As we start a new year, let's pause for a moment to appreciate the fact that the scientific landscape is becoming increasingly flat. Groundbreaking scientific discoveries are not limited to just a few countries and a handful of premier institutions. Newer scientific technologies/tools are cheaper, more efficient, user-friendly, and widely available, which has made it easier than ever to engage in meaningful research. Not surprisingly, there has been an explosion in the number of new publications, both in print and online. What makes Shock standout in this crowded field is its long-standing commitment to publishing the highest quality research, from very different sources, targeting an audience that is passionate about shock-related conditions. By acting as the official publication of the Shock Society, the European Shock Society, the Indonesian Shock Society, the International Federation of Shock Societies, and the Official and International Journal of the Japan Shock Society, this journal truly brings to life the famous quote by Malcolm Forbes: “Diversity: the art of thinking independently together”. The January 2020 issue of Shock maintains this tradition by publishing 15 high-caliber scientific articles, with very diverse geographical origins, that cover themes ranging from basic science to clinical translation. Here is our brief analysis of each article.
In this issue, two fantastic studies from Germany talk about the alterations in immune cells following sepsis and trauma. Immune cells undergo radical changes following injury. Studying these changes is critical to understanding the role of immune responses in the morbidity and mortality in septic and injured patients. Schenz et al. (1), in the first article of the issue, describe the intracellular metabolic changes in monocytes and B-lymphocytes that result in sepsis-associated immunosuppression. In this prospective observational study (septic patients and healthy volunteers; n=10 per group), they found that following sepsis, the white cells exhibit a decreased HLA-DR expression, increased anaerobic respiration, defects in TCA cycle, and an overall impaired inflammatory response. The other study (4th article in the issue) is from Ruhrmann et al. The authors studied the alterations in T-cells and monocytes 6 months after a major traumatic event (2). They found that trauma patients had significantly different expression of cell surface receptors. There was also a trend toward decreased levels of IL6 and TNF-α following LPS stimulation. Overall, these findings collectively fill an important gap in knowledge on the possible mechanisms that disrupt the subtle balance between proinflammatory and anti-inflammatory responses to sepsis and trauma that can result in immunosuppression.
We know that tissue trauma can result in systemic responses that can damage the organs that were not directly injured. It is well described that our innate immune responses play a critical role in mediating multiorgan dysfunction in trauma. Activation of complement system is one possible explanation of this phenomenon. In the second article of the issue, researchers from the Harvard Medical School describe the role of complement activation (3). They found that in trauma patients, complement factors C3d, C4d, and C5b-9 can attach to the surface of RBCs and result in the production of nitric oxide (NO) in the circulation. NO, in-turn, can affect the vascular tone and limit RBC's ability to pass through capillaries—compromising oxygen delivery to the tissues. More interestingly, this deposition of complement factors on RBCs was found to be significantly correlated with injury severity score (ISS). This finding is intriguing, and it expands on the previous knowledge that complement activation and deposition on RBCs can not only serve as a biomarker for trauma severity, but can also influence the effectiveness of the drugs that inhibit complement activation.
Traumatic brain injury (TBI) affects millions of individuals annually. We know that TBI rarely occurs in isolation and is frequently associated with polytrauma. The current understanding of the differences in inflammatory responses to TBI + polytrauma (TBI group) versus polytrauma alone (polytrauma group) is limited. In their study, Rowland et al. (4) performed a robust network analysis on the cytokine expression data between these groups. They found that the TBI patients had an augmented inflammatory response with higher IL6, IL8, and CCL2 levels at 6 hours following injury, and a higher 30-day mortality. They also discovered that the networks of cytokines in TBI and polytrauma undergo divergent trends from admission to 6 hours. However, these analyses were done on plasma samples. In future, it would be interesting to see the differences (and similarities) in central inflammation and the cerebrospinal fluid. Since TBI can disrupt the BBB, it would be important to determine how faithfully the circulating biomarkers reflect the actual changes in the brain.
