This issue of Shock offers another special collection of superb scientific articles spanning from authoritative reviews of current clinical paradigms of resuscitation to the description of novel diagnostic and therapeutic tools in surgical and critical care settings. Five basic science articles are also included in this issue and cover the latest advances in fundamental mechanisms of cell signaling, immune regulation and host–pathogen interactions during sepsis, trauma, and ischemia and reperfusion injury. On a final note, this issue concludes with an editorial comment that poses important questions confronting investigators on sepsis research.
The first article by Etchill et al. (1) is an extensive review that deals with the important topic of thrombocytopenia and platelet transfusion practices in surgical and critical care settings. Thrombocytopenia is a common problem in critically ill patients and an independent predictor of mortality. The authors provide a critical appraisal of data reported by 153 manuscripts focusing on transfusion practices in different settings of thrombocytopenia. A highlight of the study is the description of point-of-care laboratory assays, which emphasizes the importance of platelet function testing. The authors also provide a synopsis of recent advances in transfusion medicine and research into synthetic platelet substitutes that may overcome some of the complications and critical contraindications associated with platelet transfusion.
The study by Long et al. (2) of the Paediatric Research in Emergency Departments International Collaborative is a systematic review and meta-analysis of data on respiratory variation in the inferior vena cava (IVC) diameter as a predictor of fluid responsiveness in patients with acute circulatory failure. Assessment for volume responsiveness prior to fluid resuscitation is already recommended by the European Society of Intensive Care Medicine, since prediction of fluid responsiveness would allow for resuscitation with fluids to patients who would benefit, while it would reduce adverse effects of fluid overload. A noninvasive tool, such as the measurement of respiratory variation in IVC diameter, would, therefore, provide additional benefit without added risk. After a critical analysis of 17 studies assessed for the design and reporting quality and the risk of bias, the authors conclude that respiratory variation in IVC diameter is moderately predictive of fluid responsiveness. This noninvasive test is most useful in mechanically ventilated patients where invasive monitoring carries high risk or is impractical.
Another extensive review by Antonucci et al. (3) deals with the challenging management of patients with refractory septic shock and proposes a very debated topic of the need for novel vasopressor therapies. Specifically, the authors focus on the potential therapeutic benefits of angiotensin II (Ang II) in catecholamine-resistant shock. In this review, the authors first address the biological mechanisms of the renin–angiotensin–aldosterone system in septic shock by assembling an extensive number of preclinical studies. The authors then comment on the few available clinical studies, including the phase II ATHOS clinical trial, which shows some promising results in distributive shock in a single-center pilot study. The authors also outline the important drawbacks and potential deleterious effects of Ang II on microcirculation. At this stage of knowledge, we cannot agree more with the authors that it is still premature to state that Ang II is beneficial in refractory shock. Only large-scale randomized trials can provide relevant information on the clinical relevance of this treatment approach.
The article by Fox et al. (4) is an Invited Opinion on behalf of the investigators from the Pragmatic, Randomized Optimal Platelet and Plasm Ratios group and addresses the critical importance of choosing appropriate endpoints in hemorrhagic shock trials. Recent hemorrhagic shock trials have used 24 h and/or 30-day all-cause mortality as the primary endpoint. The study by Fox et al. reanalyzes data from five prospective studies with over 4,000 trauma patients with hemorrhagic shock. The authors make a strong case to support the use of early endpoints for hemorrhagic shock clinical trials, since they appear congruent with the median time of hemorrhagic deaths. Nevertheless, the authors still recommend considering multiple subsequent secondary safety endpoints, including 24 h and 30-day all-cause mortality as well as the customary safety endpoints in hemorrhagic shock clinical trials.
