High Circulating Dipeptidyl Peptidase 3 Predicts Mortality and Need for Organ Support in Cardiogenic Shock: An Ancillary Analysis of the ACCOST-HH Trial.

BACKGROUND: Cardiogenic shock (CS) is burdened with high mortality. Efforts to improve outcome are hampered by the difficulty of individual risk stratification and the lack of targetable pathways. Previous studies demonstrated that elevated circulating dipeptidyl peptidase 3 (cDPP3) is an early predictor of short-term outcome in CS, mostly of ischemic origin. Our objective was to investigate the association between cDPP3 and short-term outcomes in a diverse population of patients with CS. METHODS AND RESULTS: cDPP3 was measured at baseline and after 72 hours in the AdreCizumab against plaCebO in SubjecTs witH cardiogenic sHock (ACCOST-HH) trial. The association of cDPP3 with 30-day mortality and need for organ support was assessed. Median cDPP3 concentration at baseline was 43.2 ng/mL (95% confidence interval [CI], 21.2-74.0 ng/mL) and 77 of the 150 patients (52%) had high cDPP3 over the predefined cutoff of 40 ng/mL. Elevated cDPP3 was associated with higher 30-day mortality (adjusted hazard ratio [aHR] = 1.7; 95% CI, 1.0-2.9), fewer days alive without cardiovascular support (aHR, 3 days [95% CI, 0-24 days] vs aHR, 21 days [95% CI, 5-26 days]; P < .0001) and a greater need for renal replacement therapy (56% vs 22%; P < .0001) and mechanical ventilation (90 vs 74%; P = .04). Patients with a sustained high cDPP3 had a poor prognosis (reference group). In contrast, patients with an initially high but decreasing cDPP3 at 72 hours had markedly lower 30-day mortality (aHR, 0.17; 95% CI, 0.084-0.34), comparable with patients with a sustained low cDPP3 (aHR, 0.23; 95% CI, 0.12-0.41). The need for organ support was markedly decreased in subpopulations with sustained low or decreasing cDPP3. CONCLUSIONS: The present study confirms the prognostic value of cDPP3 in a contemporary population of patients with CS.

How preclinical models help to improve outcome in cardiogenic shock.

PURPOSE OF REVIEW: Preclinical experimentation of cardiogenic shock resuscitation on large animal models represents a powerful tool to decipher its complexity and improve its poor outcome, when small animal models are lacking external validation, and clinical investigation are limited due to technical and ethical constraints. This review illustrates the currently available preclinical models addressing reliably the physiopathology and hemodynamic phenotype of cardiogenic shock, highlighting on the opposite questionable translation based on low severity acute myocardial infarction (AMI) models. RECENT FINDINGS: Three types of preclinical models replicate reliably AMI-related cardiogenic shock, either with coronary microembolization, coronary deoxygenated blood perfusion or double critical coronary sub-occlusion. These models overcame the pitfall of frequent periprocedural cardiac arrest and offer, to different extents, robust opportunities to investigate pharmacological and/or mechanical circulatory support therapeutic strategies, cardioprotective approaches improving heart recovery and mitigation of the systemic inflammatory reaction. They all came with their respective strengths and weaknesses, allowing the researcher to select the right preclinical model for the right clinical question. SUMMARY: AMI-related cardiogenic shock preclinical models are now well established and should replace low severity AMI models. Technical and ethical constraints are not trivial, but this translational research is a key asset to build up meaningful future clinical investigations.

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.

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.

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.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper.

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.

A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock.

BACKGROUND: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. METHODS: We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. RESULTS: In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. CONCLUSIONS: This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02141607. Registered 19 May 2014.

Estimation of central arterial pressure from the radial artery in patients undergoing invasive neuroradiological procedures.

BACKGROUNDS: Central arterial pressure can be derived from analysis of the peripheral artery waveform. The aim of this study was to compare central arterial pressures measured from an intra-aortic catheter with peripheral radial arterial pressures and with central arterial pressures estimated from the peripheral pressure wave using a pressure recording analytical method (PRAM). METHODS: We studied 21 patients undergoing digital subtraction cerebral angiography under local or general anesthesia and equipped with a radial arterial catheter. A second catheter was placed in the ascending aorta for central pressure wave acquisition. Central (AO) and peripheral (RA) arterial waveforms were recorded simultaneously by PRAM for 90-180 s. During an off-line analysis, AO pressures were reconstructed (AOrec) from the RA trace using a mathematical model obtained by multi-linear regression analysis. The AOrec values obtained by PRAM were compared with the true central pressure value obtained from the catheter placed in the ascending aorta. RESULTS: Systolic, diastolic and mean pressures ranged from 79 to 180 mmHg, 47 to 102 mmHg, and 58 to 128 mmHg, respectively, for AO, and 83 to 174 mmHg, 47 to 107 mmHg, and 60 to 129 mmHg, respectively, for RA. The correlation coefficients between AO and RA were 0.86 (p < 0.01), 0.83 (p < 0.01) and 0.86 (p < 0.01) for systolic, diastolic and mean pressures, respectively, and the mean differences - 0.3 mmHg, 2.4 mmHg and 1.5 mmHg. The correlation coefficients between AO and AOrec were 0.92 (p < 0.001), 0.87 (p < 0.001) and 0.92 (p < 0.001), for systolic, diastolic and mean pressures, respectively, and the mean differences 0.01 mmHg, 1.8 mmHg and 1.2 mmHg. CONCLUSIONS: PRAM can provide reliable estimates of central arterial pressure.

