The September issue of Shock covers the wide scope of the Journal, encompassing injury, inflammation, and sepsis: laboratory and clinical approaches. In fact, interesting and challenging aspects of trauma, burns, COVID-19, and sepsis are presented in original and review papers, as both clinical and basic sciences, even though both are intrinsically imbricated.

A broad definition of biomarker is a characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention. In this issue, three original papers deal with biological markers and their clinical significance, associated organ dysfunction or prognostic value.

Wang et al. (1) evaluated the clinical significance of pro-inflammatory cytokines and their correlation with disease severity and blood coagulation in septic patients with bacterial co-infection. The presence of multiresistant bacteria is an increasing challenge in treating patients with sepsis. Among these bacteria, Klebsiella pneumoniae and Acinetobacter baumannii are often associated with high morbidity and mortality. Wang et al. bring an even more dramatic scenario, the co-infection with both agents. As expected, mortality ratio was higher in the co-infection group than in the single-infection group. Interestingly, plasma levels of IL-6 and TNF-α were higher in co-infected patients and correlated with prothrombin time, plasma levels of fibrin degradation product, and D-dimer levels. The authors emphasized that high levels of pro-inflammatory cytokines might be considered a risk factor for disseminated intravascular coagulation in septic patients co-infected by Klebsiella pneumoniae and Acinetobacter baumannii.

Mitochondrial dysfunction has consistently been reported as an important pathophysiological event in sepsis. In this issue, Huang et al. (2) presented an interesting approach to evaluate mitochondrial dysfunction in clinical settings. They measured the plasma levels of four mitochondrial quality control (MQC) markers—peroxisome proliferator-activated receptor g coactivator 1a , fission protein 1 , mitofusin2 , and Parkin—which are involved in mitochondrial biogenesis, mitochondrial fission, mitochondrial fusion, and mitophagy, respectively, in four groups of volunteers: healthy control, ICU control, septic non-shock, and septic shock. Levels were higher in patients than in healthy controls, and in the case of Fis 1, levels increased with disease severity. Interestingly, all MQC markers were correlated with organ dysfunction. The authors suggest they could be used as biomarkers for disease progression.

Going further in the search for biomarkers for relevant clinical conditions, Hu et al. (3) evaluated the prognostic value of angiopoietin-like 4 (ANGPTL4) in patients with acute respiratory distress syndrome (ARDS). ANGPTL4 is a member of angiopoietin-like proteins and plays an important role in lipid metabolism, vascular permeability, angiogenesis, and inflammatory response. Here, the authors measured ANGPTL4 levels in the bronchoalveolar lavage fluid (BALF) and serum of patients with ARDS and correlated their levels with disease severity. Control subjects were outpatients in whom bronchoscopy did not identify a pulmonary illness. BALF and serum ANGPTL4 concentrations were higher in patients with ARDS than in controls and were even higher in survivors than in non-survivors. Furthermore, BALF and serum ANGPTL4 levels correlated well with angiopoietin-2, IL-6, and TNF-α levels in BALF and serum. The authors concluded that ANGPTL4 might be a novel prognostic biomarker in ARDS.

Suttapanit et al. (4) addressed the unresolved issue of predicting mortality in patients with suspected sepsis in the emergency department. The Sepsis-3 consensus proposed that qSOFA (quick SOFA)—altered mentation, systolic blood pressure of 100 mm Hg or less, and respiratory rate of 22/min or greater—be the bedside criteria to identify adult patients with suspected infection outside the ICU who are likely to have poor outcomes. Since its publication, a number of investigations have reported controversial results regarding sepsis recognition and prognostication using this criterion. In this issue, Suttapanit et al. assessed the prognostic accuracy of venous lactate levels plus the qSOFA (VqSOFA) score for predicting 28-day mortality, in a prospective, single-center study conducted in Thailand. It is relevant to evaluate the performance of sepsis scores in clinical settings that differ from those used to generate the new definitions and operational criteria. The VqSOFA score had better predictive accuracy for 28-day mortality in patients with suspected sepsis than the qSOFA and SOFA scores. Interestingly, VqSOFA≥3 was linked to a low probability of 28-day survival and higher odds of vasopressor and ventilator use within 24 h.

The treatment of critically ill patients with organ dysfunction and shock is always puzzling, and new information on guiding therapy, choosing the best approach and adjuvant therapy, is warranted.

