For many of us, this is a time of holidays and giving of gifts. Our authors in this issue of Shock bring us the gift of excellent summaries of contemporary thinking on shock management along with ground-breaking clinical and basic science research. I enjoyed examination of the content in this issue of our Journal and trust that you will find it an appropriate seasonal gift as well.

The first of our reviews, from Wu et al. (1), examines the evidence to date for the combination of hydrocortisone, vitamin-C, and thiamine for patients with sepsis and septic shock. This resuscitation concept remains controversial since it was popularized by Marik and coworkers in 2017. PRISMA guidelines are followed in a detailed search strategy including Pub Med, the Cochrane Library, and Embase with publication dates through November 11, 2020. Adult patients were emphasized. Outcomes examined include duration of vasoactive drug therapy, Sequential Organ Failure Assessment score change and mortality. A rationale can be offered for this combination drug therapy. For example, both steroids and vasoactive drugs such as norepinephrine oppose the deleterious actions of inflammatory mediators. Multiple reports indicate that the combination of steroids and vasoactive drugs should allow reduction in the need for vasoactive drug therapy. However, vitamin-C, which also has anti-inflammatory effects in this cocktail, has an associated risk of renal injury. This risk is reduced by thiamine administration. These authors stop short of claiming a mortality benefit in this analysis but indicate that reduction of vasoactive drug use and Sequential Organ Failure Assessment scores may be found during the first 72 h after treatment initiation. Obviously, additional work is needed to build consensus on this important question.

Our second review is a summary of important preclinical trials designed to identify therapy for microvascular leakage in models of hemorrhagic shock. van Leeuwen et al. (2) present a systematic review and meta-analysis utilizing data obtained from PubMed, Embase, and the Cochrane Library. This team focused on preclinical studies of hemorrhagic shock using a combination of therapeutic agents in addition to standard fluid resuscitation. Principal outcomes investigated were vascular leakage reflected as edema, test molecule extravasation, or degradation of the glycocalyx. In all, 45 studies were identified over a period of approximately 50 years. Microvascular endothelium adapts its permeability based on stimuli including mediators released in the setting of hemorrhagic shock. Mediators identified include inducible nitric oxide synthase, cytokines such as TNF-alpha, and production of reactive oxygen species. These authors summarize pharmacologic agents that may affect cellular metabolism, inflammation, and the endothelial barrier to reduce microvascular leakage. This work provides background for additional preclinical and initial clinical trials.

Our third review, from a multinational trial group led by Santos et al. (3), examines the use of clinically approved poly-ADP-ribose polymerase (PARP) inhibitors for therapy of sepsis. Among effects reported for PARP inhibitors are reduction of oxidative stress, decreased release of inflammatory mediators including TNF-alpha, IL-6, and IL- 1 beta, and direct protection from cell injury and death. This review is designed to provide preclinical data supporting the use of a PARP inhibitor, olaparib, as a candidate agent for a proof of concept clinical trial. These writers summarize benefits of olaparib in a variety of preclinical models including neurodegeneration, neuroinflammation, hepatitis, aging, stroke, and protection of the blood–brain barrier. Trials supporting these and other benefits argue in favor of the use of the PARP inhibitor group for protection against multiple organ injury in the setting of sepsis. Clearly, factors affecting the response to these materials, for example gender and age, must be investigated.

The first three of our clinical science papers offer perspectives on sepsis. The initial paper, from Chebi et al. (4), examines the impact of weekend presentation on septic shock patient mortality using a nationwide database accessed by American University of Beirut, Lebanon. Data utilized came from the Agency for Healthcare Research and Quality in the United States. While a number of studies suggest an increased risk of adverse outcomes, this review of over 360,000 septic shock patients suggests that weekend admission was not associated with increased mortality. The second of our clinical sepsis papers, from Serafim et al. (5), examines the impact of systemic steroids on septic shock in patients with cirrhosis. The cirrhotic patient may represent a special group in contrast to other patients with sepsis. Reported mortality in the cirrhotic patient with septic shock easily exceeds 50% in previous reports. This study from the critical care team of the Mayo Clinic reported that in their hands the use of steroids did not change mortality, adverse events, or allow reduction in resource utilization. While this data is carefully gathered and analyzed, the reader should note that the size of the study sample is small. The third of this initial group of papers on aspects of sepsis management comes from a large Chinese database collected to reflect prognosis and factors affecting patients with sepsis in that country. Qu et al. (6) use a database obtained from adults admitted to the Critical Care units of 16 tertiary care hospitals on the Chinese Mainland in 2014 and 2015. In all, approximately 5,000 patients were screened from the database of whom 1,400 patients had sepsis diagnosed on admission and 1,200 patients were ultimately studied as they had complete data. Patients were divided into four groups. Groups were determined by the presence or absence of hypotension and elevated serum lactate. Mortality in the groups of patients ranged from 48% in the group where hypotension and elevated lactate were present to 25% when neither condition existed. Chronic health conditions that could affect these results were also identified. The authors present this work to compliment standard sepsis scores based largely on data gathered in Europe and North America.