The first clinical science article is the study by Park et al. (5), which focuses on the analysis of endpoints for prediction of mortality in septic shock. In septic shock the goal of treatment is to reverse and prevent further tissue hypoperfusion. Lactate is used as a marker for tissue hypoperfusion. The measurement of lactate is, therefore, important for the diagnosis of sepsis and septic shock and has been incorporated into the recent Sepsis-3 guidelines. Varis et al. examined the association of blood lactate over time with 90-day mortality in patients with septic shock. This association analysis was performed through post hoc analysis of the FINNAKI study that was a prospective, observational, multicenter study on acute kidney injury conducted in 17 Finnish intensive care units (ICU). Patients were included in the study if they met criteria for septic shock within 24 h of ICU admission, had a blood lactate measurement at the time of diagnosis, an elevated admission lactate, and received vasopressor treatment. Almost 500 patients were included in the analysis. Higher mortality was demonstrated in patients with lactate >2 mmol/L at admission and in patients with persistent hyperlactatemia (>2 mmol/L) at ≥ 72 h. Since admission variables are typically non-modifiable, it is particularly interesting to note that for septic patients a lactate that remains elevated at 72 h is associated with 90-day mortality. We agree with the authors that these findings further support the importance of lactate measurement in addition to other surrogate endpoints for mortality in the design of clinical trials.
The second clinical science article by Varis et al. (6) also deals with the major challenge of interpretation of blood lactate concentration in critically ill patients with sepsis or in septic shock. In a retroprospective study, the authors evaluated how lactate kinetics were affected by the use of metformin, an antihyperglycemic drug known to cause hyperlactatemia and lactic acidosis. The authors conducted three different analyses, propensity score matching, multiple logistic, and linear regression analyses, on data from 1,318 patients, of whom 71 were using metformin. The authors report that when baseline differences were adjusted by propensity score matching that retained only diabetic patients, no significant association was found between metformin use and lactate kinetics variables despite a trend toward a higher lactate concentration among the metformin users. As judiciously acknowledged by the authors, the statistical power of the study was limited by the small number of subjects in the metformin group in a single-centered study; therefore, these findings certainly remain to be proven in larger clinical studies. Nevertheless, the authors should be commended in their effort to further define the complexity of lactate kinetics and their value as biomarkers in critically ill patients.
The goal of the next study by Janak et al. (7) was to determine whether endotoxemia exists in patients with cardiogenic shock. In a prospective observational study the authors enrolled 37 patients with cardiogenic shock and observed that all the patients had elevated procalcitonin levels and anti-endotoxin antibodies below the normal median value, which is generally indicative of endotoxin exposure. These findings demonstrate that even inflammatory noninfection conditions, which were not thought to have a bacterial component, may have pathophysiology that involves or is complicated by bacterial translocation. Nevertheless, the authors acknowledge that because of the several limitations of this small study these findings still need to be confirmed in larger and more comprehensive clinical investigations.
The study reported by Ramirez et al. (8) investigates another method to detect trauma injury severity, which could have a significant impact on field triage for military personnel in combat areas. The authors examined a military cohort who sustained combat-related injuries and evaluated the association of injury severity score with selected urinary biomarkers, which are commonly used as biomarkers of kidney injury. Interestingly, the authors found that these biomarkers were higher in patients with severe combat-related injuries from explosive injuries when compared with victims of gunshot wound injuries. The authors speculated that burn injury in the civilian setting could serve as a model for explosive injury in biomarker research. Although these findings certainly need to be confirmed in separate and larger studies, the authors should be commended for the attempt to identify meaningful biomarkers easily detectable in austere settings.
Another interesting study that could have significant impact on shock triage is presented by Mathias et al. (9). The authors report data on the use of muscle oxygenation (MOx) measurement for the early identification of the severity of shock in trauma patients. The authors suggest that decreased muscle oxygenation may be an early indicator of hypoperfusion. The authors tested the potential utility of a prototype, recently developed in their laboratory, in trauma patients who presented to the emergency department. This tool measures spectra in the visible and near-infrared wavelength regions. Muscle oximetry data were captured before resuscitation and shock severity measurements were determined post hoc after MOx measurements were obtained. The data demonstrate that the use of MOx measured shock as well as the shock index in mild, moderate, and severe shock groups; however, MOx measurements identified mild shock better than the shock index. Therefore, as the authors conclude, this novel technology holds promise to identify patients in the mild shock category, which may be difficult to identify based on clinical assessment only.
