Inhibition of circulating dipeptidyl-peptidase 3 by procizumab in experimental septic shock reduces catecholamine exposure and myocardial injury.

BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock. METHODS: In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65-75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (99mtechnetium albumin). cDPP3 activity, equilibrium analysis of the renin-angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples. RESULTS: PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO2/FiO2 ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression. CONCLUSIONS: In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.

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.

NHH promotes Sepsis-associated Encephalopathy with the expression of AQP4 in astrocytes through the gut-brain Axis.

Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.

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.

The impact of the new acute respiratory distress syndrome (ARDS) criteria on Berlin criteria ARDS patients: a multicenter cohort study.

OBJECTIVE: The European Society of Intensive Care Medicine (ESICM) recently recommended changes to the criteria of acute respiratory distress syndrome (ARDS), patients with high-flow oxygen were included, however, the effect of these changes remains unclear. Our objectives were to evaluate the performance of these new criteria and to compare the outcomes of patients meeting the new ARDS criteria with those meeting the Berlin ARDS criteria. METHODS: This was a retrospective cohort. The patients admitted to the intensive care unit (ICU) were diagnosed with ARDS. Patients were classified as meeting Berlin criteria ARDS (n = 4279), high-flow nasal oxygen (HFNO) criteria ARDS (n = 559), or new criteria ARDS (n = 4838). RESULTS: In comparison with HFNO criteria ARDS and new criteria ARDS, patients with Berlin criteria ARDS demonstrated lower blood oxygen levels assessed by PaO2/FiO2, SpO2/FiO2, and ROX (SpO2/FiO2/respiratory rate) (p < 0.001); and higher severity of illness assessed by the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology And Chronic Health Evaluations (APACHE II), Simplified Acute Physiology Score (SAPS II) (p < 0.001), (p < 0.001), and longer ICU and hospital stays (p < 0.001). In comparison with the HFNO criteria, patients meeting Berlin criteria ARDS had higher hospital mortality (10.6% vs. 16.9%; p = 0.0082), 28-day mortality (10.6% vs. 16.5%; p = 0.0079), and 90-day mortality (10.7% vs. 17.1%; p = 0.0083). ARDS patients with HFNO did not have severe ARDS; Berlin criteria ARDS patients with severe ARDS had the highest mortality rate (approximately 33%). PaO2/FiO2, SpO2/FiO2, and ROX negatively correlated with the SOFA and APACHE II scores. The SOFA and APACHE II scores had high specificity and sensitivity for prognosis in patients with new criteria ARDS. CONCLUSION: The new criteria of ARDS reduced the severity of illness, length of stay in the ICU, length of hospital stays, and overall mortality. SOFA and APACHE II scores remain important in assessing the prognosis of patients with new criteria ARDS. TRIAL REGISTRATION: Registration number: ChiCTR2200067084.

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.

Pulse wave analysis as a tool for the evaluation of resuscitation therapy in septic shock.

Objective. Pulse wave analysis (PWA) can provide insights into cardiovascular biomechanical properties. The use of PWA in critically ill patients, such as septic shock patients, is still limited, but it can provide complementary information on the cardiovascular effects of treatment when compared to standard indices outlined in international guidelines. Previous works have highlighted how sepsis induces severe cardiovascular derangement with altered arterial blood pressure waveform morphology and how resuscitation according to standard haemodynamic targets is not able to restore the physiological functioning of the cardiovascular system. The aim of this work is to test the effectiveness of PWA in characterizing arterial waveforms obtained from a swine experiment involving polymicrobial septic shock and resuscitation with different drugs.Methods. During the experiment, morphological aortic waveform features, such as indices related to the dicrotic notch and inflection point, were extracted by means of PWA techniques. Finally, all the PWA indices were used to compute a clustering classification (mini batch K-means) of the pigs according to the different phases of the experiment. This analysis aimed to test if PWA features alone could be used to distinguish between the different responses to the administered therapies.Results. The PWA indices highlighted different cardiovascular conditions of the pigs in response to different treatments, despite the mean haemodynamic values typically used to guide therapy administration being similar in all animals. The clustering algorithm was able to distinguish between the different phases of the experiment and the different responses of the animals based on the unique information derived from the aortic PWA.Conclusion. Even when used alone, PWA indices were highly informative when assessing therapy responses in cases of septic shock.Significance. A complex pathological condition like septic shock requires extensive monitoring without neglecting important information from commonly measured signals such as arterial blood pressure. Future studies are needed to understand how individual differences in the response to therapy are associated with different cardiovascular conditions that may become specific therapy targets.

