Infusion of sodium DL-3-ß-hydroxybutyrate decreases cerebral injury biomarkers after resuscitation in experimental cardiac arrest.

AIMS: Cerebral complications after cardiac arrest (CA) remain a major problem worldwide. The aim was to test the effects of sodium-ß-hydroxybutyrate (SBHB) infusion on brain injury in a clinically relevant swine model of CA. RESULTS: CA was electrically induced in 20 adult swine. After 10 min, cardiopulmonary resuscitation was performed for 5 min. After return of spontaneous circulation (ROSC), the animals were randomly assigned to receive an infusion of balanced crystalloid (controls, n = 11) or SBHB (theoretical osmolarity 1189 mOsm/l, n = 8) for 12 h. Multimodal neurological and cardiovascular monitoring were implemented in all animals. Nineteen of the 20 animals achieved ROSC. Blood sodium concentrations, osmolarity and circulating KBs were higher in the treated animals than in the controls. SBHB infusion was associated with significantly lower plasma biomarkers of brain injury at 6 (glial fibrillary acid protein, GFAP and neuron specific enolase, NSE) and 12 h (neurofilament light chain, NFL, GFAP and NSE) compared to controls. The amplitude of the stereoelectroencephalograph (sEEG) increased in treated animals after ROSC compared to controls. Cerebral glucose uptake was lower in treated animals. CONCLUSIONS: In this experimental model, SBHB infusion after resuscitated CA was associated with reduced circulating markers of cerebral injury and increased sEEG amplitude.

The Sublingual Microcirculation in Critically Ill Children with Septic Shock Undergoing Hemoadsorption: A Pilot Study.

Background: The importance of perfusion-guided resuscitation in septic shock has recently emerged. We explored whether the use of hemoadsorption led to a potential beneficial role in microvascular alterations in this clinical setting. Methods: A pre-planned secondary analysis of a Phase-II interventional single-arm pilot study (NCT05658588) was carried out, where 17 consecutive septic shock children admitted into PICU were treated with continuous renal replacement therapy (CRRT) and CytoSorb. Thirteen patients were eligible to be investigated with sublingual microcirculation at baseline, 24, 48, 72 and 96 h from the onset of blood purification. Patients achieving a microvascular flow index (MFI) ≥ 2.5 and/or proportion of perfused vessels (PPV) exceeding 90% by 96 h were defined as responders. Results: In 10/13 (77%), there was a significant improvement in MFIs (p = 0.01) and PPVs% (p = 0.04) between baseline and 24 h from the end of treatment. Eight patients displayed a high heterogenicity index (HI > 0.5) during blood purification and among these, five showed an improvement by the end of treatment (HI < 0.5). Conclusions: In this pilot study, we have found a potential association between CytoSorb hemoadsorption and a microcirculation improvement in pediatric patients with septic shock, particularly when this observation has been associated with hemodynamic improvement.

Altered Microvascular Reactivity During a Skin Thermal Challenge Is Associated With Organ Dysfunction and Slow Recovery After Cardiac Surgery.

OBJECTIVES: To assess microvascular reactivity during a skin thermal challenge early post-cardiac surgery and its association with outcomes. DESIGN: Noninvasive physiological study. SETTING: Thirty-five-bed department of intensive care. PARTICIPANTS: Patients admitted to the intensive care unit post-cardiac surgery. INTERVENTIONS: Thermal challenge. MEASUREMENTS AND MAIN RESULTS: A total of 46 patients were included; 14 needed vasoactive or ventilatory support for at least 48 hours (slow recovery), and 32 had a more rapid recovery. Skin blood flow (SBF) was measured on the anterior proximal forearm using skin laser Doppler. A thermal challenge was performed by abruptly increasing local skin temperature from 37°C to 43°C while monitoring SBF. The ratio between SBFs at 43°C and 37°C was calculated to measure microvascular reactivity. SBF at 37°C was not significantly different in patients with a slow recovery and those with a rapid recovery, but SBF after 9 minutes at 43°C was lower (48.5 [17.3-69.0] v 85.1 [45.2-125.7], p < 0.01), resulting in a lower SBF ratio (2.8 [1.5-4.7] v 4.8 [3.7-7.8], p < 0.01). Patients with lower SBF ratios were more likely to have dysfunction of at least one organ (assessed using the sequential organ dysfunction score) 48 hours post-cardiac surgery than those with higher ratios: 88% versus 40% versus 27% (p < 0.01), respectively, for the lowest, middle, and highest tertiles of SBF ratio. In multivariable analysis, a lower SBF ratio was an independent risk factor for slow recovery. CONCLUSIONS: Early alterations in microvascular reactivity, evaluated by a skin thermal challenge, are correlated with organ dysfunction. These observations may help in the development of new, simple, noninvasive monitoring systems in postoperative patients.