An important effort toward a better understanding of the pathophysiology of neonatal sepsis is then the article by Kao et al. (10), who attempted to apply genomic approaches to characterize the innate immune and inflammatory responses of newborn-specific neutrophils. The authors compared neutrophil genomic and whole blood responses to lipopolysaccharide (LPS) from full-term neonate umbilical cord blood and healthy adult volunteers. The authors found that, while there was no difference in gene expression patterns at baseline, neutrophils from neonates were less capable to mount a transcriptional process in response to LPS for genes related to neutrophil activation, phagocytosis, and chemotaxis when compared with neutrophils from healthy adult controls. To unravel biological complexities, the genomic data were integrated with data on whole blood cytokine expression, which confirmed that neutrophils from neonates are unable to mount an inflammatory response to LPS stimulation. In the era of emerging precision medicine, these data are important because they argue for “omics” tools enabling a careful stratification of high-risk neonates and low-risk neonates in the clinical managements of neonatal infections.
The last clinical science article by Arakaki et al. (11) elucidates the role of coinfection in outcomes of pneumonia. Pneumonia is a common risk factor that increases the risk of acute respiratory distress syndrome (ARDS). Multiple infectious etiologies lead to the development of pneumonia. In this current age of increasing antibiotic resistance, it is imperative that we accurately identify pathogen-associated pneumonias that contribute to ARDS. This is important for optimizing timely and appropriate antimicrobial therapy but also for decreasing the use of unnecessary antimicrobial therapy since most viruses do not have treatment options. In a prospective observational study, the authors evaluated 255 patients with pneumonia-related ARDS and classified them according to the presence of a microbial pathogen (virus, bacterium, or fungus) detected in the bronchoalveolar lavage. The authors report that coinfection with a virus and another pathogen was associated with increased hospital mortality in pneumonia-related ARDS patients. The authors, however, cautiously conclude that the findings cannot represent the general population of patients with pneumonia because of the limited size of their study group. Nevertheless, these findings are certainly supportive of the impact of viral coinfection in bacterial infections.
Understanding how cells detect and respond to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) during an infection has important implications not only for comprehending the immune response to pathogens but also for elucidating the causes of inflammation and organ injury. The first basic science article by Heipertz et al. (12) represents a valid effort into the elucidation of these mechanisms. This study in a clinically relevant model of sepsis by cecal and legation puncture in mice elegantly demonstrates that the degree of initial insult, antibiotic therapy, and fluid resuscitation modify the severity of the disease by altering the release of PAMPs and DAMPs and, consequently, leading to the activation of different signaling pathways downstream of the interferon regulatory factor 3, a transcription factor regulating innate immune responses. By using knock-out mice, the authors demonstrated that during severe sepsis both the Stimulator of Interferon Genes (STING) pathway (that senses cytosolic DNA) and the TIR-domain containing adapter-inducing interferon-β (TRIF) pathway (that senses dsRNA and LPS via Toll-like receptors 3 and 4) contribute to sepsis-induced inflammatory response and mortality. On the contrary, only the TRIF pathway appears to be involved during a less severe model of sepsis. Although the findings cannot determine whether STING or TRIF are potential targets for treatment in septic shock, the study clearly adds an important piece to the puzzle of the complex pathophysiology of sepsis. Furthermore, the authors should be commended for using an experimental design that nicely takes into consideration criteria for clinical relevance including antibiotics and fluid resuscitation.
The preclinical study by Chang et al. (13) provides crucial insights into the pathogenetic mechanisms of transfusion-related morbidity. Blood products and derivatives are indispensable resources in medical therapies. Despite the adoption of strict hemovigilance norms, there is a risk of adverse effects such as transfusion-related acute lung injury with the use of stored blood. The authors demonstrated that microparticles derived from murine packed red blood cells induced a pro-inflammatory phenotype in endothelial cells in a coculture setting. The authors validated the in vitro findings using an in vivo murine model, in which transfusion of microparticles to healthy mice induced lung leukosequestration. The study has clinical relevance as it reinforces the importance of the need of blood conservation strategies to prevent potential harm from storage.