“In all causes of hypotension, a primary clinical challenge is to distinguish between those who will respond to fluid administration, defined by an increased cardiac output, versus those who will not.” This apparently easy-to-reach goal has been one of the greatest challenges in fluid resuscitation in septic patients. In this issue, Liteplo et al. (5) assessed whether ultrasound measurements of carotid flow time (CFTc) and carotid blood flow (CBF) could predict fluid responsiveness in patients with suspected sepsis. They conducted a prospective trial with 69 patients admitted to the emergency department with suspected sepsis, of whom 36 (52%) were clinical fluid responders and 33 (48%) were non-responders. CFTc values increased significantly with both passive leg raise and intravenous fluid administration, a result that was not obtained for CBF. Unhappily, the authors concluded that neither CFTc nor CBF, as measured by carotid ultrasound, predicted fluid responsiveness, in-hospital mortality, or the need for ICU admission.

In line with fluid resuscitation challenges in septic shock, Chapalain et al. (6) addressed an unresolved question: does chloride intake at the early phase of septic shock resuscitation impact on renal outcome? Crystalloids, especially normal saline solution (0.9% of NaCl) which contains a “supra-physiologic” concentration of chloride, have been associated with hyperchloremia and metabolic acidosis in septic shock patients. Two randomized trials showed the benefits of using balanced solutions compared with saline solutions; and recently the use of balanced solutions has been recommended. The authors, however, pointed out that most studies often focus on chloremia and do not analyze the chloride intake itself, making it difficult to evaluate the impact of the chloride load. They propose a diverse approach to investigate the impact of cumulative chloride infusion at the early phase of septic shock resuscitation on acute kidney injury (AKI) and other prespecified outcomes, including 28-day mortality. In a sub-study of a cohort studied for tracheal intubation in septic shock, they compared the outcomes of patients who received a “high dose” of chloride (>18 g/48 h) to patients receiving a “low dose” (<18 g/48 h) of chloride by the end of the 48 first hours of ICU care. They did not find any association between chloride intake at the early stage of septic shock management and the occurrence of AKI requiring renal replacement therapy, length of stay in ICU, or mortality.

Fluid resuscitation and vasopressor administration are the primary interventions in patients with shock. In fact, vasopressors are commonly used in critically ill patients to increase mean arterial blood pressure (MAP), and recently vasopressors have been introduced shortly after fluid resuscitation. Aneman et al. (7) provide a conceptual systematic review of vasopressor responsiveness with the provocative conclusion that hemodynamic changes induced by vasopressor therapy are inadequately represented by the change in MAP alone, despite its common use as a clinical endpoint. To come to this conclusion, they reviewed 28 clinical trials of vasopressor therapy in shock, most of them with noradrenaline, including 678 subjects, and applied a “comprehensive physiological approach using the interacting domains of intravascular volume, heart pump performance, and vascular resistance.” Their main findings, as stated by the authors, are that beyond the expected rise in MAP, vasopressors were associated with significant increases in mean systemic filling pressure and the pressure gradient for venous return, while variable effects on central venous pressure and the pump efficiency of the heart resulted in heterogeneous cardiac output responses.

Sepsis, disseminated intravascular coagulation , and continuous hemodiafiltration (CHDF) in patients with acute renal dysfunction (AKI) were the background to the evaluation of the potential adjuvant effect of Recombinant Human Thrombomodulin (rhTM) by Kono et al. (8), in Japan. They conducted a case-control study of patients who underwent CHDF for AKI due to sepsis, with and without treatment with rhTM, between 2004 and 2016. Since treatment with rhTM is the current standard therapy in Japan, the control group was enrolled before 2008. They found clinically and laboratory results supporting the benefits of rhTM, shorter CHDF treatment and ICU admission periods, suppressed C-reactive protein and D-dimer levels, and faster recovery of platelet counts in treated patients. Interestingly, a protective effect on inflammatory mediators and sepsis-induced acute lung injury was demonstrated in a cecal ligation and puncture experimental sepsis model.

The pandemic of COVID-19 has had a huge social, health, and economic impact worldwide. The daily life of health professionals in hospitals and researchers in laboratories was dramatically reshaped by the pandemic. Interestingly, many advances in COVID-19 knowledge converged to our previous and long experience with other severe infections, such as sepsis. Cytokine storms, lymphopenia, NETosis, and coagulopathies are among the converging findings between sepsis and COVID-19. One original paper and one review contemplate COVID-19 in its clinical and pathophysiological aspects.