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.

Incoherence between systemic and skin tissue response to transfusion in volume-resuscitated patients withoutacute bleeding.

Alterations in skin blood flow (SBF) may help to detect occult hypoperfusion in critically ill patients after fluid resuscitation. In this study, SBF is globally unaltered by red blood cell transfusion (RBCT) in non-bleeding critically ill patients after initial resuscitation; however, 37.5% of patients showed a significant increase in SBF. No correlation between relative changes in SBF and systemic variables after RBCT was observed.

Delayed Deterioration of Electroencephalogram in Patients with Cardiac Arrest: A Cohort Study.

BACKGROUND: The aim of this study was to assess the prevalence of delayed deterioration of electroencephalogram (EEG) in patients with cardiac arrest (CA) without early highly malignant patterns and to determine their associations with clinical findings. METHODS: This was a retrospective study of adult patients with CA admitted to the intensive care unit (ICU) of a university hospital. We included all patients with CA who had a normal voltage EEG, no more than 10% discontinuity, and absence of sporadic epileptic discharges, periodic discharges, or electrographic seizures. Delayed deterioration was classified as the following: (1) epileptic deterioration, defined as the appearance, at least 24 h after CA, of sporadic epileptic discharges, periodic discharges, and status epilepticus; or (2) background deterioration, defined as increasing discontinuity or progressive attenuation of the background at least 24 h after CA. The end points were the incidence of EEG deteriorations and their association with clinical features and ICU mortality. RESULTS: We enrolled 188 patients in the analysis. The ICU mortality was 46%. Overall, 30 (16%) patients presented with epileptic deterioration and 9 (5%) patients presented with background deterioration; of those, two patients presented both deteriorations. Patients with epileptic deterioration more frequently had an out-of-hospital CA, and higher time to return of spontaneous circulation and less frequently had bystander resuscitation than others. Patients with background deterioration showed a predominantly noncardiac cause, more frequently developed shock, and had multiple organ failure compared with others. Patients with epileptic deterioration presented with a higher ICU mortality (77% vs. 41%; p < 0.01) than others, whereas all patients with background deterioration died in the ICU. CONCLUSIONS: Delayed EEG deterioration was associated with high mortality rate. Epileptic deterioration was associated with worse characteristics of CA, whereas background deterioration was associated with shock and multiple organ failure.

Estimated Cerebral Perfusion Pressure and Intracranial Pressure in Septic Patients.