Next in line is a secondary analysis of the famous CardShock study, in which Lindholm et al. (5) evaluate the changes and prognostic ability of lactate levels in cardiogenic shock. Lactate is produced widely in the body, both as a result of tissue hypoperfusion and adrenergic stress. Role of lactate in cardiogenic shock is a rapidly evolving area of research. The authors discovered that for patients in cardiogenic shock, the baseline lactate level was a strong predictor of 30-day mortality with the hazard ratio (HR) of 1.20 mmol/L (95% CI, 1.14–1.27). This correlation between lactate levels and 30-day mortality was significant on serial measurements at 6, 12, and 24 h following admission. It was also noted that a relative change in lactate in the first 24 h following admission to intensive care unit (ICU) was significantly linked to a reduction in mortality. This information is critical in determining the role of lactate monitoring, and its reliability in predicting mortality in cardiogenic shock. Even though the patient cohort recruited for the study was heterogeneous, and the treatment provided was tailored to the personal needs of each patient, we think that this is an excellent study that adds to the growing knowledge that can help clinical decision making in these challenging patients.
Next article is a meta-analysis by Wu et al. (6) from China in which they evaluate the two commonly used vasopressors; norepinephrine (NE) and vasopressin (VP), in the management of septic shock. Targeting a mean arterial pressure (MAP) goal to maintain tissue perfusion is routine in the management of septic shock, and this often requires administration of vasoactive agents like NE and VP. Recent Surviving Sepsis Campaign (SSC) guidelines encourage attaining the targeted MAPs quickly, which typically requires aggressive fluid resuscitation, and often the administration of both of these vasoactive agents (NE followed by VP). However, these guidelines do not highlight which one of the vasopressors should be discontinued first once the shock has resolved. The authors, through this study, tried to address this simple yet thoughtful question. In their meta-analysis, the primary outcome was the incidence of hypotension, and the secondary outcomes were overall mortality, ICU mortality, and length of stay (LOS). They found that the incidence of hypotension was significantly lower when NE was discontinued first (odds ratio (OR), NE vs VP = 0.3, 95% CI, 0.10–0.86, P = 0.02). But no difference was observed in the overall or ICU mortality, and LOS. However, it is to be noted that the meta-analysis included 7 retrospective cohort studies and only one prospective trial, and the cumulative sample size was too small to provide sufficient evidence to draw conclusions. It should also be pointed out that a higher MAP does not necessarily translate into better tissue perfusion (blood flow). In relating Ohm's Law to blood flow, resistance is as important as pressure. Thus, vasoactive agents can generate a higher MAP, while theoretically still have low flow (or worse tissue perfusion) due to increased arteriolar/capillary tone (higher resistance). Furthermore, it is important to realize that while NE has inotropic effects, vasopressin does not directly augment cardiac stroke volume. Clearly, we need a trial where in addition to measuring the MAP, we are also evaluating parameters of tissue perfusion, to really answer the question—which of these agents to wean first?
The next two articles are about the essential micronutrient—selenium (Se). Se is a component of antioxidative enzymes like glutathione peroxidase, and therefore plays a vital role in the elimination of reactive oxygen species (ROS) during oxidative stress. Majority of Se in our body is transported and stored in the form of selenoprotein P (SelP). Animal models of myocardial infarction (MI) have demonstrated that Se administration results in the neutralization of ROS and decreases myocardial injury following ischemia/reperfusion (I/R). Büttner et al. (7) investigated the relationship of SelP levels and patient outcomes post-acute MI. In this follow-up study to the Intra-Aortic Balloon Pump in Cardiogenic Shock (IABP-SHOCK II) trial, the authors found that SelP levels were significantly elevated on days 1 and 3 following an MI (day 1: 2.7-fold increase, day 3: 5.7-fold increase, both P < 0.0001). Paired sample analysis showed that there was a significant increase in SelP levels from day 1 to day 3 (day 1: 6.1 mg/mL (IQR 3.5–12.3); day 3: 22.5 mg/mL (IQR 13.4–27.5); P < 0.0001) following MI. There was also a proportional correlation between C-reactive protein (CRP), an acute phase reactant, and Se1P levels at days 1 and 3 following MI. They also noted that the patients with highest SelP at day 3 had a higher risk of mortality; however, this association was not valid after performing a multivariate analysis. This shows that there may be other more significant contributors to mortality. Overall, we think that Se and SelP monitoring in cardiogenic shock shows promise and its utility should be verified in future prospective studies.