Identification of a transcriptome profile associated with improvement of organ function in septic shock patients after early supportive therapy.

BACKGROUND: Septic shock is the most severe complication of sepsis and this syndrome is associated with high mortality. Treatment of septic shock remains largely supportive of hemodynamics and tissue perfusion. Early changes in organ function assessed by the Sequential Organ Function Assessment (SOFA) score are highly predictive of the outcome. However, the individual patient's response to supportive therapy is very heterogeneous, and the mechanisms underlying this variable response remain elusive. The aim of the study was to investigate the transcriptome of whole blood in septic shock patients with different responses to early supportive hemodynamic therapy assessed by changes in SOFA scores within the first 48 h from intensive care unit (ICU) admission. METHODS: We performed whole blood RNA sequencing in 31 patients: 17 classified as responders (R) and 14 as non-responders (NR). Gene expression was investigated at ICU admission (time point 1, or T1), comparing R with NR [padj < 0.01; Benjamini-Hochberg (BH)] and over time from T1 to T2 (48 h later) in R and NR independently (paired analysis, padj < 0.01; BH). Then the differences in gene expression trends over time were evaluated (Mann-Whitney, P <0.01). To identify enriched biological processes, we performed an over-representation analysis based on a right-sided hypergeometric test with Bonferroni step-down as multiple testing correction (padj < 0.05). RESULTS: At ICU admission, we did not identify differentially expressed genes (DEGs) between the two groups. In the transition from T1 to T2, the activation of genes involved in T cell-mediated immunity, granulocyte and natural killer (NK) cell functions, and pathogen lipid clearance was noted in the R group. Genes involved in acute inflammation were downregulated in both groups. CONCLUSIONS: Within the limits of a small sample size, our results could suggest that early activation of genes of the adaptive immune response is associated with an improvement in organ function.

Effects of the cardiac myosin activator Omecamtiv-mecarbil on severe chronic aortic regurgitation in Wistar rats.

BACKGROUND: Aortic regurgitation (AR) is a valvular disease that can lead to systolic heart failure. Treatment options besides cardiac surgery are limited and consequently severe AR is associated with higher mortality and morbidity when not operated. In this investigation, we examined the effects of a novel cardiac myosin activator, Omecamtiv-mecarbil (OM), in rats with chronic severe AR. METHODS: AR was created by retrograde puncture of the aortic valve leaflets in 20 adults Wistar rats. 12 animals survived the acute AR phase and were randomized 2 months thereafter into OM (n = 7) or placebo groups (n = 5). Two rats underwent a sham operation and served as controls. Equal volumes of OM or placebo (NaCl 0.9%) were perfused in the femoral vein by continuous infusion (1.2 mg/kg/hour) during 30 min. Doppler-echocardiography was performed before and at the end of the infusion periods. RESULTS: OM increased indices of global cardiac function (cardiac output, stroke volume), and increased systolic performance (fractional shortening, ejection fraction, left ventricular end systolic diameter) (all p < 0.05). These effects concurred with decreases in indices of LV preload (left atrial size, left ventricular end diastolic diameter) as well in the aortic pre-ejection period / left ventricular ejection time ratio (all p < 0.05). The severity score of the regurgitant AR jet did not change. Placebo infusion did not affect these parameters. CONCLUSION: The cardiac myosin activator OM exerts favorable hemodynamic effects in rats with experimental chronic AR.

Changes in kidney perfusion and renal cortex metabolism in septic shock: an experimental study.