Resuscitation markers and efficacy in children are featured in the next two papers in the clinical aspects portion of our Journal. In a report from Israel, Shostak et al. (7) examined prediction of fluid responsiveness in children undergoing pediatric cardiac surgery. The child undergoing complex procedures offers a variety of technical challenges. Literature supporting dynamic and static parameters of resuscitation is inconclusive in this specialized pediatric population. As the authors note in their literature review, ultrasound has been evaluated in a variety of studies but results remain inconclusive. In this study comparing latest generation ultrasound technology to change in central venous pressure with modification of intrathoracic pressure, the authors identified changes in central venous pressure as the only parameter providing at least modest fluid responsiveness prediction. In contrast to the evaluation of vascular bed predictors just discussed, tissue perfusion parameters and clearance of lactate were assessed in a pediatric patient group by Bazaraa et al. (8) from Cairo University. This team studied a Perfusion Index using signal extraction technology based on a pulse oximetry to noninvasively monitor perfusion status. Perfusion Index is a ratio of pulsatile and nonpulsatile portions of the pulse oximeter waveforms obtained. The pulsatile portion of the waveform decreases with vasoconstriction and increases with vascular dilatation. Perfusion Index, thus, indicates change in peripheral vasomotor tone. This team combines Perfusion Index with time honored serial lactate determination as an effective evaluation protocol in the pediatric patient.

Schurr et al. (9) from Stony Brook, in the next clinical report describing efficacy of resuscitation, examine their experience using venoarterial Extracorporeal Membrane Oxygenation (ECMO) in adult patients experiencing cardiac arrest. Predictors of improved outcome included lower body mass index, improved renal function with avoidance of renal replacement therapy, shorter time for Cardiopulmonary Resuscitation, and utilization of tracheostomy. Survival After Venoarterial ECMO scoring as enhanced by lactate data was also predictive. Overall survival for patients treated in hospital was 38.2%.

Markers of successful resuscitation and optimal fluid use were examined in the next two clinical papers from this issue of the Journal. Patients experiencing burns typically present complex resuscitation problems. Lin et al. (10) from Fujian Medical University examine markers of fibrinolysis and pro- inflammatory and anti-inflammatory mediator balance in patients experiencing severe burns. A particular interest of this group is soluble urokinase-type plasminogen activator receptor (suPAR), a mediator of fibrinolysis and inflammation (10). Sixty-four patients with burns measuring at least 30% of the total body surface area were compared with 26 healthy volunteers. There were no differences in gender or age between controls, burn survivors, and burn non-survivors. Not surprisingly, clinical markers of poor outcome were clearly higher at admission in patients with burns who ultimately did not survive. Septic complications occurred in over 90% of nonsurvivors. Enzyme-linked Immunosorbent Assay was used to evaluate markers of platelet function, proinflammatory mediators, and drivers of anti-inflammatory response. In this preliminary work, a reduced level of suPAR was associated with increased 30 day mortality and inflammation in this patient population. In another study of resuscitation fluids, Liu et al. (11) from the Mayo Clinic and Wuhan University evaluated the impact of albumin use on initial resuscitation of adult sepsis or septic shock. From a database of over 2,500 patients, approximately 300 patients receiving albumin during early resuscitation were compared with approximately 550 individuals who did not receive albumin as part of initial fluid resuscitation. These workers found that patients receiving albumin required more intravenous fluid, had a higher net fluid balance, experienced lower mean arterial pressure, and had a lower base excess between 6 and 24 h of resuscitation. Resource consumption and 28 day mortality were not different between groups based on albumin administration. Surely albumin administration will receive continued investigation. This trial, however, does not support early administration of this expensive material during the initial hours of resuscitation for patients with medical sepsis.