Even though the severe acute respiratory syndrome is the hallmark of COVID-19 patients, multi-organ involvement is quite common, especially in those patients with more severe forms of the disease. A high prevalence of impairment in skeletal muscle strength and physical performance has been reported in hospitalized patients recovering from COVID-19 pneumonia. In this issue, Geng et al. (9) addressed the presence of rhabdomyolysis (RM) in a large cohort of patients, admitted, early in the pandemic, to a single hospital in Wuhan, China. Skeletal muscle (SKM) injury was divided into mild SKM injury and RM, according to the levels of creatine kinase (CK) and creatine kinase cardiac isoenzyme . RM was documented in 22 (2.2%) of the 1,014 patients. Patients with RM presented with more severe disease, were more often transferred to the ICU and mechanically ventilated, and had much higher lethality. Adding RM to age, sex, and comorbidity improved the ROC for predicting death among COVID-19 patients. Since most of the patients did manifest RM after hospital admission, the authors suggest that monitoring serum CK and MYO concentrations might help early diagnosis and intervention.

In this issue, Cui et al. (10) provide us with a timely review of the “Immunopathological Roles of Neutrophils in Virus Infection and COVID-19.” As a first important aspect, they pointed out the interactions of neutrophils with viruses and the involvement of neutrophils in host defense as well as in amplifying the inflammatory response and inducing tissue damage. The interaction of neutrophils with cytokines and their role in thrombosis are further described. The need for more research and the potential avenue for new therapeutics targeting dysfunctional neutrophil responses are emphasized.

Neutrophils are also the theme of investigation in an original paper by Goswai et al. (11), focused on neutrophil extracellular trap (NET) formation and its correlation with endothelial and coagulation changes in trauma. They hypothesized that trauma patients with accelerated thrombin generation would have increased levels of NETs and syndecan-1 early after time of injury . They prospectively evaluated 30 trauma patients (50 samples) and 21 healthy volunteers (21 samples) and found increased thrombin generation (peak height and time to peak, markers of NETosis [citrullinated H3 nucleosomes and citrullinated histones]), and syndecan-1 levels in patients as compared with controls. There was a positive correlation between syndecan-1 shedding and markers of NETosis (H3Free and H3NUC) in trauma patients. Thus, in this pilot study, the authors demonstrate their hypothesis, showing increased NETosis, increased syndecan-1 shedding, and accelerated thrombin generation kinetics early after injury. Future studies are necessary to correlate these markers with clinical severity and the outcomes of trauma patients.

In this Shock issue, Luck et al. (12) present a welcome review of the “Gut Microbial Changes and their Contribution to Post-Burn Pathology.” Initially, it is worth noting the huge burden of burns worldwide and their great impact on low-income countries. The host response to burns is complex and in more severe cases may lead to organ dysfunction and shock. Burns and other injuries are known to affect the microbiome, and the injury-induced dysbiosis will contribute to and amplify the dysfunctional host response with further clinical deterioration. Luck et al. provide us with an in-depth review of the mechanisms linking dysbiosis to burns and vice versa, including changes in the microbiome and long-term disruptions in immunity. The increasing knowledge in the field opens avenues for new mechanistic research questions and interventional therapies.

Supplemental O2 is often required to prevent or reverse hypoxia in a wide range of medical interventions, from planned anesthesia and surgery to different shock scenarios. The effects of excessive O2 supply are well-recognized, but little is known about its effects on leukocytes and platelets redox balance. Hafner et al. (13) conducted a randomized pilot study in 30 healthy male volunteers exposed to high oxygen concentration (non-rebreather mask, 8 L/min, 100% O2) and synthetic air (non-rebreather mask, 8 L/min, 21% O2), in a cross-over design for 20 min at a 3-week interval. High oxygen exposure induced oxidative stress in leukocytes and platelets in comparison with synthetic air. The expression of oxidative stress-related genes following exposure to high oxygen concentration was also evaluated in a random subset of patients but was possibly limited by the low number of samples. The authors conclude that although O2 can prevent hypoxic episodes and injury, excessive O2 therapy may be harmful, and support the use of supplement O2 according to individual patient need.

Four basic science papers addressed mechanisms and target-oriented therapy and compared different approaches in preclinical models.

