treatment group. Fluid administration and antimicrobial therapy were initiated 4 h T4 after feces injection, peritoneal lavage performed, and a norepinephrine infusion titrated to maintain mean arterial pressure (MAP) between 65-75 mmHg. The experiment was blinded and lasted maximum 24 h. RESULTS: During the first 4 h, MAP remained > 65 mmHg in the early treatment group but decreased significantly in the others (p < 0.01 for interaction, median value at T4: (79 [70-90] mmHg for early treatment, 57 [70-90] mmHg for late treatment, and 55 [49-60] mmHg for the control group). mCBS-treated animals required significantly less norepinephrine to maintain MAP than controls (p < 0.01 for interaction) and had lower creatinine (p < 0.01), lactate (p < 0.01), and interleukin-6 (p < 0.01) levels, associated with reduced changes in H3.1 nucleosome levels (p = 0.02). Early treatment was associated with lower norepinephrine requirements than later treatment. Two control animals died; all the mCBS-treated animals survived. CONCLUSIONS: Neutralization of extracellular histones with mCBS was associated with reduced norepinephrine requirements, improved tissue perfusion, less renal dysfunction, and lower circulating IL-6 in experimental septic shock and may represent a new therapeutic approach to be tested in clinical trials.

Evaluation of a new magnetically suspended centrifugal neonatal pump in healthy animals using a veno-venous extracorporeal membrane oxygenation configuration.

BACKGROUND: The objective of this animal study was to evaluate the hemodynamic performance of a new centrifugal pump for extra-corporeal membrane oxygenation (ECMO) support in neonates. METHODS: Six healthy swines were supported with veno-venous ECMO with the New Born ECMOLife centrifugal pump (Eurosets, Medolla, Italy) at different flow rates: 0.25, 0.5, 0.6, and 0.8 L/min; three animals were evaluated at low-flows (0.25 and 0.5 L/min) and three at high-flows (0.6 and 0.8 L/min). Each flow was maintained for 4 hours. Blood samples were collected at different time-points. Hematological and biochemical parameters and ECMO parameters [flow, revolutions per minute (RPM), drainage pressure, and the oxygenator pressure drop] were evaluated. RESULTS: The increase of the pump flow from 0.25 to 0.5 L/min or from 0.6 to 0.8 L/min required significantly higher RPM and produced significantly higher pump pressures [from 0.25 to 0.5 L/min: 1470 (1253-1569) versus 2652 (2589-2750) RPM and 40 (26-57) versus 125 (113-139) mmHg, respectively; p < .0001 for both - from 0.60 to 0.8 L/min: 1950 (1901-2271) versus 2428 (2400-2518) RPM and 66 (62-86) versus 106 (101-113) mmHg, respectively; p < .0001 for both]. Median drainage pressure significantly decreased from -18 (-22; -16) mmHg to -55 (-63; -48) mmHg when the pump flow was increased from 0.25 to 0.5 L/min (p < .0001). When pump flow increased from 0.6 to 0.8 L/min, drainage pressure decreased from -32 (-39; -24) mmHg to -50 (-52; -43) mmHg, (p < .0001). Compared to pre-ECMO values, the median levels of lactate dehydrogenase, d-dimer, hematocrit, and platelet count decreased after ECMO start at all flow rates, probably due to hemodilution. Plasma-free hemoglobin, instead, showed a modest increase compared to pre-ECMO values during all experiments at different pump flow rates. However, these changes were not clinically relevant. CONCLUSIONS: In this animal study, the "New Born ECMOLife" centrifugal pump showed good hemodynamic performance. Long-term studies are needed to evaluate biocompatibility of this new ECMO pump.

Angiotensin 1-7 in an experimental septic shock model.

BACKGROUND: Alterations in the renin-angiotensin system have been implicated in the pathophysiology of septic shock. In particular, angiotensin 1-7 (Ang-(1-7)), an anti-inflammatory heptapeptide, has been hypothesized to have beneficial effects. The aim of the present study was to test the effects of Ang-(1-7) infusion on the development and severity of septic shock. METHODS: This randomized, open-label, controlled study was performed in 14 anesthetized and mechanically ventilated sheep. Immediately after sepsis induction by bacterial peritonitis, animals received either Ang-(1-7) (n = 7) or placebo (n = 7) intravenously. Fluid resuscitation, antimicrobial therapy, and peritoneal lavage were initiated 4 h after sepsis induction. Norepinephrine administration was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg. RESULTS: There were no differences in baseline characteristics between groups. Septic shock was prevented in 6 of the 7 animals in the Ang-(1-7) group at the end of the 24-h period. Fluid balance and MAP were similar in the two groups; however, MAP was achieved with a mean norepinephrine dose of 0.4 µg/kg/min in the Ang-(1-7) group compared to 4.3 µg/kg/min in the control group. Heart rate and cardiac output index were lower in the Ang (1-7) than in the control group, as were plasma interleukin-6 levels, and creatinine levels. Platelet count and PaO2/FiO2 ratio were higher in the Ang-(1-7) group. Mean arterial lactate at the end of the experiment was 1.6 mmol/L in the Ang-(1-7) group compared to 7.4 mmol/L in the control group. CONCLUSIONS: In this experimental septic shock model, early Ang-(1-7) infusion prevented the development of septic shock, reduced norepinephrine requirements, limited interleukine-6 increase and prevented renal dysfunction.

The use of induced hypothermia in extracorporeal membrane oxygenation: A narrative review.