COVID-19 is showing us that resuscitation is also dependent on response of the vascular bed. To further evaluate microvascular changes in patients with critical COVID-19, Tehrani and Gille-Johnson (12) from the Karolinska Institute studied skin microvascular function at three separate time points in patients infected with COVID-19: at admission to the intermediate care unit or ICU, later during hospitalization and at least 90 days after COVID-19 onset. Twelve patients with documented COVID-19 were compared with an equal number of uninfected controls. COVID-19 patients experienced sufficient disease severity to require mechanical ventilation or high-flow nasal oxygen support. Evaluation that included acetylcholine responsiveness suggested microvascular impairment associated with COVID-19 featuring significant reduction in endothelial function which was not fully recovered for 3 months after disease onset. These findings are consistent with other persistent symptoms of COVID-19 which may last for an extended period of time even in the setting of relatively mild initial symptoms.

In another clinical paper relating outcomes to complete or incomplete sepsis resuscitation during the first hour in the emergency department, 28 day mortality was examined in two groups of patients (13). 55.9% of patients received a complete Hour-1 Sepsis Bundle as advocated by the Surviving Sepsis Campaign in 2018. Other patients did not receive all parts of the protocol. Components of the bundle reviewed included lactate determination, collection of blood cultures, antibiotic administration, crystalloid infusion, and selected use of vasoactive drug therapy. This report comes from tertiary care and University Hospitals in Thailand. Prachanukool et al. (13) found no difference in outcome based on excluded components of the bundle. Additional data is needed.

Two final studies in the Clinical Aspects portion of this issue of the Journal highlight new and old resuscitation tools. First, in a report from McMaster University in Canada, Sohrabipour et al. (14) examine DNase I as a therapy for sepsis. This work takes advantage of the linkage between the pathways of infection, inflammation, and coagulation. In fact, heparins, which also work through the above relationships, may have therapeutic roles complimenting DNase l in sepsis management. Favorable activity of DNase 1 may be promoted by heparin in addition to its role in inhibition of coagulation. Studying specimens obtained from septic patients, a positive effect of DNase 1 is seen which warrants additional study of this material as a treatment avenue for sepsis. Finally, Weiss et al. (15) from the Medical College of Wisconsin examine outcomes dependent on whether vasoactive drug therapy is norepinephrine or epinephrine after initial resuscitation from cardiac arrest. While comorbidities including recurrent arrest, arrhythmias, or progression to death were higher in patients treated with epinephrine, patient characteristics and other resuscitation factors were not controlled in this data obtained from a review of medical records for cardiac arrest patients obtained over 32 months. As the authors note, retrospective study design and the impossibility of controlling confounders limits the opportunity to make a definitive statement despite our long history with these two drugs.

A robust group of preclinical research papers begins with a study originating from multiple sites in the United States and China. Fu et al. (16) examine the relationship between immune cells, platelets, and the coagulation cascade within cellular compartments including the bone marrow and systemic circulation. The complement system is seen as a key link between the various compartments and C3 deletion, in fact, attenuates secondary injury after tissue trauma and associated hemorrhagic shock. This assertion is supported by elegant studies using C3 knockout mice where interaction of the various immune compartments was examined. The role of C3 in secondary inflammatory response to tissue trauma and hemorrhage is proposed as an avenue for investigation based on promising and elegant data from the murine model proposed here.

Cardiac dysfunction with sepsis is another avenue of shock and inflammation studied in preclinical work from the Southern Medical University in China. Li et al. (17) examine the link between Irisin and myocardial dysfunction in mice experiencing sepsis secondary to lipopolysaccharide injection. Irisin is a fragment of fibronectin involved in glucose and lipid metabolism along with inflammatory disease. This molecule appears to limit apoptosis, pyroptosis, and inflammation. Previous studies suggest a negative correlation between disease severity and Irisin level in patients with sepsis. Cardiac function as assessed by marker levels, titers of injury mediators, and echocardiography was clearly protected in animals treated with Irisin. Within the limits of this LPS model, Irisin appears to have a cardioprotective role.