BACKGROUND: Sepsis-associated brain dysfunction (SABD) is frequent and is associated with poor outcome. Changes in brain hemodynamics remain poorly described in this setting. The aim of this study was to investigate the alterations of cerebral perfusion pressure and intracranial pressure in a cohort of septic patients. METHODS: We conducted a retrospective analysis of prospectively collected data in septic adults admitted to our intensive care unit (ICU). We included patients in whom transcranial Doppler recording performed within 48 h from diagnosis of sepsis was available. Exclusion criteria were intracranial disease, known vascular stenosis, cardiac arrhythmias, pacemaker, mechanical cardiac support, severe hypotension, and severe hypocapnia or hypercapnia. SABD was clinically diagnosed by the attending physician, anytime during the ICU stay. Estimated cerebral perfusion pressure (eCPP) and estimated intracranial pressure (eICP) were calculated from the blood flow velocity of the middle cerebral artery and invasive arterial pressure using a previously validated formula. Normal eCPP was defined as eCPP ≥ 60 mm Hg, low eCPP was defined as eCPP < 60 mm Hg; normal eICP was defined as eICP ≤ 20 mm Hg, and high eICP was defined as eICP > 20 mm Hg. RESULTS: A total of 132 patients were included in the final analysis (71% male, median [interquartile range (IQR)] age was 64 [52-71] years, median [IQR] Acute Physiology and Chronic Health Evaluation II score on admission was 21 [15-28]). Sixty-nine (49%) patients developed SABD during the ICU stay, and 38 (29%) were dead at hospital discharge. Transcranial Doppler recording lasted 9 (IQR 7-12) min. Median (IQR) eCPP was 63 (58-71) mm Hg in the cohort; 44 of 132 (33%) patients had low eCPP. Median (IQR) eICP was 8 (4-13) mm Hg; five (4%) patients had high eICP. SABD occurrence and in-hospital mortality did not differ between patients with normal eCPP and patients with low eCPP or between patients with normal eICP and patients with high eICP. Eighty-six (65%) patients had normal eCPP and normal eICP, 41 (31%) patients had low eCPP and normal eICP, three (2%) patients had low eCPP and high eICP, and two (2%) patients had normal eCPP and high eICP; however, SABD occurrence and in-hospital mortality were not significantly different among these subgroups. CONCLUSIONS: Brain hemodynamics, in particular CPP, were altered in one third of critically ill septic patients at a steady state of monitoring performed early during the course of sepsis. However, these alterations were equally common in patients who developed or did not develop SABD during the ICU stay and in patients with favorable or unfavorable outcome.

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.

Critically ill patients with acute kidney injury: clinical determinants and post-mortem histology.

Background: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) in the intensive care unit (ICU) portends a poor prognosis. We aimed to better characterize predictors of survival and the mechanism of kidney failure in these patients. Methods: This was a retrospective observational study using clinical and radiological electronic health records, analysed by univariable and multivariable binary logistic regression. Histopathological examination of post-mortem renal tissue was performed. Results: Among 157 patients with AKI requiring RRT, higher serum creatinine at RRT initiation associated with increased ICU survival [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.17-0.62, P = .001]; however, muscle mass (a marker of frailty) interacted with creatinine (P = .02) and superseded creatinine as a predictor of survival (OR 0.26, 95% CI 0.08-0.82; P = .02). Achieving lower cumulative fluid balance (mL/kg) predicted ICU survival (OR 1.01, 95% CI 1.00-1.01, P < .001), as supported by sensitivity analyses showing improved ICU survival with the use of furosemide (OR 0.40, 95% CI 0.18-0.87, P = .02) and increasing net ultrafiltration (OR 0.97, 95% CI 0.95-0.99, P = .02). A urine output of >500 mL/24 h strongly predicted successful liberation from RRT (OR 0.125, 95% CI 0.05-0.35, P < .001). Post-mortem reports were available for 32 patients; clinically unrecognized renal findings were described in 6 patients, 1 of whom had interstitial nephritis. Experimental staining of renal tissue from patients with sepsis-associated AKI (S-AKI) showed glomerular loss of synaptopodin (P = .02). Conclusions: Confounding of creatinine by muscle mass undermines its use as a marker of AKI severity in clinical studies. Volume management and urine output are key determinants of outcome. Loss of synaptopodin implicates glomerular injury in the pathogenesis of S-AKI.

Impact of CytoSorb and CKRT on hemodynamics in pediatric patients with septic shock: the PedCyto study.

Background: There is a lack of data to support the use of hemoadsorption in pediatric septic shock. The aim of our study was to assess the effectiveness and safety of CytoSorb therapy in this setting. Methods: Phase II interventional single arm pilot study in which 17 consecutive children admitted with septic shock who required continuous kidney replacement therapy (CKRT) and weighed ≥10 kg were included. A CytoSorb (CytoSorbents Inc, New Jersey, USA) hemoadsorption cartridge was added to the CKRT every 24 h for a maximum of 96 h. A control group of 13 children with septic shock treated with CKRT but not hemoadsorption at Children's Hospital Bambino Gesù and enrolled in the EuroAKId register was selected as an historical cohort. The primary outcome of the study was a reduction in vasopressor or inotrope dose of >50% from baseline by the end of CytoSorb therapy. Secondary outcomes included hemodynamic and biological changes, changes in severity scores, and 28-day mortality. Results: There were significant decreases in the Vasoactive Inotropic Score (VIS) and the Pediatric Logistic Organ Dysfunction 2 (PELOD-2) score at 72 and 96 h from the start of the CytoSorb therapy compared to baseline; the reductions were larger in the hemoadsorption group than in the control group (historical cohort). 28-day mortality was lower, although not significantly, in the hemoadsorption group when compared to the control group (5/17 [29%] vs. 8/13 [61%] OR 0.26 [95% CI: 0.05-1.2]; p = 0.08). Conclusions: CytoSorb therapy may have some benefits in pediatric patients with septic shock. Future larger randomized trials are needed in this setting. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05658588, identifier (Clinicaltrials.gov NCT05658588).