Hypertonic sodium lactate infusion reduces vasopressor requirements and biomarkers of brain and cardiac injury after experimental cardiac arrest.

INTRODUCTION: Prognosis after resuscitation from cardiac arrest (CA) remains poor, with high morbidity and mortality as a result of extensive cardiac and brain injury and lack of effective treatments. Hypertonic sodium lactate (HSL) may be beneficial after CA by buffering severe metabolic acidosis, increasing brain perfusion and cardiac performance, reducing cerebral swelling, and serving as an alternative energetic cellular substrate. The aim of this study was to test the effects of HSL infusion on brain and cardiac injury in an experimental model of CA. METHODS: After a 10-min electrically induced CA followed by 5 min of cardiopulmonary resuscitation maneuvers, adult swine (n = 35) were randomly assigned to receive either balanced crystalloid (controls, n = 11) or HSL infusion started during cardiopulmonary resuscitation (CPR, Intra-arrest, n = 12) or after return of spontaneous circulation (Post-ROSC, n = 11) for the subsequent 12 h. In all animals, extensive multimodal neurological and cardiovascular monitoring was implemented. All animals were treated with targeted temperature management at 34 °C. RESULTS: Thirty-four of the 35 (97.1%) animals achieved ROSC; one animal in the Intra-arrest group died before completing the observation period. Arterial pH, lactate and sodium concentrations, and plasma osmolarity were higher in HSL-treated animals than in controls (p < 0.001), whereas potassium concentrations were lower (p = 0.004). Intra-arrest and Post-ROSC HSL infusion improved hemodynamic status compared to controls, as shown by reduced vasopressor requirements to maintain a mean arterial pressure target > 65 mmHg (p = 0.005 for interaction; p = 0.01 for groups). Moreover, plasma troponin I and glial fibrillary acid protein (GFAP) concentrations were lower in HSL-treated groups at several time-points than in controls. CONCLUSIONS: In this experimental CA model, HSL infusion was associated with reduced vasopressor requirements and decreased plasma concentrations of measured biomarkers of cardiac and cerebral injury.

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.

The Effects of Temperature Management on Brain Microcirculation, Oxygenation and Metabolism.

PURPOSE: Target temperature management (TTM) is often used in patients after cardiac arrest, but the effects of cooling on cerebral microcirculation, oxygenation and metabolism are poorly understood. We studied the time course of these variables in a healthy swine model. METHODS: Fifteen invasively monitored, mechanically ventilated pigs were allocated to sham procedure (normothermia, NT; n = 5), cooling (hypothermia, HT, n = 5) or cooling with controlled oxygenation (HT-Oxy, n = 5). Cooling was induced by cold intravenous saline infusion, ice packs and nasal cooling to achieve a body temperature of 33-35 °C. After 6 h, animals were rewarmed to baseline temperature (within 5 h). The cerebral microvascular network was evaluated (at baseline and 2, 7 and 12 h thereafter) using sidestream dark-field (SDF) video-microscopy. Cerebral blood flow (laser Doppler MNP100XP, Oxyflow, Oxford Optronix, Oxford, UK), oxygenation (PbtO2, Licox catheter, Integra Lifesciences, USA) and lactate/pyruvate ratio (LPR) using brain microdialysis (CMA, Stockholm, Sweden) were measured hourly. RESULTS: In HT animals, cerebral functional capillary density (FCD) and proportion of small-perfused vessels (PSPV) significantly decreased over time during the cooling phase; concomitantly, PbtO2 increased and LPR decreased. After rewarming, all microcirculatory variables returned to normal values, except LPR, which increased during the rewarming phase in the two groups subjected to HT when compared to the group maintained at normothermia. CONCLUSIONS: In healthy animals, TTM can be associated with alterations in cerebral microcirculation during cooling and altered metabolism at rewarming.