Despite venovenous or venoarterial extracorporeal membrane oxygenation (ECMO) being increasingly used in patients with severe acute respiratory disease syndrome, severe cardiogenic shock, and refractory cardiac arrest, mortality rates still remain high mainly because of the severity of the underlying disease and the numerous complications associated with initiation of ECMO. Induced hypothermia might minimize several pathological pathways present in patients requiring ECMO; even though numerous studies conducted in the experimental setting have reported promising results, there are currently no recommendations suggesting the routine use of this therapy in patients requiring ECMO. In this review, we summarized the existing evidence on the use of induced hypothermia in patients requiring ECMO. Induced hypothermia was a feasible and relatively safe intervention in this setting; however, the effects on clinical outcomes remain uncertain. Whether controlled normothermia has an impact on these patients compared with no temperature control remains unknown. Further randomized controlled trials are required to better understand the role and impact of such therapy in patients requiring ECMO according to the underlying disease.

Effects of Preconditioning on RBC Deformability in Critically Ill Patients.

RBCs from critically ill patients have depressed deformability, especially in sepsis. Prolonged exposure of RBCs from healthy volunteers to physiologic shear stress (the preconditioning technique) has been associated with improved deformability, but the effect of preconditioning on RBCs from critically ill patients with or without sepsis has never been studied. DESIGN: Prospective study. SETTING: A 32-bed medico-surgical ICU and a university-affiliated cell biology laboratory. SUBJECTS: RBCs from 26 healthy volunteers and 40 critically ill patients (20 with and 20 without sepsis). INTERVENTIONS: RBC deformability was measured using the elongation index (EI) with an ektacytometer, at shear stress levels ranging from 0.3 to 50 Pa. To assess the effects of preconditioning in the three groups, we measured EI after first applying a shear stress of 5 Pa for 300 seconds. To study the potential mechanisms involved in preconditioning, we looked at deformability after incubation of an RBC solution from the healthy volunteers with glutaraldehyde, a membrane-stabilizing protein, and neuraminidase, an enzyme that releases membrane sialic acid. MEASUREMENTS AND MAIN RESULTS: Baseline RBC deformability was significantly depressed in the septic patients compared with the volunteers at all shear stress levels greater than or equal to 4.89 Pa. Preconditioning improved deformability only in the volunteers (at shear stress levels of 0.48 and 0.76 Pa). Among the critically ill patients, preconditioning worsened RBC deformability at higher shear stress levels. After incubation (with glutaraldehyde or neuraminidase) of RBCs from five volunteers in whom preconditioning had significantly improved deformability, the positive effect of preconditioning was lost with glutaraldehyde. CONCLUSIONS: RBC deformability is depressed in septic patients. There was a deleterious effect of preconditioning on RBC deformability in septic patients, unlike the positive effect on RBCs from healthy volunteers. The effect of preconditioning may be associated with elasticity of the cell membrane.

Soluble ST2 is increased in systemic lupus erythematous and is a potential marker of lupus nephritis.

OBJECTIVES: To investigate the role of the interleukin IL-33/ST2 axis in systemic lupus erythematosus (SLE). METHODS: Serum concentrations of IL-33 and sST2 were measured by sandwich ELISA in SLE patients (n=111) compared to sex- and age-matched healthy controls (n=36). The serum concentrations of IL-33 and sST2 were correlated with various clinical and biological parameters. The expressions of IL-33 and ST2L were investigated in kidney sections by immunohistochemistry in lupus nephritis patients (n=23) and controls (n=10). RESULTS: Serum levels of IL-33 were significantly higher in SLE patients (11.64±3.141 pg/mL) than in controls (1.043±0.8526 pg/mL) (p<0.0001). Similarly, the serum concentrations of sST2 were significantly higher in SLE patients (34.013±2.043 pg/mL) than in controls (25.278±2.258 pg/mL) (p=0.046). sST2, but not IL-33, correlated significantly with disease activity index (SLEDAI). In addition, serum levels of sST2 were significantly higher in patients with lupus nephritis (45.438±5.661 pg/mL) that in SLE patients without renal involvement (30.691±1.941 pg/mL) (p=0.016). The immunoreactivity of IL-33 in renal biopsies of patients with lupus nephritis was not increased compared to controls, while the glomerular expression of ST2L was significantly higher in nephritis patients compared to controls. CONCLUSIONS: Although IL-33 and sST2 levels are both increased in SLE, sST2 represents a surrogate marker of disease activity and complications of nephritis.

Interleukine-6 in critically ill COVID-19 patients: A retrospective analysis.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) appeared in China in December 2019 and has spread around the world. High Interleukin-6 (IL-6) levels in COVID-19 patients suggest that a cytokine storm may play a major role in the pathophysiology and are considered as a relevant parameter in predicting most severe course of disease. The aim of this study was to assess repeated IL-6 levels in critically ill COVID-19 patients admitted to our Intensive Care Unit (ICU) and to evaluate their relationship with patient's severity and outcome. METHODS: We conducted a retrospective study on patients admitted to the ICU with a diagnosis of COVID-19 between March 10 (i.e. the date of the first admitted patients) and April 30, 2020. Demographic, clinical and laboratory data were collected at admission. On the day of IL-6 blood concentration measurement, we also collected results of D-Dimers, C-Reactive Protein, white blood cells and lymphocytes count, lactate dehydrogenase (LDH) and ferritin as well as microbiological samples, whenever present. RESULTS: Of a total of 65 patients with COVID-19 admitted to our ICU we included 41 patients with repeated measure of IL-6. There was a significant difference in IL-6 levels between survivors and non-survivors over time (p = 0.001); moreover, non survivors had a significantly higher IL-6 maximal value when compared to survivors (720 [349-2116] vs. 336 [195-646] pg/mL, p = 0.01). The IL-6 maximal value had a significant predictive value of ICU mortality (AUROC 0.73 [95% CI 0.57-0.89]; p = 0.01). CONCLUSIONS: Repeated measurements of IL-6 can help clinicians in identifying critically ill COVID-19 patients with the highest risk of poor prognosis.