Transfusion increased skin blood flow when initially low in volume-resuscitated patients without acute bleeding.

Background: Alterations in skin blood flow is a marker of inadequate tissue perfusion in critically ill patients after initial resuscitation. The effects of red blood cell transfusions (RBCT) on skin perfusion are not described in this setting. We evaluated the effects of red blood cell transfusions on skin tissue perfusion in critically ill patients without acute bleeding after initial resuscitation. Methods: A prospective observational study included 175 non-bleeding adult patients after fluid resuscitation requiring red blood cell transfusions. Using laser Doppler, we measured finger skin blood flow (SBF) at skin basal temperature (SBFBT), together with mean arterial pressure (MAP), heart rate (HR), hemoglobin (Hb), central venous pressure (CVP), lactate, and central or mixed venous oxygen saturation before and 1 h after RBCT. SBF responders were those with a 20% increase in SBFBT after RBCT. Results: Overall, SBFBT did not significantly change after RBCT [from 79.8 (4.3-479.4) to 83.4 (4.9-561.6); p = 0.67]. A relative increase equal to or more than 20% in SBFBT after RBCT (SBF responders) was observed in 77/175 of RBCT (44%). SBF responders had significantly lower SBFBT [41.3 (4.3-279.3) vs. 136.3 (6.5-479.4) perfusion units; p < 0.01], mixed or central venous oxygen saturation (62.5 ± 9.2 vs. 67.3% ± 12.0%; p < 0.01) and CVP (8.3 ± 5.1 vs. 10.3 ± 5.6 mmHg; p = 0.03) at baseline than non-responders. SBFBT increased in responders [from 41.3 (4.3-279.3) to 93.1 (9.8-561.6) perfusion units; p < 0.01], and decreased in the non-responders [from 136.3 (6.5-479.4) to 80.0 (4.9-540.8) perfusion units; p < 0.01] after RBCT. Pre-transfusion SBFBT was independently associated with a 20% increase in SBFBT after RBCT. Baseline SBFBT had an area under receiver operator characteristic of 0.73 (95% CI, 0.68-0.83) to predict SBFBT increase; A SBFBT of 73.0 perfusion units (PU) had a sensitivity of 71.4% and a specificity of 70.4% to predict SBFBT increase after RBCT. No significant differences in SBFBT were observed after RBCT in different subgroup analyses. Conclusion: The skin blood flow is globally unaltered by red blood cell transfusions in non-bleeding critically ill patients after initial resuscitation. However, a lower SBFBT at baseline was associated with a relative increase in skin tissue perfusion after RBCT.

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.

Beneficial Effects of Tacrolimus on Brain-Death-Associated Right Ventricular Dysfunction in Pigs.