Ischemia/reperfusion (IR) may trigger pathophysiological events that can ultimately lead to cellular dysfunction and death. This process is of paramount importance in ischemic hearts since coronary artery reperfusion is the major goal to limit the infarct size. Thus, preventing IR is a therapeutic target in Myocardial ischemia/reperfusion (MIR) injury (MIRI). In this issue Lv (14) and coworkers evaluated the effect of etomidate (ETO), a short-acting anesthetic, in postconditioning in MIRI rats. They ran three sets of experiments, first evaluating the protective effects of ETO, then the role of ferroptosis and, finally, the involvement of the NrF2 pathway. ETO mitigated cardiac dysfunction and myocardium damage and inhibited IR-induced ferroptosis. These protective effects were reverted pretreatment with the ferroptosis inducer erastin or the Nrf2 inhibitor ML385, administered intraperitoneally 1 h prior to MIR surgery. Thus, the authors conclude that ETO attenuated the myocardial injury by inhibiting IR-induced ferroptosis via Nrf2 pathway, providing insights into a potential treatment for MIRI.

Mechanical ventilation is lifesaving in patients with ARDS and also the cause of an injury, the ventilator-induced lung injury (VILI). Searching for the best ventilator support and pathogenesis-oriented target therapy is of paramount importance to reduce morbidity and mortality of patients with ARDS. In this issue, Liu et al. (15) present an interesting paper, unraveling the mechanism of VILI in a two-hit model. With their solid background of previous results, the authors have a well-characterized two-hit model of mechanical ventilation exacerbating sepsis (cecal ligation and puncture) induced acute lung injury (ALI), in which IL-33 and WNT1-inducible secreted protein (WISP1) play central roles. Here, they investigated the interrelationship between IL-33 and WISP1 and the associated signaling pathways in this process. In a series of elegant experiments, they could demonstrate that genetic ablation of IL33 or its cognate receptor, ST2, or pharmacologic inhibition of WISP1 significantly reduced acute lung injury. Mechanistically, IL-33 increased WISP1 synthesis in a PI3K/AKT and ERK-dependent pathway involving WNT b-catenin. They suggest that components of this pathway may be potential targets for patients with ARDS and requiring ventilatory support.

Therapeutic temperature management , which means to maintain the temperature of a post-resuscitation patient between 32oC and 36oC for at least 24 h, is recommended by the American Heart Association to improve prognosis following cardiac arrest. The target temperature, however, is not clear, and conflicting results are reported in the literature. Wang et al. (16) addressed the protective effects on intestinal injury of targeting mild hypothermia at 33°C and 35°C, compared with 37°C, in an experimental model of cardiopulmonary resuscitation in rats. Intestinal injury was elegantly demonstrated assessing intestinal microcirculation, morphological changes, and intestinal injury markers. Their results showed the beneficial effects of mild hypothermia, with a target temperature of 33oC exerting more protective effects than 35oC on post-resuscitation intestinal injury, improving intestinal microcirculation, decreasing intestinal ischemia factor iFABP, inhibiting the NF-kB signaling pathway and downstream myosin light chain phosphorylation, and suppressing the loss of intestinal tight junctions and E-cadherin. Thus, searching for a predefined target temperature may optimize the beneficial effects of hypothermia.

Refractory cardiac arrest is defined by the absence of return of spontaneous circulation within a period of 30 min of cardiopulmonary resuscitation under medical supervision. There is hardly a clinical emergency situation that can be compared with it. Extracorporeal membrane oxygenation (ECMO) is helpful in restoring circulatory flow, but it is associated with a complex hemodynamic state, a shock state combining mechanical and ischemia–reperfusion mechanisms. The choice of vasopressors might have an impact on the outcomes of VA-ECMO because of their effects on microcirculatory/ tissue perfusion, lactate metabolism, vascular permeability, and inflammation. Klein et al. (17) compared vasopressin versus norepinephrine in a pig model of refractory cardiogenic shock complicated by cardiac arrest and resuscitated with veno-arterial ECMO. They induced myocardial infarction by proximal ligation of the left anterior descending coronary artery in 20 domestic male pigs and randomly allocated them to receive vasopressin or noradrenaline. Hemodynamic measurements and biological samples for laboratory assays were collected after surgery at baseline, after 30 min of refractory cardiac arrest (at ECMO initiation), after 3 and 6 h under ECMO. The target blood pressure was reached in both groups. However, the use of vasopressin for increasing mean arterial pressure was associated with a faster lactate clearance, less fluid administration, and less pulmonary edema when compared with norepinephrine. This study suggests that vasopressin, considering its biological effects besides being a vasopressor, might be considered as a first-line drug in this clinical setting.

In conclusion, this issue of Shock brings a lot of new information, with the excellent original contributions and revisions making the transition from basic to clinical science as smooth as possible.

