The April 2019 issue of Shock provides a fresh mixture of clinical observational and preclinical translational studies centered on important aspects of sepsis, inflammation, organ injury, and critical illness. The main theme of the clinical studies in this issue of Shock is the quest for biomarkers to predict outcomes in critical illness. In a single-center prospective observational study, Kastl et al. (1) evaluated whether systemic levels of intestinal fatty acid-binding protein (iFABP, also known as fatty acid-binding protein 2 (FABP2)) could serve as outcomes biomarker in patients with acute heart failure or cardiogenic shock. The authors observed in 90 consecutive patients that high iFABP levels on the day of intensive care unit admission were associated with low 30-day survival, thus suggesting potential predictive value of iFABP in these patient populations. Because iFABP expression is limited to the intestine and released into the systemic circulation from injured or hypoxic enterocytes, the authors conclude that early intestinal hypoperfusion might be associated with mortality in patients with acute heart failure or cardiogenic shock (1). In another prospective observational study Barnaby et al. (2) enrolled 1,247 patients to derive and evaluate a predictive model containing clinical, laboratory, and heart rate variability measures to quantify risk of deterioration in patients with sepsis admitted to the emergency department. The authors show that the combination of laboratory values and heart rate variability metrics improves prediction of clinical deterioration, suggesting that such a model could facilitate risk stratification for sepsis patients in the emergency department.
In two retrospective observational studies, changes in leukocyte counts and morphology were associated with outcomes (3, 4). Chung et al. (3) performed a retrospective analysis of prospectively collected data to evaluate the associations of circulating monocyte counts with mortality, bacteremia and organ dysfunction in sepsis and septic shock patients. Furthermore, the authors were able to compare monocyte counts at the manifestation of sepsis with monocyte counts that were obtained 3 months to 2 weeks prior to the manifestation of sepsis. Chung et al. report that monocyte counts were independently associated with mortality in multivariate logistic regression analyses and that sepsis patients with low initial monocyte counts showed the highest mortality, rates of bacteremia, and organ dysfunction. Interestingly, relative to their presepsis monocyte counts, initial monocyte counts at the manifestation of sepsis were increased in survivors but decreased in non-survivors. The authors conclude that the associations between monocyte counts and mortality, bacteremia or organ dysfunction could be due to the relative lack of monocytopoiesis related to septic insults in non-survivors.
In a retrospective clinical study, Hesselink et al. (4) observed that patients who develop organ dysfunction postinjury show changes in neutrophil characteristics before organ dysfunction becomes clinically evident. Although the number of patients who developed organ dysfunction was small (11 out of 157), a rise in neutrophil cell size preceded the clinical manifestation of organ dysfunction in every single patient, suggesting that these observations could have the potential to facilitate development of new prognostic tools for trauma-related complications.
Glyphosate-surfactant herbicide is one of the most commonly used herbicides and accounts for large proportions of patients with herbicide poisoning. Mortality from glyphosate-surfactant herbicide poisoning is significant and no antidote is available. As treatment of glyphosate-surfactant herbicide poisoning is limited to supportive therapy, early identification of patients who develop organ dysfunction is important. In a retrospective observational study Cho et al. (5) report that the quick sequential organ failure assessment (qSOFA) score measured upon arrival to the emergency department shows good prognostic performance in patients with glyphosate-surfactant herbicide poisoning and may predict the development of life-threatening complications.
Besides these clinical correlative studies to predict outcomes, another clinical study addressed the timely topic of stem and progenitor cell mobilization in severely injured patients. Although the mobilization of endogenous and the administration of exogenous stem and progenitor cells are thought to be beneficial after severe trauma, little information on the temporal pattern of the mobilization of endogenous stem and progenitor cells into the systemic circulation is available. To fill this gap, Vogel et al. (6) performed a prospective observational case series that included 10 severely injured patients with an Injury Severity Score > 21 and analyzed the temporal patterns of stem and progenitor cells along with a panel of cytokines/chemokines that have been linked to stem cell mobilization and inflammation in the peripheral blood within 0 to 120 hours post-trauma. The authors identified specific patterns of stem and progenitor cell mobilization, suggesting that migration of these cells into damaged tissues is not a continuous process and rather occurs at specific time points after trauma.
Several of the preclinical studies in this issue of Shock are focused on translational aspects in the pathophysiology and treatment of sepsis. Expanding upon their previous observations that chronic ethanol consumption worsens outcomes in a cecal ligation and puncture model, Klingensmith et al. (7) tested whether these previous findings can be confirmed in another sepsis model. The authors show in a Pseudomonas aeruginosa pneumonia model in mice that chronic alcohol consumption prior to the septic insult is associated with altered organ immune responses and increases mortality. Thus, the authors provide another line of preclinical evidence that chronic alcohol consumption increases the risk of sepsis-associated mortality.