We know that a deficiency of Se is associated with systemic inflammatory response syndrome (SIRS) following trauma, which may worsen outcomes. In the next study, Braunstein et al. (8) characterized the relationship of Se and SelP to outcomes in critically ill trauma patients. Blood was serially drawn from trauma patients for 72 hours following admission and the levels of Se and SelP were compared with various clinical parameters. The authors found that the Se and SelP levels decreased very rapidly following trauma and remained lower than those in healthy subjects at all time points. Among the trauma patients, those who had lower levels of Se and SelP at 1 h time point had higher 30-day mortality rates. A similar association was seen between Se and SelP levels and the APACHE II score; a commonly used mortality predicator in current clinical practice. However, it is to be noted that these trauma patients received individualized fluid resuscitation upon admission, which may have affected the results. In future studies, it will be interesting to see whether an early administration of Se can result in better clinical outcomes in trauma patients.
Next in the issue is an article from an ever-evolving area of research—ageing and burn mortality. Dr. Kovacs and her team from Colorado used a murine model of scald burn injury to identify age-related differences in gut microbiome in response to burns (9). Fecal pellets were collected from young and aged mice at 24 h following injury and 16S rRNA gene sequencing was performed to profile the bacterial colonies. The authors found that burn injury resulted in a more severe dysbiosis in gut microbiota in the aged mice as compared to the young mice. They are the first to discover an age-dependent variation in ileal AMP expression profiles between young and aged mice, showing an age-related disparity in host responses toward bacterial elimination. They propose that this disparity in host responses is likely to be exaggerated following burn injury. Even though this is a proof-of-concept study at this stage, these findings fill in major gaps in knowledge and provide directions for future studies to identify specific factors that result in higher mortality in the older burn patients.
Microvesicles (MVs) are a novel and rapidly expanding area of exciting research. In their study, Qiao et al. (10) from Germany tested the role of MVs (derived from murine femoral fracture model) in osteoblast function. They found that MVs were incorporated into the osteoblasts (cultured from the cranial bone of neonatal rats) in a time-dependent fashion. Interestingly, there was a positive correlation in the stimulatory effect of MVs and the post-fracture time at which they were collected. It was noted that while MVs improved the viability of osteoblasts, they had only minimal effect on osteoblast differentiation. These findings provide an insight into the potential of MVs as a therapeutic agent than can modulate fracture healing.
Moderate hypercapnia is a common by-product of acute respiratory distress (ARDS) in sepsis. During sepsis, hypercapnia improves intestinal microcirculation and attenuates intestinal hypoxia. At the same time, there is growing evidence that statins, commonly prescribed for hypertriglyceridemia and heart disease, can improve intestinal circulation in sepsis. However, a recent meta-analysis showed that this therapeutic effect of statins is washed out in the patients with ARDS (who have moderate hypercapnia). Schulz et al. (11), in their well-designed study in a murine model of colon ascendens stent peritonitis (CASP)-induced sepsis, showed that pravastatin pretreatment improves the intestinal microvascular oxygenation without changes in the microcirculatory flow, and this effect is eliminated when these pravastatin pretreated rats were exposed to hypercapnia. We find this proof-of-concept study to be very interesting, and it demonstrates that statins may have a limited role in septic patients with ARDS; however, any clinical extrapolation from this preclinical murine study should be made with caution. It will be important to verify these findings in more translational, larger animal models.