Acute kidney injury is associated with a critical care mortality of up to 60% in some reports. Multiple etiologies have been identified including direct renal trauma, hemorrhagic shock, toxins from rhabdomyolysis and other sources, nephrotoxic drugs, and infection. Hypoxia and ischemia may be the final common pathway of a variety of circulatory alterations within the renal parenchyma. Guerrieri et al. (18) from Buenos Aires examine Secretory Leukocyte Proteinase Inhibitor (SLIPI) which is protective of the kidney through a variety of pathways. SLIPI is an anti-inflammatory agent with antimicrobial activity which contributes to wound healing and tissue repair. Synthesis of SLIPI has been identified in renal tubular epithelium. In this rodent model of ischemia and reperfusion injury with direct gentamicin-induced renal toxicity, evaluation with histopathology, cell proliferation assays, and assessment for apoptosis support the use of SLIPI in a standard renal injury model. SLIPI demonstrates immediate support of renal tubular epithelium and allows direct renal protection in this model of acute kidney injury. Another study of renal protection utilizes a rodent model of crush injury. With this model, investigators from the Institute of Disaster Medicine in China identified proportional increase in serum potassium, creatine kinase, blood urea nitrogen, creatinine and myoglobin at 12 to 24 h after crush trauma (19). From this reproducible injury model, the authors evaluated protein profiles in study animals. Among biomarkers indicating severity of injury was alpha-1-acid glycoprotein (alpha1-AGP) an acute phase protein produced by hepatocytes along with other cell types in response to infection or injury. Alpha-1-AGP demonstrates anti-inflammatory properties including inhibition of neutrophil activation and induction of receptor antagonists for interleukin -1. Thus, alpha-1-AGP is both a marker and may be identified as a mediator of improved response to crush injury.

Another cellular driver of metabolic response to injury is the macrophage. The alveolar macrophage is a critical leukocyte in the air space and an important factor in acute lung injury after a variety of pulmonary insults. Ding et al. (20) from Shanghai and the University of Pittsburgh investigated macrophage activity with administration of a N-methyl-D-aspartic acid receptor antagonist, memantine, a Food and Drug Administration (FDA)-approved therapy for a variety of neurologic conditions and an investigative agent for pulmonary fibrosis along with inflammation induced by lipopolysaccharide (LPS). It should be noted that memantine was given in a pretreatment model for this murine study. After administration of memantine, test animals underwent cecal ligation and puncture. Macrophages for study were harvested from the bone marrow of the test mice. In this model, memantine decreased macrophage activity suggesting an opportunity to reduce of lung injury with cecal ligation and puncture. Lung injury was assessed by wet-to-dry weight ratio and the Evans Blue dye extravasion method. This work suggests a new application for a FDA-approved drug.

Another study examines new use for FDA-approved drugs with endothelial effects given recent experience with COVID-19 which emphasizes the importance of endothelial changes in various states of inflammation. Pape et al. (21) from laboratories in Germany and Switzerland examined the impact of FDA approved agents on the release of Angiopoietin-2 which is a driver of increased endothelial permeability. One agent of interest for this team in the role of endothelial stabilization is Bifonazole, a FDA-approved antifungal that in other preclinical trials decreases release of Angiopoetin-2. Using a human umbilical vein cell line, these authors demonstrate inhibition of Angiopoietin-2 release by stimulated human umbilical endothelial cells with Bifonazole. Additional preclinical and mechanistic trials are pending.

Consistent with ongoing clinical experience, an important target in the treatment of sepsis is optimization of metabolic support. One mechanism for metabolic compromise in sepsis is hepatic growth hormone resistance caused by cytokine-mediated compromise of normal growth hormone signaling. Affarent and efferent vagus nerve pathways may also be active in this process. Pruekprasert and Cooney from the State University of New York at Syracuse examined the effect of selective affarent vagotomy and modulation of nicotinic acetylcholine receptor pathways on hepatic growth hormone resistance and metabolic dysfunction in sepsis (22). Mortality in the rodent model utilized by these investigators was increased by selective afferent vagotomy and reduced with administration of an agonist to the cholinergic anti-inflammatory pathway that reduces hepatic inflammatory cytokine production. These results support stimulation of the cholinergic anti-inflammatory pathway possibly in combination with vagal function mediators to support hepatic performance and response to growth hormone in sepsis. A second preclinical paper examining hepatic function in sepsis comes from Song et al. (23) based in several medical facilities in China. In this study, sepsis was induced by intravenous LPS administration to rats. Specimens of liver tissue were obtained at 1, 6, and 24 h after injection of LPS. Rats with breeding for the absence of lipopolysaccharide binding protein (LBP) appeared to have stable hepatocyte mitochondrial function in this rat sepsis model at 1 and 6 h after administration of LPS. By 24 h after LPS administration, however, evidence of mitochondrial damage and reactive oxygen species was higher in livers where LBP was absent than in wild-type animals exposed to LPS. Reactive oxygen species levels were higher in animals lacking LBP than in animals lacking LBP. This work appears to suggest a protective effect of LBP against some of the pathways producing liver damage with administration of LPS.