Myocardial effects of angiotensin II compared to norepinephrine in an animal model of septic shock.

BACKGROUND: Angiotensin II is one of the vasopressors available for use in septic shock. However, its effects on the septic myocardium remain unclear. The aim of the study was to compare the effects of angiotensin II and norepinephrine on cardiac function and myocardial oxygen consumption, inflammation and injury in experimental septic shock. METHODS: This randomized, open-label, controlled study was performed in 20 anesthetized and mechanically ventilated pigs. Septic shock was induced by fecal peritonitis in 16 animals, and four pigs served as shams. Resuscitation with fluids, antimicrobial therapy and abdominal drainage was initiated one hour after the onset of septic shock. Septic pigs were randomly allocated to receive one of the two drugs to maintain mean arterial pressure between 65 and 75 mmHg for 8 h. RESULTS: There were no differences in MAP, cardiac output, heart rate, fluid balance or tissue perfusion indices in the two treatment groups but myocardial oxygen consumption was greater in the norepinephrine-treated animals. Myocardial mRNA expression of interleukin-6, interleukin-6 receptor, interleukin-1 alpha, and interleukin-1 beta was higher in the norepinephrine than in the angiotensin II group. CONCLUSIONS: In septic shock, angiotensin II administration is associated with a similar level of cardiovascular resuscitation and less myocardial oxygen consumption, and inflammation compared to norepinephrine.

Sepsis modulates cortical excitability and alters the local and systemic hemodynamic response to seizures.

Non-convulsive seizures and status epilepticus are frequent and associated with increased mortality in septic patients. However, the mechanism through which seizures impact outcome in these patients is unclear. As previous studies yielded an alteration of neurovascular coupling (NVC) during sepsis, we hypothesized that non-convulsive seizures, might further impair NVC, leading to brain tissue hypoxia. We used a previously developed ovine model of sepsis. Animals were allocated to sham procedure or sepsis; septic animals were studied either during the hyperdynamic phase (sepsis group) or after septic shock occurrence (septic shock group). After allocation, seizures were induced by cortical application of penicillin. We recorded a greater seizure-induced increase in the EEG gamma power in the sepsis group than in sham. Using a neural mass model, we also found that the theoretical activity of the modeled inhibitory interneurons, thought to be important to reproduce gamma oscillations, were relatively greater in the sepsis group. However, the NVC was impaired in sepsis animals, despite a normal brain tissue oxygenation. In septic shock animals, it was not possible to induce seizures. Cortical activity declined in case of septic shock, but it did not differ between sham or sepsis animals. As the alteration in NVC preceded cortical activity reduction, we suggest that, during sepsis progression, the NVC inefficiency could be partially responsible for the alteration of brain function, which might prevent seizure occurrence during septic shock. Moreover, we showed that cardiac output decreased during seizures in sepsis animals instead of increasing as in shams. The alteration of the seizure-induced systemic hemodynamic variations in sepsis might further affect cerebrovascular response to neuronal activation. Our findings support the hypothesis that anomalies in the cerebral blood flow regulation may contribute to the sepsis-associated encephalopathy and that seizures might be dangerous in such a vulnerable setting.

Effects of Reversal of Hypotension on Cerebral Microcirculation and Metabolism in Experimental Sepsis.