While stem-cell-based therapies for sepsis show great promise and are under intense investigation, Collins et al. (8) shed light on fibrocyte transfer as a potential new cell-based therapy for sepsis. The authors show that adoptive transfer of fibrocytes at the time of cecal ligation and puncture as well as 2 hours after cecal ligation and puncture increased survival in mice. In addition, the authors provide evidence that direct phagocytic activity of the transferred fibrocytes may enhance bacterial clearance and contribute to the beneficial effects observed in their model, thus providing a mechanistic basis for their observations (8).
Xu et al. (9) investigated whether end-tidal carbon dioxide could be useful to guide fluid resuscitation in a cecal ligation and puncture sepsis model in rats. Utilizing physiologically relevant read outs, the authors report that end-tidal carbon dioxide-guided fluid resuscitation is superior to blood pressure-guided fluid resuscitation in this model. These findings suggest that incorporating end-tidal carbon dioxide into resuscitation algorithms may help to optimize sepsis resuscitation and to improve outcomes.
Di Caro et al. (10) expanded on their previous findings that dietary supplementation of cellulose, a non-fermentable fiber, conferred a survival benefit in sepsis models and was associated with altered immune responses and changes in the gut microbiome. In the present study Di Caro et al. utilized a mouse endotoxin-induced peritonitis model to characterize the immunological profile and activation status of macrophages, dendritic and T cells in mice on a high-fiber cellulose diet. They observed decreased number and activation of splenic macrophages and dendritic cells, and amplification of the suppressive function of Tregs and induced anergy in T cells with dietary cellulose supplementation. Although the potential therapeutic effects of a cellulose supplemented diet that is initiated after the onset of sepsis remain to be determined, their findings further support the concept that a cellulose supplemented diet could limit a harmful immune activation in sepsis.
Hessler et al. (11) evaluated whether the conjunctiva could be used as an easily accessible location for monitoring microcirculation in ovine models of septic and hemorrhagic shock. Utilizing the sublingual microcirculation as a reference point, the authors show that changes in the conjunctival microcirculation during hemorrhagic and septic shock resemble those of the sublingual microcirculation, suggesting the conjunctiva as an alternative monitoring site.
Three of the preclinical studies in this issue of Shock address basic science and therapeutic aspects of traumatic-hemorrhagic shock and lung injury. Hydrogen sulfide availability is thought to be important during hemorrhage and acute lung injury. While protective roles of cystathionine-γ-lyase have been well described, Gröger et al. studied the potential contribution of 3-mercaptopyruvate sulfurtransferase, which is primarily responsible for mitochondrial hydrogen sulfide production, to physiologically relevant outcomes in a genetic model. Here the authors utilized the Δ3-mercaptopyruvate sulfurtransferase strain of mice, which shows 3-mercaptopyruvate sulfurtransferase deficiency in the lung and spleen (12). Consistent with previous observations in murine endotoxemia, the authors did not observe physiologically relevant effects of 3-mercaptopyruvate sulfurtransferase deficiency on organ function in a sophisticated mouse model of hemorrhagic shock and blunt chest trauma, based on which the authors conclude that 3-mercaptopyruvate sulfurtransferase does not play a significant role in the pathophysiology of traumatic hemorrhagic shock (12).
Therapeutic interventions for acute lung injury and acute respiratory distress syndrome are currently limited to lung-protective treatment strategies and novel therapeutic approaches are urgently needed. Two preclinical translational studies suggest new therapeutic targets for therapeutic intervention in indirect acute lung injury. Cheng et al. (13) studied the functional role of the transmembrane molecule herpes virus entry mediator (HVEM, also known as tumor necrosis factor receptor superfamily-14) in the development of acute lung injury induced in a two-hit model of hemorrhagic shock and cecal ligation and puncture in mice. The authors provide evidence for upregulation of pulmonary HVEM in acute lung injury and show that intrabronchial HVEM-siRNA treatment reduces inflammation, attenuates development of lung injury, and provides an early survival benefit. Furthermore, based on previous observations on glutamate levels and inhibition of the adenosine A2A receptor, Bai et al. (14) tested how modulation of blood glutamate levels in combination with inhibition of the adenosine A2A receptor would reduce traumatic brain injury-induced acute lung injury in mice. The authors provide pharmacological evidence that L-glutamate worsens traumatic brain injury-induced acute lung injury and that this effect is exaggerated when an adenosine A2A receptor agonist is coadministered. Conversely, strategies that reduced endogenous glutamate levels attenuated traumatic brain injury-induced acute lung injury, which was further enhanced in adenosine A2A receptor knockout mice.