BACKGROUND: The etiology of renal dysfunction in sepsis is currently attributed to altered perfusion, microcirculatory abnormalities and cellular alterations. To clarify these mechanisms, we characterized the changes in renal perfusion and cortex metabolism in a large animal model of sepsis. METHODS: We studied 12 adult female sheep randomized to peritonitis-induced sepsis (n = 8) or to sham procedure (n = 4). A flow probe was positioned around the renal artery to measure renal blood flow (RBF). Laser Doppler was used to measure regional flow in the kidney cortex and medulla. A microdialysis probe was inserted into the renal cortex to measure cortical glucose, lactate, and pyruvate. Fluid resuscitation was provided to keep pulmonary artery occlusion pressure at baseline levels. All animals were observed for 18 h. RESULTS: Hypotension occurred after 9 h in the septic animals (P = 0.02 versus baseline). RBF and cortical flow were significantly lower than at baseline from 12 h in the septic animals (P = 0.01 and P = 0.03, respectively). Cortical lactate and pyruvate levels increased in the septic animals from 3 and from 6 h, respectively (both P = 0.02 versus baseline), and the L/P ratio from 15 h (P = 0.01). There was a correlation between cortical flow and cortical L/P ratio after shock onset (r = -0.60, P = 0.002) but not before. CONCLUSIONS: In this peritonitis model, sepsis was associated with metabolic alterations that may reflect early induction of cortical glycolysis. Septic shock was associated with reduced renal perfusion and decreased cortical and medullary blood flow, followed by signs of anaerobic metabolism in the cortex when flow reductions became critical.

Esmolol Administration to Control Tachycardia in an Ovine Model of Peritonitis.

BACKGROUND: Excessive adrenergic signaling may be harmful in sepsis. Using ß-blockers to reduce sympathetic overactivity may modulate sepsis-induced cardiovascular, metabolic, immunologic, and coagulation alterations. Using a randomized ovine fecal peritonitis model, we investigated whether administration of a short-acting ß-blocker, esmolol, could control tachycardia without deleterious effects on hemodynamics, renal perfusion, cerebral perfusion, cerebral metabolism, or outcome. METHODS: After induction of fecal peritonitis, 14 anesthetized, mechanically ventilated, and hemodynamically monitored adult female sheep were randomly assigned to receive a continuous intravenous infusion of esmolol to control heart rate between 80 and 100 bpm (n = 7) or a saline infusion (control group, n = 7). Esmolol was discontinued when the mean arterial pressure decreased below 60 mm Hg. Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline values. Left renal blood flow and cerebral cortex perfusion and metabolism were monitored in addition to standard hemodynamic variables. RESULTS: Esmolol was infused for 11 (9-14) hours; the target heart rate (80-100 bpm) was achieved between 3 and 8 hours after feces injection. In the first 5 hours after the start of the infusion, the decrease in heart rate was compensated by an increase in stroke volume index; later, stroke volume index was not statistically significantly different in the 2 groups, so that the cardiac work index was lower in the esmolol than in the control group. Hypotension (mean arterial pressure <60 mm Hg) occurred earlier (10 [8-12] vs 14 [11-20] hours; P= .01) in the esmolol group than in the control animals. Renal blood flow decreased earlier in the esmolol group, but there were no differences in urine output, cerebral cortex perfusion, metabolism, or survival between the groups. CONCLUSIONS: In this ovine model of abdominal sepsis, early control of tachycardia by esmolol was associated with a transient increase in stroke volume, followed by earlier hypotension. There were no significant effects of esmolol on cerebral perfusion, metabolism, urine output, or survival.

The effects of acute renal denervation on kidney perfusion and metabolism in experimental septic shock.

BACKGROUND: Perfusion deficits likely play an important role in the development of renal dysfunction in sepsis. Renal denervation may improve kidney perfusion and metabolism. METHODS: We randomized 14 female sheep to undergo bilateral surgical renal denervation (n = 7) or sham procedure (n = 7) prior to induction of sepsis. Renal blood flow (RBF) was measured with a pre-calibrated flowprobe. Laser Doppler probes were implanted to measure cortical and medullary perfusion. Cortical glucose, lactate and pyruvate levels were measured using the microdialysis technique. Creatinine clearance was determined. Sepsis was induced by peritonitis and fluid resuscitation was provided to avoid hypovolemia. RESULTS: RBF and cortical perfusion were higher in the denervated group during the first 6 h after induction of sepsis (P < 0.001 and P < 0.05, respectively), while medullary perfusion decreased similarly in both groups. After hypotension developed, RBF decreased to similar levels in both groups. Cortical pyruvate and lactate levels were lower in the denervated animals (P < 0.001 and P < 0.001, respectively). There were no differences between groups in creatinine clearance, urine output or time to oliguria. CONCLUSION: Denervation thus caused an early increase in RBF that was distributed towards the kidney cortex. Although associated with an attenuation of early cortical metabolic alterations, denervation failed to prevent the deterioration in renal function.