The effects of reversal of hypotension on the cerebral microcirculation, oxygenation, and metabolism in septic shock remain unclear. In 12 sheep, peritonitis was induced by injection of feces into the abdominal cavity. At the onset of septic shock (mean arterial pressure (MAP) < 65 mmHg, unresponsive to fluid challenge), a norepinephrine infusion was titrated in eight sheep to restore a MAP ≥ 75 mmHg; the other four sheep were kept hypotensive. The microcirculation of the cerebral cortex was evaluated using side-stream dark-field video-microscopy. Brain partial pressure of oxygen (PbtO2) was measured, and cerebral metabolism was assessed using microdialysis. All animals developed septic shock after a median of 15 (14−19) h. When MAP was raised using norepinephrine, the PbtO2 increased significantly (from 41 ± 4 to 55 ± 5 mmHg), and the cerebral lactate/pyruvate ratio decreased (from 47 ± 13 to 28 ± 4) compared with values at shock onset. Changes in the microcirculation were unchanged with restoration of MAP and the glutamate increased further (from 17 ± 11 to 23 ± 16 µM), as it did in the untreated animals. In septic shock, the correction of hypotension with vasopressors may improve cerebral oxygenation but does not reverse the alterations in brain microcirculation or cerebral metabolism.

A comprehensive neuromonitoring approach in a large animal model of cardiac arrest.

BACKGROUND: Anoxic brain injuries represent the main determinant of poor outcome after cardiac arrest (CA). Large animal models have been described to investigate new treatments during CA and post-resuscitation phase, but a detailed model that includes extensive neuromonitoring is lacking. METHOD: Before an electrically-induced 10-minute CA and resuscitation, 46 adult pigs underwent neurosurgery for placement of a multifunctional probe (intracranial pressure or ICP, tissue oxygen tension or PbtO2 and cerebral temperature) and a bolt-based technique for the placement and securing of a regional blood flow probe and two sEEG electrodes; two modified cerebral microdialysis (CMD) probes were also inserted in the frontal lobes and accidental misplacement was prevented using a perforated head support. RESULT: 42 animals underwent the CA procedure and 41 achieved the return of spontaneous circulation (ROSC). In 4 cases (8.6%) an adverse event took place during preparation, but only in two cases (4.3%) this was related to the neurosurgery. In 6 animals (13.3%) the minor complications that occurred resolved after probe repositioning. CONCLUSION: Herein we provide a detailed comprehensive neuromonitoring approach in a large animal model of CA that might help future research.

Early Hyperdynamic Sepsis Alters Coronary Blood Flow Regulation in Porcine Fecal Peritonitis.

Background: Sepsis is a common condition known to impair blood flow regulation and microcirculation, which can ultimately lead to organ dysfunction but such contribution of the coronary circulation remains to be clarified. We investigated coronary blood flow regulatory mechanisms, including autoregulation, metabolic regulation, and endothelial vasodilatory response, in an experimental porcine model of early hyperdynamic sepsis. Methods: Fourteen pigs were randomized to sham (n = 7) or fecal peritonitis-induced sepsis (n = 7) procedures. At baseline, 6 and 12 h after peritonitis induction, the animals underwent general and coronary hemodynamic evaluation, including determination of autoregulatory breakpoint pressure and adenosine-induced maximal coronary vasodilation for coronary flow reserve and hyperemic microvascular resistance calculation. Endothelial-derived vasodilatory response was assessed both in vivo and ex vivo using bradykinin. Coronary arteries were sampled for pathobiological evaluation. Results: Sepsis resulted in a right shift of the autoregulatory breakpoint pressure, decreased coronary blood flow reserve and increased hyperemic microvascular resistance from the 6th h after peritonitis induction. In vivo and ex vivo endothelial vasomotor function was preserved. Sepsis increased coronary arteries expressions of nitric oxide synthases, prostaglandin I2 receptor, and prostaglandin F2α receptor. Conclusion: Autoregulation and metabolic blood flow regulation were both impaired in the coronary circulation during experimental hyperdynamic sepsis, although endothelial vasodilatory response was preserved.

Cerebral and systemic hemodynamic effect of recurring seizures.