In addition, Cao et al. (15) investigated the contribution of Nod-like receptor protein (NLRP) 1 inflammasome activation to myocardial ischemia-reperfusion injury in a mouse model of left anterior descending coronary artery ligation and reperfusion and in hypoxia/reoxygenation-treated primary mouse cardiomyocytes. The authors provide several lines of molecular evidence suggesting that activation of the NLRP1 inflammasome, possibly via endoplasmatic reticulum stress-induced activation of the NF-κB signaling pathway, promotes myocardial ischemia-reperfusion injury.
Finally, in their efforts to optimize organ quality in brain dead organ donors, de Jesus Correia et al. utilized a rat brain death model to compare resuscitation with normal and hypertonic saline solution. The authors show that hypertonic saline resuscitation improves mesenteric microcirculation and reduces inflammation, a finding that could lead to the use of hypertonic saline to improve organ integrity in brain dead organ donors (16).
1. Kastl SP, Krychtiuk KA, Lenz M, Distelmaier K, Goliasch G, Huber K, Wojta J, Heinz G, Speidl WS. Intestinal fatty acid binding protein is associated with mortality in patients with acute heart failure or cardiogenic shock. Shock
2. Barnaby DP, Fernando SM, Herry CL, Scales NB, Gallagher EJ, Seely AJE. Heart rate variability, clinical and laboratory measures to predict future deterioration in patients presenting with sepsis. Shock
3. Chung H, Lee JH, Jo YH, Hwang JE, Kim J. Circulating monocyte counts and its impact on outcomes in patients with severe sepsis including septic shock. Shock
4. Hesselink L, Heeres M, Paraschiakos F, ten Berg M, Huisman A, Hoefer IE, de Groot MCH, van Solinge WW, Dijkgraaf M, Hellebrekers P, et al. A rise in neutrophil cell size precedes organ dysfunction after trauma. Shock
5. Cho YS, Moon JM, Chun BJ, Lee BK. Use of qSOFA score in predicting the outcomes of patients with glyphosate surfactant herbicide poisoning immediately upon arrival at the emergency department. Shock
6. Vogel M, Christow H, Manz I, Denkinger M, Amoah A, Schütz D, Brown A, Möhrle B, Schaffer A, Kalbitz M, et al. Distinct dynamics of stem and progenitor cells in blood of polytraumatized patients. Shock
7. Klingensmith NJ, Fay KT, Lyons JD, Chen C-w, Otani S, Liang Z, Chihade DB, Burd EM, Ford ML, Coopersmith CM. Chronic alcohol ingestion worsens survival and alters gut epithelial apoptosis and CD8+
T cell function after pseudomonas aeruginosa
pneumonia-induced sepsis. Shock
8. Collins D, Fry C, Moore BB, Nemzek JA. Phagocytosis by fibrocytes as a mechanism to decrease bacterial burden and increase survival in sepsis. Shock
9. Xu J, Zheng G, Wu L, Fang X, Wang Y, Jiang L, Ling Q, Yang Z, Tang W. Effects of end-tidal carbon dioxide-guided fluid resuscitation on outcomes in a cecal ligation and puncture induced rat model of sepsis. Shock
10. Di Caro V, Cummings JL, Alcamo AM, Piganelli JD, Clark RSB, Morowitz MJ, Aneja RK. Dietary cellulose supplementation modulates the immune response in a murine endotoxemia model. Shock
11. Hessler M, Arnemann P-H, Zamit F, Seidel L, Kampmeier T-G, Kathöfer U, Alnaweisch M, Tchaichian S, Rehberg S, Ertmer C. Monitoring of conjunctival microcirculation reflects sublingual microcirculation in ovine septic and hemorrhagic shock. Shock
12. Gröger M, Wepler M, Wachter U, Merz T, McCook O, Kress S, Lukaschewski B, Hafner S, Huber-Lang M, Calzia E, et al. The effects of genetic 3-mercaptopyruvate sulfurtransferase deficiency in murine traumatic-hemorrhagic shock. Shock
13. Cheng T, Bai J, Chung C-S, Chen Y, Fallon EA, Ayala A. Herpes virus entry mediator (HVEM) expression promotes inflammation/organ injury in response to experimental indirect-acute lung injury. Shock
14. Bai W, Li P, Ning Y-L, Jiang Y-L, Yang N, Chen X, Zhou Y-G. Reduction in blood glutamate levels combined with the genetic inactivation of A2A
R significantly alleviate traumatic brain injury-induced acute lung injury. Shock
15. Cao L, Chen Y, Zhang Z, Li Y, Zhao P. Endoplasmic reticulum stress-induced NLRP1 inflammasome activation contributes to myocardial ischemia/reperfusion injury. Shock
16. de Jesus Correia C, Armstrong R Jr, Oliveira de Carvalho P, Simas R, Sanches DCJ, Breithaupt-Faloppa AC, Sannomiya P, Moreira LFP. Hypertonic saline solution reduces microcirculatory dysfunction and inflammation in a rat model of brain death. Shock