1. Wang X, Zhang Q, Yan Y, Yang Y, Shang X, Li Y. Clinical significance of pro-inflammatory cytokines and their correlation with disease severity and blood coagulation in septic patients with bacterial co-infection. Shock 56:396–402, 2021. 2. Huang W, Wang X, Zhang H, Wang G, Xie F, Liu D. Serum mitochondrial quality control related biomarker levels are associated with organ dysfunction in septic patients. Shock 56:412–418, 2021. 3. Hu J, Liu L, Zeng X, Wang K, Wang H, Zeng Z, Cao Y, Gao L, Cheng M, Wang T, et al. Prognostic value of angiopoietin-like 4 in patients with acute respiratory distress syndrome. Shock 56:403–411, 2021. 4. Suttapanit K, Wisan M, Sanguanwit P, Prachanukool T. Prognostic accuracy of VqSOFA for predicting 28-day mortality in patients with suspected sepsis in the emergency department. Shock 56:368–373, 2021. 5. Liteplo AS, Schleifer J, Marill KA, Huang CK, Gouker SK, Ratanski D, Diamond E, Filbin MR, Shokoohi H. Carotid ultrasound in assessing fluid responsiveness in patients with hypotension and suspected sepsis. Shock 56:419–424, 2021. 6. Chapalain X, Huet O, Balzer T, Delbove A, Martino F, Jacquier S, Egreteau P-Y, Darreau C, Saint-Martin M, Lerolle N, et al. Does chloride intake at the early phase of septic shock resuscitation impact on renal outcome? Shock 56:425–432, 2021. 7. Åneman A, Wilander P, Zoerner F, Lipcsey M, Chew MS. Vasopressor responsiveness beyond arterial pressure: a conceptual systematic review using venous return physiology. Shock 56:352–359, 2021. 8. Kono H, Hosomura N, Amemiya H, Kawaida H, Furuya S, Akaike H, Kawaguchi Y, Sudo M, Ichikawa D. Recombinant human thrombomodulin has additive effects in septic patients undergoing continuous hemodiafiltration due to intestinal perforation. Shock 56:374–383, 2021. 9. Geng Y, Ma Q, Du Y-s, Peng N, Yang T, Zhang S-y, Wu F-f, Lin H-l, Su L. Rhabdomyolysis is associated with in-hospital mortality in patients with COVID-19. Shock 56:360–367, 2021. 10. Cui S-N, Tan H-Y, Fan G-C. Immunopathological roles of neutrophils in virus infection and COVID-19. Shock 56:345–351, 2021. 11. Goswami J, MacArthur T, Bailey K, Spears G, Kozar RA, Auton M, Dong J-F, Key NS, Heller S, Loomis E, et al. Neutrophil extracellular trap formation and Syndecan-1 shedding are increased after trauma. Shock 56:433–439, 2021. 12. Luck ME, Herrnreiter CJ, Choudhry MA. Gut microbial changes and their contribution to post-burn pathology. Shock 56:329–344, 2021. 13. Hafner C, Pramhas S, Schaubmayr W, Assinger A, Gleiss A, Tretter EV, Klein KU, Scharbert G. Brief high oxygen concentration induces oxidative stress in leukocytes and platelets: a randomised cross-over pilot study in healthy male volunteers. Shock 56:384–395, 2021. 14. Lv Z, Wang F, Zhang X, Zhang X, Zhang J, Liu R. Etomidate attenuates the ferroptosis in myocardial ischemia/reperfusion rat model via Nrf2/HO-1 pathway. Shock 56:440–449, 2021. 15. Liu S, Deng M, Pan P, Turnquist HR, Pitt BR, Billiar TR, Zhang L-M. Mechanical ventilation with moderate tidal volume exacerbates extrapulmonary sepsis-induced lung injury via IL33-WISP1 signaling pathway. Shock 56:461–472, 2021. 16. Wang X, Li M, Yang Z, Li H, Yang W, Tang W, Wu Y, Xiao P, Jiang S, Shi Q, et al. Comparison of the protective effect of different mild therapeutic hypothermia temperatures on intestinal injury after cardiopulmonary resuscitation in rats. Shock 56:450–460, 2021. 17. Klein T, Grandmougin D, Liu Y, Orlowski S, Albuisson E, Tran N, Levy B. Comparison of vasopressin versus norepinephrine in a pig model of refractory cardiogenic shock complicated by cardiac arrest and resuscitated with veno-arterial ECMO. Shock 56:473–478, 2021.