Refractory insulin resistance and hemophagocytic lymphohistiocytosis following enfortumab vedotin treatment: A case report.

The increasing incidence of urothelial carcinoma, coupled with advancements in its therapeutic landscape, has resulted in improved survival rates for patients. This, in turn, has led to a growing population of patients requiring specialized oncological care, with Enfortumab vedotin (EV) emerging as a pivotal treatment for metastatic urothelial carcinoma. While EV is associated with hyperglycemia, ketoacidosis is exceedingly rare. To the best of our knowledge, the link between EV and hemophagocytic lymphohistiocytosis (HLH) has not yet been explored. A 56-year-old patient diagnosed with metastatic urothelial carcinoma underwent EV treatment as a third-line treatment after progression following treatment with cisplatin/gemcitabine and pembrolizumab. Notably, after receiving two doses of EV, the patient exhibited refractory insulin resistance, leading to ketoacidosis. Subsequently, HLH emerged, necessitating a treatment regimen involving dexamethasone and etoposide. Despite intensive efforts, the patient experienced septic shock, resulting in death. The present case report highlights refractory insulin resistance and ketoacidosis, followed by reactive HLH, in the context of EV therapy. The limited literature on these complications demonstrates the need for further research to improve the understanding of the underlying mechanisms. With growing evidence of the efficacy of EV and evolving survival rates in urothelial carcinoma, healthcare professionals must remain vigilant for potential adverse effects, ensuring early recognition and optimal patient care.

Impaired angiotensin II signaling in septic shock.

Recent years have seen a resurgence of interest for the renin-angiotensin-aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II-angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin-angiotensin-aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin-angiotensin-aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin-angiotensin-aldosterone system alterations in septic shock should help to decipher patients' phenotypes and to implement targeted interventions.

Mortality in patients with septic cardiomyopathy identified by longitudinal strain by speckle tracking echocardiography: An updated systematic review and meta-analysis with trial sequential analysis.

BACKGROUND: Septic cardiomyopathy is associated with poor outcomes but its definition remains unclear. In a previous meta-analysis, left ventricular (LV) longitudinal strain (LS) showed significant prognostic value in septic patients, but findings were not robust due to a limited number of studies, differences in effect size and no adjustment for confounders. METHODS: We conducted an updated systematic review (PubMed and Scopus up to 14.02.2023) and meta-analysis to investigate the association between LS and survival in septic patients. We included studies reporting global (from three apical views) or regional LS (one or two apical windows). A secondary analysis evaluated the association between LV ejection fraction (EF) and survival using data from the selected studies. RESULTS: We included fourteen studies (1678 patients, survival 69.6%) and demonstrated an association between better performance (more negative LS) and survival with a mean difference (MD) of -1.45%[-2.10, -0.80] (p < 0.0001;I2 = 42%). No subgroup differences were found stratifying studies according to number of views used to calculate LS (p = 0.31;I2 = 16%), severity of sepsis (p = 0.42;I2 = 0%), and sepsis criteria (p = 0.59;I2 = 0%). Trial sequential analysis and sensitivity analyses confirmed the primary findings. Grade of evidence was low. In the included studies, thirteen reported LVEF and we found an association between higher LVEF and survival (MD = 2.44% [0.44,4.45]; p = 0.02;I2 = 42%). CONCLUSIONS: We confirmed that more negative LS values are associated with higher survival in septic patients. The clinical relevance of this difference and whether the use of LS may improve understanding of septic cardiomyopathy and prognostication deserve further investigation. The association found between LVEF and survival is of unlikely clinical meaning. REGISTRATION: PROSPERO number CRD42023432354.

A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.

In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.

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.

The role of invasive techniques in cardiopulmonary evaluation.

PURPOSE OF REVIEW: To discuss the role of the invasive monitoring techniques pulmonary artery catheter (PAC) and transpulmonary thermodilution (TPD) for cardiopulmonary monitoring in the critically ill patient. RECENT FINDINGS: Characterization of the nature of hemodynamic alterations and hemodynamic optimization can be achieved both with PAC and TPD. Some recent trials suggest that volumetric measurements may be preferred in conditions with preserved left ventricular systolic function, whereas pressure measurements should be preferred in patients with altered left ventricular systolic function. Extravascular lung water is strongly associated with outcome and may be used to reflect the impact of fluid management strategies. The time response of this measurement needs still to be better defined. SUMMARY: This review highlights that PAC and TPD have an important role in cardiopulmonary monitoring of critically ill patients. Both techniques can be used efficiently to diagnose the nature of circulatory or respiratory failure and to monitor the effects of therapies. The choice of the technique should be guided by the patient's condition and the need for additional measurements rather than based on physician's preferences.