Next study in the issue is by Dr. Chen's team from China, who describe the role of early peritoneal dialysis (PD) in attenuating blast injury (12). The authors discovered that in a murine model of shock-tube induced blast injury, pulmonary edema and histopathological lung injury scores were significantly lower in rats that received early PD and PD + glucocorticoids (GC) as compared to control. No synergy was noticed between PD and GC. Lung function parameters such as PO2/FiO2, vital capacity, and functional residual capacity were also significantly higher in PD and PD+GC groups when compared to control. Considering that this study involves a small animal model and therefore the findings have limited clinical relevance, we think that the role of early PD in blast induced trauma is promising and should be confirmed in future studies.
Next in the issue is another excellent contribution from China in which Liu et al. (13) demonstrate the possible mechanisms through which α-ketoglutarate (α-KG) attenuates sepsis-induced ALI/ARDS. In healthy individuals, the M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages in the lung maintain a fine balance, which is disturbed by sepsis-induced ALI/ARDS. α-KG attenuates inflammation by increasing macrophage polarization toward the M2 phenotype. In the current study, the authors demonstrated that α-KG administration decreases ALI in rats with LPS-induced sepsis. They found that α-KG shifted the macrophage polarization toward the M2 phenotype in MH-S cells (a cell-line of murine alveolar macrophages) via various pathways (including the MTOR and PPARY pathways). These findings are novel, and certainly of interest as they may provide future targets for pharmacologic treatment of sepsis-induced ALI/ARDS. We look forward to more work from this team of researchers to test these findings in other cell-lines and large animal models.
Sepsis causes impairment in neutrophil chemotaxis. Tan et al. (14) discovered that glycolytic inhibitor 2-deoxyglucose (2-DG) provides a survival benefit in a cecal ligation and puncture (CLP)-model in mice through improved neutrophil migration and bacterial clearance. The authors found that by inhibiting the induction of G-protein-related receptor kinase 2 (GRK2) expression following sepsis, 2-DG counteracted the downregulation in chemokine receptor 2 (CXCR-2) expression that normally occurs in sepsis. Increased CXCR-2 expression on neutrophils consequently reversed the impairment in neutrophil chemotaxis and improved neutrophil migration and bacterial clearance. This is a valuable addition to the growing literature of sepsis-induced neutrophil dysfunction. We are anticipating future work from this team and would encourage them to verify these findings in more clinically translational models.
Last, but not the least, is an excellent porcine study from Czech Republic by Chvojka et al. (15). They use a model of intraperitoneal fecal inoculation to produce refractory vasodilatory shock (RVS) in swine to test whether mechanical ventilation via extracorporeal membrane oxygenation (ECMO) has any benefit in RVS. Due to its high mortality rates and the paucity of alternative treatments, treating RVS can be very challenging. While mechanical support with ECMO has gained significant attention recently, its implications in adult RVS are not well described. With no convincing guidelines, there is a tremendous discord in the utilization of ECMO for RVS in sepsis. In the current study, the authors demonstrated that the addition of ECMO to the management of RVS in swine resulted in a significantly elevated fluid (fluids; ECMO vs control (mL/kg/h); 21 (20–25) vs 10 (10–16), P = 0.0103) and vasopressor requirement with no changes in time-to-death (time from randomization to death; ECMO vs control (hours); 7.1 (5.9–9.6) vs 7.9 (7.1–8.7), P = 0.10). There was also a delayed deterioration in the renal and carotid blood flow in the ECMO group. Upon detailed testing of organ function, the authors did not find any differences between the ECMO group and control. This study fills an important gap in knowledge using a clinically translational model of sepsis-induced RSV. However, we think that more studies are required to validate these findings. Also, it would be interesting to see more work on the mechanisms that result in worse vasodilatory status following the use of ECMO in RVS.
Overall, we are excited to report that this issue of Shock is filled with cutting edge research from prolific research teams around the world. We hope that you enjoy reading it as much as we did. Have a Happy New Year.