In line with the investigation of the pathophysiological mechanisms of acute lung injury is another basic science study by Zhou et al. (14), which focuses on the role of epoxyeicosatrienoic acids (EETs), cytochrome P450-dependent derivatives of polyunsaturated fatty acids known for their anti-inflammatory properties in certain cardiovascular and kidney diseases. Using an in vivo murine model of endotoxin-induced acute lung injury, the authors showed for the first time that pharmacological inhibition of the soluble epoxide hydrolase (sEH), the enzyme that degrades EETs into less potent metabolites, attenuated lung edema and neutrophil infiltration, and reduced the systemic elevation of pro-inflammatory cytokines. These beneficial effects of the sEH inhibitor and the direct anti-inflammatory properties of the EETs were also confirmed in macrophages in vitro. It is important to note that great efforts have been recently made to develop drugs targeting the EET pathway. Some of these agents are currently under evaluation in clinical trials for treatment of hypertension and diabetes. Therefore, the findings by Zhou et al. raise the possibility about using EET analogs as well as sEH inhibitors to treat patients with acute lung injury.
A further step in the investigation of the complexity of inflammatory and immune responses is the study by Ri et al. (15), which focuses on the role of vagal reflex in the control of intestinal injury consequent to ischemia and reperfusion. The authors demonstrated that vagotomy worsens the inflammatory response and intestinal damage and increases mortality in a murine model of ischemia and reperfusion injury. This enhancement of gut injury after vagotomy is a clear evidence that a vagal anti-inflammatory pathway is physiologically active under conditions of gut ischemia and mediates the inflammatory reflex. As the authors well acknowledge in their discussion, this neuroimmunomodulatory mechanism has potentials to contribute additional therapeutic strategies for limiting injury associated with clinical conditions of gut hypoperfusion. While these observations are promising, however, question remains whether maintenance of the cholinergic antiinflammatory pathway through pharmacological agonists should be considered in patients where the vagotomy procedure is an unavoidable treatment approach.
The last basic science study by Wu et al. (16) further reinforces the importance of the cholinergic pathway in the control of the inflammatory and immune responses. The study focuses on the macrophage signaling pathways downstream of the nucleotide-binding oligomerization domain-like receptors that respond to bacterial insults by recognizing muramyl dipeptide (MDP). In a series of comprehensive in vitro studies, the authors document that the macrophage inflammatory response elicited by MDP stimulation is effectively inhibited by activation of the cholinergic pathway through the α7 nicotinic acetylcholine receptor agonist, GTS-21. The authors provide also evidence that upregulation of erbin, a widely expressed protein that participates in inhibition of several intracellular signaling pathways, is the most likely mechanism of action of the anti-inflammatory effect of GTS-21. The work of Wu et al. is, therefore, extremely important because it offers molecular insights into the beneficial effects of vagal stimulation that have been observed in several inflammatory models of inflammation, sepsis, trauma, and ischemia and reperfusion injury. Based on these findings, it would be also very interesting to further examine the role of erbin as a potential therapeutic target in these conditions.
Finally, this remarkable issue of Shock concludes with an editorial comment on the future of basic science research in sepsis in view of the revised definition and guidelines for sepsis and septic shock (Sepsis 3) (17). Despite the significant advances in fundamental basic science, Osuchowski et al. (17) argue for a much more careful process in the design of preclinical models of sepsis to promote rapid yet responsible advances appropriate for clinical translation. The authors propose that guidelines for the conduct of preclinical sepsis research should be developed and should set high standards yet offering concrete mechanisms of research, such as the creation of minimum quality threshold in preclinical sepsis studies. The authors also describe key elements of a hypothetical process through the organization of working groups from which these guidelines should emerge. We certainly agree with the authors that more integrated set of principles and best practices are needed to assure clinical relevance; however, we must acknowledge that new challenges can always arise and the collaborative work between basic scientists and clinicians is very important for the reinterpretation and revision of such principles.
In summary, this is another great issue of Shock. We are certain that these exceptional 17 articles will satisfy scientists interested in sepsis, trauma, and burn and we would like to express our appreciation to all the authors for their commitment to basic science and clinical research for a better care of our patients.