BACKGROUND: Right ventricular (RV) dysfunction remains a major problem after heart transplantation and may be associated with brain death (BD) in a donor. A calcineurin inhibitor tacrolimus was recently found to have beneficial effects on heart function. Here, we examined whether tacrolimus might prevent BD-induced RV dysfunction and the associated pathobiological changes. METHODS: After randomized tacrolimus (n = 8; 0.05 mg·kg-1·day-1) or placebo (n = 9) pretreatment, pigs were assigned to a BD procedure and hemodynamically investigated 1, 3, 5, and 7 h after the Cushing reflex. After euthanasia, myocardial tissue was sampled for pathobiological evaluation. Seven pigs were used as controls. RESULTS: Calcineurin inhibition prevented increases in pulmonary vascular resistance and RV-arterial decoupling induced by BD. BD was associated with an increased RV pro-apoptotic Bax-to-Bcl2 ratio and RV and LV apoptotic rates, which were prevented by tacrolimus. BD induced increased expression of the pro-inflammatory IL-6-to-IL-10 ratio, their related receptors, and vascular cell adhesion molecule-1 in both the RV and LV. These changes were prevented by tacrolimus. RV and LV neutrophil infiltration induced by BD was partly prevented by tacrolimus. BD was associated with decreased RV expression of the ß-1 adrenergic receptor and sarcomere (myosin heavy chain [MYH]7-to-MYH6 ratio) components, while ß-3 adrenergic receptor, nitric oxide-synthase 3, and glucose transporter 1 expression increased. These changes were prevented by tacrolimus. CONCLUSIONS: Brain death was associated with isolated RV dysfunction. Tacrolimus prevented RV dysfunction induced by BD through the inhibition of apoptosis and inflammation activation.

vCSF Danger-associated Molecular Patterns After Traumatic and Nontraumatic Acute Brain Injury: A Prospective Study.

BACKGROUND: Danger-associated molecular patterns (DAMPs) may be implicated in the pathophysiological pathways associated with an unfavorable outcome after acute brain injury (ABI). METHODS: We collected samples of ventricular cerebrospinal fluid (vCSF) for 5 days in 50 consecutive patients at risk of intracranial hypertension after traumatic and nontraumatic ABI. Differences in vCSF protein expression over time were evaluated using linear models and selected for functional network analysis using the PANTHER and STRING databases. The primary exposure of interest was the type of brain injury (traumatic vs. nontraumatic), and the primary outcome was the vCSF expression of DAMPs. Secondary exposures of interest included the occurrence of intracranial pressure ≥20 or ≥ 30 mm Hg during the 5 days post-ABI, intensive care unit (ICU) mortality, and neurological outcome (assessed using the Glasgow Outcome Score) at 3 months post-ICU discharge. Secondary outcomes included associations of these exposures with the vCSF expression of DAMPs. RESULTS: A network of 6 DAMPs (DAMP_trauma; protein-protein interaction [PPI] P=0.04) was differentially expressed in patients with ABI of traumatic origin compared with those with nontraumatic ABI. ABI patients with intracranial pressure ≥30 mm Hg differentially expressed a set of 38 DAMPS (DAMP_ICP30; PPI P< 0.001). Proteins in DAMP_ICP30 are involved in cellular proteolysis, complement pathway activation, and post-translational modifications. There were no relationships between DAMP expression and ICU mortality or unfavorable versus favorable outcomes. CONCLUSIONS: Specific patterns of vCSF DAMP expression differentiated between traumatic and nontraumatic types of ABI and were associated with increased episodes of severe intracranial hypertension.

The association between the presence and burden of periodic discharges and outcome in septic patients: an observational prospective study.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is frequent in septic patients. Electroencephalography (EEG) is very sensitive to detect early epileptic abnormalities, such as seizures and periodic discharges (PDs), and to quantify their duration (the so-called burden). However, the prevalence of these EEG abnormalities in septic patients, as well as their effect on morbidity and mortality, are still unclear. The aims of this study were to assess whether the presence of electrographic abnormalities (i.e. the absence of reactivity, the presence and burden of seizures and PDs) was associated with functional outcome and mortality in septic patients and whether these abnormalities were associated with sepsis-associated encephalopathy (SAE). METHODS: We prospectively included septic patients, without known chronic or acute intracranial disease or pre-existing acute encephalopathy, requiring ICU admission in a tertiary academic centre. Continuous EEG monitoring was started within 72 h after inclusion and performed for up to 7 days. A comprehensive assessment of consciousness and delirium was performed twice daily by a trained neuropsychologist. Primary endpoints were unfavourable functional outcome (UO, defined as a Glasgow Outcome Scale-Extended-GOSE-score < 5), and mortality collected at hospital discharge and secondary endpoint was the association of PDs with SAE. Mann-Whitney, Fisher's exact and χ2 tests were used to assess differences in variables between groups, as appropriate. Multivariable logistic regression analysis with in-hospital mortality, functional outcome, SAE or PDs as the dependent variables were performed. RESULTS: We included 92 patients. No seizures were identified. Nearly 25% of patients had PDs. The presence of PDs and PDs burden was associated with UO in univariate (n = 15 [41%], p = 0.005 and p = 0.008, respectively) and, for PDs presence, also in multivariate analysis after correcting for disease severity (OR 3.82, IC 95% [1.27-11.49], p = 0.02). The PDs burden negatively correlated with GOSE (Spearman's coefficient ρ = - 0.2, p = 0.047). The presence of PDs was also independently associated with SAE (OR 8.98 [1.11-72.8], p = 0.04). Reactivity was observed in the majority of patients and was associated with outcomes (p = 0.044 for both functional outcome and mortality). CONCLUSION: Our findings suggest that PDs and PDs burden are associated with SAE and might affect outcome in septic patients.