1. Schenz J, Tamulyte S, Nusshag C, Brenner T, Poschet G, Weigand MA, Uhle F. Population-specific metabolic alterations in professional antigen-presenting cells contribute to sepsis-associated immunosuppression. Shock
2. Ruhrmann S, Schneck E, Markmann M, Zink J, Zajonz TS, Arens C, Uhle F, Sander M, Koch C. Trauma-induced long-term alterations of human T cells and monocytes—results of an explorative, cross-sectional study. Shock
3. Satyam A, Andreo K, Lapchak PH, Dalle Lucca JJ, Davis RB, Tsokos MG, Shapiro NI, Tsokos GC. Complement deposition on the surface of RBC after trauma serves a biomarker of moderate trauma severity: a prospective study. Shock
4. Rowland B, Savarraj JPJ, Karri J, Zhang X, Cardenas J, Choi HA, Holcomb JB, Wade CE. Acute inflammation in traumatic brain injury and polytrauma patients using network analysis. Shock
5. Lindholm MG, Hongisto M, Lassus J, Spinar J, Parissis J, Banaszewski M, Silva-Cardoso J, Carubelli V, Salvatore dS, Sionis A, et al. Serum lactate and a relative change in lactate as predictors of mortality in patients with cardiogenic shock – results from the CardShock study. Shock
6. Wu Z, Zhang S, Xu J, Xie J, Huang L, Huang Y, Yang Y, Qiu H. Norepinephrine vs. vasopressin: which vasopressor should be discontinued first in septic shock? A meta-analysis. Shock
7. Büttner P, Obradovic D, Wunderlich S, Feistritzer H-J, Holzwirth E, Lauten P, Fuernau G, de Waha-Thiele S, Desch S, Thiele H. Selenoprotein P in myocardial infarction with cardiogenic shock. Shock
8. Braunstein M, Kusmenkov T, Zuck C, Angstwurm M, Becker N-P, Böcker W, Schomburg L, Bogner-Flatz V. Selenium and selenoprotein P deficiency correlates with complications and adverse outcome after major trauma. Shock
9. Wheatley EG, Curtis BJ, Hulsebus HJ, Boe DM, Najarro K, Ir D, Robertson CE, Choudhry MA, Frank DN, Kovacs EJ. Advanced age impairs intestinal antimicrobial peptide response and worsens fecal microbiome dysbiosis following burn injury in mice. Shock
10. Qiao Z, Wang W, Luo P, Hofman M, Horst K, Müller-Newen G, Greven J, Hildebrand F. The impact of plasma-derived microvesicles from a femoral fracture animal model on osteoblast function. Shock
11. Schulz J, Vollmer C, Truse R, Bauer I, Beck C, Picker O, Herminghaus A. Effect of pravastatin pretreatment and hypercapnia on intestinal microvascular oxygenation and blood flow during sepsis. Shock
12. Chen K, Yang J, Xiao F, Chen J, Hu W, Wang X, Wang L, Du J, Jiang J, He Y. Early peritoneal dialysis ameliorates blast lung injury by alleviating pulmonary edema and inflammation. Shock
13. Liu M, Chen Y, Wang S, Zhou H, Feng D, Wei J, Shi X, Wu L, Zhang P, Yang H, et al. α-Ketoglutarate modulates macrophage polarization through regulation of PPARγ transcription and MTORC1/P70S6K pathway to ameliorate ALI/ARDS. Shock
14. Tan C, Gu J, Chen H, Li T, Deng H, Liu K, Liu M, Tan S, Xiao Z, Zhang H, et al. Inhibition of aerobic glycolysis promotes neutrophil to influx to the infectious site via CXCR2 in sepsis. Shock
15. Chvojka J, Martinkova V, Benes J, Valesova L, Danihel V, Nalos L, Matejovic M. Mechanical circulatory support in refractory vasodilatory sepsis shock: a randomized controlled porcine study. Shock