1. Etchill EW, Myers SP, Raval JS, Hassoune A, SenGupta A, Neal MD. Platelet transfusion in critical care and surgery: evidence-based review of contemporary practice and future directions. Shock
2. Long E, Oakley E, Duke T, Babl FE. on behalf of the Paediatric Research in Emergency Departments International Collaborative (PREDICT). Does respiratory variation in inferior vena cava diameter predict fluid responsiveness: a systematic review and meta-analysis. Shock
3. Antonucci E, Gleeson PJ, Annoni F, Agosta S, Orlando S, Taccone FS, Velissaris D, Scolletta S. Angiotensin II in refractory septic shock. Shock
4. Fox EE, Holcomb JB, Wade CE, Bulger EM, Tilley BC. on behalf of the PROPPR Study Group. Earlier endpoints are required for hemorrhagic shock trials among severely injured patients. Shock
5. Park J, Hwang SY, Jo IJ, Jeon K, Suh GY, Lee TR, Yoon H, Cha WC, Sim MS, Carriere KC, et al. Impact of metformin use on lactate kinetics in patients with severe sepsis and septic shock. Shock
6. Varis E, Pettilä V, Poukkanen M, Jakob SM, Karlsson S, Perner A, Takala J, Wilkman E. the FINNAKI study group. Evolution of blood lactate and 90-day mortality in septic shock. a post hoc
analysis of the FINNAKI study. Shock
7. Janak JC, Stewart IJ, Sosnov JA, Howard JT, Siew ED, Chan MM, Wickersham N, Ikizler TA, Chung KK. Urinary biomarkers are associated with severity and mechanism of injury. Shock
8. Ramirez P, Villarreal E, Gordon M, Gómez MD, de Hevia L, Vacacela K, Gisbert T, Quinzá A, Ruiz J, Alonso R, et al. Septic participation in cardiogenic shock: exposure to bacterial endotoxin. Shock
9. Mathias B, Mira JC, Rehfuss JP, Rincon JC, Ungaro R, Nacionales DC, Lopez MC, Baker HV, Moldawer LL, Larson SD. LPS stimulation of cord blood reveals a newborn-specific neutrophil transcriptomic response and cytokine production. Shock
10. Kao K-C, Chiu L-C, Hung C-Y, Chang C-H, Yang C-T, Huang C-C, Hu H-C. Coinfection and mortality in pneumonia-related acute respiratory distress syndrome patients with bronchoalveolar lavage: a prospective observational study. Shock
11. Arakaki LSL, Bulger EM, Ciesielski WA, Carlbom DJ, Fisk DM, Sheehan KL, Asplund KM, Schenkman KA. Muscle oxygenation as an early predictor of shock severity in trauma patients. Shock
12. Heipertz EL, Harper J, Walker WE. STING and TRIF contribute to mouse sepsis, depending on severity of the disease model. Shock
13. Chang AL, Kim Y, Seitz AP, Schuster RM, Lentsch AB, Pritts TA. Erythrocyte-derived microparticles activate pulmonary endothelial cells in a murine model of transfusion. Shock
14. Zhou Y, Liu T, Duan J-X, Li P, Sun G-Y, Liu Y-P, Zhang J, Dong L, Lee KSS, Hammock BD, et al. Soluble epoxide hydrolase inhibitor attenuates lipopolysaccharide-induced acute lung injury and improves survival in mice. Shock
15. Ri M, Fukatsu K, Miyakuni T, Yanagawa M, Murakoshi S, Yasuhara H, Seto Y. Influences of vagotomy on gut ischemia-reperfusion injury in mice. Shock
16. Wu X-J, Yang X-M, Song X-M, Xu Y, Li J-G, Wang Y-L, Zhang Z-Z, Le L-L, Liang H, Zhang Y. The role of Erbin in GTS-21 regulating inflammatory responses in MDP-stimulated macrophages. Shock
17. Osuchowski MF, Thiemermann C, Remick DG. Sepsis-3 on the block: what does it mean for preclinical sepsis modeling? Shock