Finally, our attention turns to hemorrhagic shock, resuscitation, and management of tissue oxygen debt in the final preclinical paper in this issue of Shock. Dyer with an international group of coworkers examine the use of non-invasive measures of tissue oxygen delivery to guide resuscitation in the subject with shock due to bleeding (24). In this study, sheep underwent anesthesia and were monitored for regional tissue oxygen saturation along with sublingual capillary imaging and arterial lactate monitoring during shock induced by stepwise withdrawal of venous blood until a mean arterial pressure of 30 mm Hg was reached with a mixed venous oxygen saturation less than 60% and arterial lactate greater than 4 millimoles. Plasmalyte was then used for resuscitation. Serial invasive organ monitoring for oxygen content confirmed reduced tissue oxygen delivery in parallel with less invasive monitors. Volume replacement limited to Plasmalyte confirmed organ-specific measurements despite a continued hemoglobin level below baseline. Data obtained from less invasive monitoring changed in parallel with that from invasive tissue monitors supporting the use of less invasive techniques listed above as a means to guide oxygen transport in the setting of hemorrhage with reduced hemoglobin concentration.

Please accept our best for the coming year.

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Clinical effect of systemic steroids in patients with cirrhosis and septic shock. Shock 56:916–920, 2021. 6. Qu Z, Zhu Y, Wang M, Li W, Zhu B, Jiang L, Xi X. Prognosis and risk factors of sepsis patients in Chinese ICUs: a retrospective analysis of a cohort database. Shock 56:921–926, 2021. 7. Shostak E, Shochat T, Manor O, Nahum E, Dagan O, Schiller O. Fluid responsiveness predictability in immediate postoperative pediatric cardiac surgery. Is the old slandered central venous pressure back again? Shock 56:927–932, 2021. 8. Bazaraa H, Roby S, Salah ES, Algebaly HA. Assessment of tissue perfusion using the peripheral perfusion index and lactate clearance in shock in pediatric patients. Shock 56:933–938, 2021. 9. Schurr JW, Noubani M, Santore LA, Rabenstein AP, Dhundale K, Fitzgerald J, Cahill J, Bilfinger TV, Seifert FC, McLarty AJ. Survival and outcomes after cardiac arrest with VA-ECMO rescue therapy. Shock 56:939–947, 2021. 10. Lin J-C, Chen X-D, Xu Z-R, Zheng L-W, Chen Z-H. Association of the circulating SuPAR levels with inflammation, fibrinolysis, and outcome in severe burn patients. Shock 56:948–955, 2021. 11. Liu C, Li H, Peng Z, Hu B, Dong Y, Gao X, Frank RD, Kashyap R, Gajic O, Kashani KB. Inclusion of albumin in the initial resuscitation of adult patients with medical sepsis or septic shock: a propensity score-matched analysis. Shock 56:956–963, 2021. 12. Tehrani S, Gille-Johnson P. Microvascular dysfunction in patients with critical COVID-19. a pilot study. Shock 56:964–968, 2021. 13. Prachanukool T, Sanguanwit P, Thodamrong F, Suttapanit K. The 28-day mortality outcome of the complete hour-1 sepsis bundle in the emergency department. Shock 56:969–974, 2021. 14. Sohrabipour S, Muniz VS, Sharma N, Dwivedi DJ, Liaw PC. Mechanistic studies of DNase I activity: impact of heparin variants and PAD4. Shock 56:975–987, 2021. 15. Weiss A, Dang C, Mabrey D, Stanton M, Feih J, Rein L, Feldman R. Comparison of clinical outcomes with initial norepinephrine or epinephrine for hemodynamic support after return of spontaneous circulation. Shock 56:988–993, 2021. 16. Fu G, Chen T, Wu J, Jiang T, Tang D, Bonaroti J, Conroy J, Scott MJ, Deng M, Billiar TR. Single-cell transcriptomics reveals compartment-specific differences in immune responses and contributions for complement factor 3 in hemorrhagic shock plus tissue trauma. Shock 56:994–1008, 2021. 17. Li Q, Zhang M, Zhao Y, Dong M. Irisin protects against LPS-stressed cardiac damage through inhibiting inflammation, apoptosis, and pyroptosis. Shock 56:1009–1018, 2021. 18. Guerrieri D, Ambrosi NG, Romeo H, Salaberry J, Toniolo F, Remolins C, Incardona C, Casadei D, Chuluyan ME. Secretory leukocyte proteinase inhibitor protects acute kidney injury through immune and non-immune pathways. Shock 56:1019–1027, 2021. 19. Lv Q, Long M, Wang X, Shi J, Wang P, Guo X, Song J, Midgley AC, Fan H, Hou S. 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