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.

Evaluation of nociception in unconscious critically ill patients using a multimodal approach.

This prospective observational study included 80 adults (>18 years) patients admitted to the intensive care unit who were unconscious (Glasgow Coma Scale [GCS] score <9 with a motor response <5) and receiving mechanical ventilation. A tetanic stimulation was used to assess nociception; automated pupillometry (Algiscan, ID-MED, France) was used to compute the pupillary pain index score (PPI), with a PPI > 4 considered as nociception. Concomitantly, the number of skin conductance fluctuations (NSCF) per second, measured using a Skin Conductance Algesimeter (SCA, MEDSTORM Innovation AS, Norway; > 0.27 fluctuations/sec indicating nociception), and the instantaneous Analgesia Nociception Index (iANI, MDoloris Medical Systems, France; <50 indicating nociception) were collected. Tetanic stimulation resulted in a median pupillary dilation of 16 [6-25]% and a PPI of 5 [2-7]. According to the PPI assessment, 44 patients (55%) had nociception, whereas 23 (29%) and 18 (23%) showed nociception according to the algesimeter and iANI assessment, respectively. No significant changes in measured physiologic variables were observed after the tetanic stimulation. There were no correlations between PPI, post-stimulation iANI, and SCA-derived variables. There were no differences in PPI, iANI, and SCA variables in patients with low and normal baseline EEG power at baseline. PERSPECTIVES: Detection of nociception varies across different devices in unconscious critically ill patients. Further studies are required to understand which method to implement for analgesic administration in this patient population.

Correlation between heart rate variability and cerebral autoregulation in septic patients.

BACKGROUND: Heart rate variability (HRV) may provide an estimation of the autonomous nervous system (ANS) integrity in critically ill patients. Disturbances of cerebral autoregulation (CAR) may share common pathways of ANS dysfunction. AIM: To explore whether changes in HRV and CAR index correlate in critically ill septic patients. METHODS: Prospectively collected data on septic adult (> 18 years) patients admitted into a mixed Intensive Care between February 2016 and August 2019 with a recorded transcranial doppler CAR assessment. CAR was assessed calculating the Pearson's correlation coefficient (i.e. mean flow index, Mxa) between the left middle cerebral artery flow velocity (FV), insonated with a 2-MHz probe, and invasive blood pressure (BP) signal, both recorded simultaneously through a Doppler Box (DWL, Germany). MATLAB software was used for CAR assessment using a validated script; a Mxa >0.3 was considered as impaired CAR. HRV was assessed during the same time period using a specific software (Kubios HRV 3.2.0) and analyzed in both time-domain and frequency domain methods. Correlation between HRV-derived variables and Mxa were assessed using the Spearman's coefficient. RESULTS: A total of 141 septic patients was studied; median Mxa was 0.35 [0.13-0.60], with 77 (54.6 %) patients having an impaired CAR. Mxa had a significant although weak correlation with HRV time domain (SDNN, r = 0.17, p = 0.04; RMSSD, r = 0.18, p = 0.03; NN50, r = 0.23, p = 0.006; pNN50, r = 0.23, p = 0.007), frequency domain (FFT-HF, r = 0.21; p = 0.01; AR-HF, r = 0.19; p = 0.02), and non-linear domain (SD1, r = 0.18, p = 0.03) parameters. Impaired CAR patients had also all of these HRV-derived parameters higher than those with intact CAR. CONCLUSIONS: In this exploratory study, a potential association of ANS dysfunction and impaired CAR during sepsis was observed.