The increase in neuronal activity induced by a single seizure is supported by a rise in the cerebral blood flow and tissue oxygenation, a mechanism called neurovascular coupling (NVC). Whether cerebral and systemic hemodynamics are able to match neuronal activity during recurring seizures is unclear, as data from rodent models are at odds with human studies. In order to clarify this issue, we used an invasive brain and systemic monitoring to study the effects of chemically induced non-convulsive seizures in sheep. Despite an increase in neuronal activity as seizures repeat (Spearman's ρ coefficient 0.31, P < 0.001), ictal variations of cerebral blood flow remained stable while it progressively increased in the inter-ictal intervals (ρ = 0.06, P = 0.44 and ρ = 0.22; P = 0.008). We also observed a progressive reduction in the inter-ictal brain tissue oxygenation (ρ = - 0.18; P = 0.04), suggesting that NVC was unable to compensate for the metabolic demand of these closely repeating seizures. At the systemic level, there was a progressive reduction in blood pressure and a progressive rise in cardiac output (ρ = - 0.22; P = 0.01 and ρ = 0.22; P = 0.01, respectively), suggesting seizure-induced autonomic dysfunction.

Quantification of Cardiac Kinetic Energy and Its Changes During Transmural Myocardial Infarction Assessed by Multi-Dimensional Seismocardiography.

Introduction: Seismocardiography (SCG) records cardiac and blood-induced motions transmitted to the chest surface as vibratory phenomena. Evidences demonstrate that acute myocardial ischemia (AMI) profoundly affects the SCG signals. Multidimensional SCG records cardiac vibrations in linear and rotational dimensions, and scalar parameters of kinetic energy can be computed. We speculate that AMI and revascularization profoundly modify cardiac kinetic energy as recorded by SCG. Methods: Under general anesthesia, 21 swine underwent 90 min of myocardial ischemia induced by percutaneous sub-occlusion of the proximal left anterior descending (LAD) coronary artery and subsequent revascularization. Invasive hemodynamic parameters were continuously recorded. SCG was recorded during baseline, immediately and 80 min after LAD sub-occlusion, and immediately and 60 min after LAD reperfusion. iK was automatically computed for each cardiac cycle (iK CC ) in linear (iK Lin ) and rotational (iK Rot ) dimensions. iK was calculated as well during systole and diastole (iK Sys and iK Dia , respectively). Echocardiography was performed at baseline and after revascularization, and the left ventricle ejection fraction (LVEF) along with regional left ventricle (LV) wall abnormalities were evaluated. Results: Upon LAD sub-occlusion, 77% of STEMI and 24% of NSTEMI were observed. Compared to baseline, troponins increased from 13.0 (6.5; 21.3) ng/dl to 170.5 (102.5; 475.0) ng/dl, and LVEF dropped from 65.0 ± 0.0 to 30.6 ± 5.7% at the end of revascularization (both p < 0.0001). Regional LV wall abnormalities were observed as follows: anterior MI, 17.6% (three out of 17); septal MI, 5.8% (one out of 17); antero-septal MI, 47.1% (eight out of 17); and infero-septal MI, 29.4% (five out of 17). In the linear dimension, i K L i n C C , i K L i n S y s , and i K L i n D i a dropped by 43, 52, and 53%, respectively (p < 0.0001, p < 0.0001, and p = 0.03, respectively) from baseline to the end of reperfusion. In the rotational dimension, i K R o t C C and i K R o t S y s dropped by 30 and 36%, respectively (p = 0.0006 and p < 0.0001, respectively), but i K R o t D i a did not change (p = 0.41). All the hemodynamic parameters, except the pulmonary artery pulse pressure, were significantly correlated with the parameters of iK, except for the diastolic component. Conclusions: In this very context of experimental AMI with acute LV regional dysfunction and no concomitant AMI-related heart valve disease, linear and rotational iK parameters, in particular, systolic ones, provide reliable information on LV contractile dysfunction and its effects on the downstream circulation. Multidimensional SCG may provide information on the cardiac contractile status expressed in terms of iK during AMI and reperfusion. This automatic system may empower health care providers and patients to remotely monitor cardiovascular status in the near future.

Evaluation of a New Extracorporeal CO2 Removal Device in an Experimental Setting.

BACKGROUND: Ultra-protective lung ventilation in acute respiratory distress syndrome or early weaning and/or avoidance of mechanical ventilation in decompensated chronic obstructive pulmonary disease may be facilitated by the use of extracorporeal CO2 removal (ECCO2R). We tested the CO2 removal performance of a new ECCO2R (CO2RESET) device in an experimental animal model. METHODS: Three healthy pigs were mechanically ventilated and connected to the CO2RESET device (surface area = 1.8 m2, EUROSETS S.r.l., Medolla, Italy). Respiratory settings were adjusted to induce respiratory acidosis with the adjunct of an external source of pure CO2 (target pre membrane lung venous PCO2 (PpreCO2): 80-120 mmHg). The amount of CO2 removed (VCO2, mL/min) by the membrane lung was assessed directly by the ECCO2R device. RESULTS: Before the initiation of ECCO2R, the median PpreCO2 was 102.50 (95.30-118.20) mmHg. Using fixed incremental steps of the sweep gas flow and maintaining a fixed blood flow of 600 mL/min, VCO2 progressively increased from 0 mL/min (gas flow of 0 mL/min) to 170.00 (160.00-200.00) mL/min at a gas flow of 10 L/min. In particular, a high increase of VCO2 was observed increasing the gas flow from 0 to 2 L/min, then, VCO2 tended to progressively achieve a steady-state for higher gas flows. No animal or pump complications were observed. CONCLUSIONS: Medium-flow ECCO2R devices with a blood flow of 600 mL/min and a high surface membrane lung (1.8 m2) provided a high VCO2 using moderate sweep gas flows (i.e., >2 L/min) in an experimental swine models with healthy lungs.

Cerebral autoregulation and neurovascular coupling are progressively impaired during septic shock: an experimental study.

BACKGROUND: Alteration of the mechanisms of cerebral blood flow (CBF) regulation might contribute to the pathophysiology of sepsis-associated encephalopathy (SAE). However, previous clinical studies on dynamic cerebral autoregulation (dCA) in sepsis had several cofounders. Furthermore, little is known on the potential impairment of neurovascular coupling (NVC) in sepsis. The aim of our study was to determine the presence and time course of dCA and NVC alterations in a clinically relevant animal model and their potential impact on the development of SAE. METHODS: Thirty-six anesthetized, mechanically ventilated female sheep were randomized to sham procedures (sham, n = 15), sepsis (n = 14), or septic shock (n = 7). Blood pressure, CBF, and electrocorticography were continuously recorded. Pearson's correlation coefficient Lxa and transfer function analysis were used to estimate dCA. NVC was assessed by the analysis of CBF variations induced by cortical gamma activity (Eγ) peaks and by the magnitude-squared coherence (MSC) between the spontaneous fluctuations of CBF and Eγ. Cortical function was estimated by the alpha-delta ratio. Wilcoxon signed rank and rank sum tests, Friedman tests, and RMANOVA test were used as appropriate. RESULTS: Sepsis and sham animals did not differ neither in dCA nor in NVC parameters. A significant impairment of dCA occurred only after septic shock (Lxa, p = 0.03, TFA gain p = 0.03, phase p = 0.01). Similarly, NVC was altered during septic shock, as indicated by a lower MSC in the frequency band 0.03-0.06 Hz (p < 0.001). dCA and NVC impairments were associated with cortical dysfunction (reduction in the alpha-delta ratio (p = 0.03)). CONCLUSIONS: A progressive loss of dCA and NVC occurs during septic shock and is associated with cortical dysfunction. These findings indicate that the alteration of mechanisms controlling cortical perfusion plays a late role in the pathophysiology of SAE and suggest that alterations of CBF regulation mechanisms in less severe phases of sepsis reported in clinical studies might be due to patients' comorbidities or other confounders. Furthermore, a mean arterial pressure targeting therapy aiming to optimize dCA might not be sufficient to prevent neuronal dysfunction in sepsis since it would not improve NVC.