This issue of Shock features a wide diversity of articles surely to be of interest to our readers, ranging from clinical to translational to basic science on topics ranging from sepsis and inflammation to trauma and burns. To begin with, let us speak from, or at least about, the heart. Xu et al. (1) examined the effect of aortic balloon occlusion in a swine model of hemorrhage-induced cardiac arrest. As the use of aortic balloon occlusion is increasingly being used clinically for patients in severe hemorrhagic shock, studying those in cardiac arrest after hemorrhage is an important area of investigation. The authors demonstrated that a short period (30 min) of aortic occlusion resulted in augmented efficacy of cardiopulmonary arrest and greater cardiac and cerebral protection with milder injuries to the kidneys and intestine compared with a longer period (60 min) of aortic occlusion. This study supports the brief use of aortic occlusion following traumatic arrest. Clinically, this means that upon achievement of return of spontaneous circulation, prompt hemorrhage control is vital. Continuing on the theme of the heart, Takase et al. (2) used a rat model of hemorrhagic shock to investigate whether a liposome-encapsulated human hemoglobin oxygen carrier is comparable in effectiveness to autologous washed red blood cells for improving arrhythmogenic properties after hemorrhage. The authors nicely demonstrated that transfusion of their carrier prevented ventricular tachycardia/fibrillation comparable to transfusion of red cells. This was achieved by preventing electrical remodeling and preserving myocardial structures in hemorrhagic shock-induced cardiac dysfunction. Their artificial oxygen carrier is composed of polyethylene glycol [PEG]-modified liposome-encapsulated hemoglobin that can lead to a longer circulation time but also suppresses intravascular aggregation. Its smaller size may also allow the carrier to more effectively pass through the microcirculation. Who said natural is always better? To end our heart-friendly review, by conducting a systematic review with meta-analysis, Sun et al. (3) sought to determine if Fenoldopam had nephroprotective effects in adult patients undergoing cardiac surgery. Fenoldopam is a short-acting selective dopamine agonist that causes systemic and renal vasodilation through the stimulation of dopamine 1 (DA1) receptors. Results of seven randomized studies involving over 1,000 patients suggest that Fenoldopam did reduce the incidence of acute kidney injury but at the expense of increased hypotension and with no change in the need for renal replacement therapy or mortality. Well, not this time Fenoldopam!
Now onto the lung as the next important organ focus of this issue of Shock. In this cohort study of 746 patients, Holm et al. (4) tackle the difficult problem of describing those patients who do not meet the criteria for adult respiratory distress syndrome (ARDS) but still die or experience persistent dependence on mechanical ventilation. They hypothesized that in patients with ventilator-demanding respiratory failure, a low level of the actin-scavenging protein, gelsolin, would predict a poor prognosis. The authors showed that patients with low baseline gelsolin had a 29% lower chance of being successfully weaned from mechanical ventilation within 28 days and had fewer ventilator free days. However, this prediction did not hold true for surgical patients, illustrating once more a fundamental difference between critically ill medical and surgical patients. Interestingly, endothelial damage did not appear to be associated with a low gelsolin level, suggesting that the lung damage detected by low gelsolin levels is not mediated by endothelial injury. When patients are mechanically ventilated, even moderate tidal volume ventilation can lead to ventilator-induced lung injury, whereas low tidal volume ventilation is known to be protective including following sepsis-related ARDS. Ding et al. (5) investigated the underlying mechanism by subjecting mice to cecal ligation and puncture (CLP). They found that moderate tidal volume dramatically increased systemic and lung inflammation as well as lung injury in an IL-33- and ST2-dependent manner. In contrast, low tidal volume ventilation reduced inflammation and injury relative to non-ventilated mice and suppressed CLP-induced IL-33 upregulation in the lungs. IL-33 is a member of the IL-1 family, which in alveolar type two cells, also functions as a cytokine when released from cells. The receptor complex for IL-33 consists of the specific subunit ST2. This study therefore demonstrates that IL-33 levels after CLP are highly dependent on the mode of ventilation.
Now we shift from an organ specific to a more disease-specific topic. Immunosuppression, whether from sterile inflammation or infection, is associated with morbidity and mortality in disease states such as trauma, surgery, hemorrhage, burns, and sepsis. In the review article by Cavaillon et al. (6), the authors suggest that “immunosuppression” is not appropriate for the described pathogenesis of these diseases. They attempt to demonstrate the concept of immunosuppression as an oversimplification of the complex anti-inflammatory response that occurs in patients. They found that while certain functions of immune cells can be significantly diminished, other functions are either unchanged or even enhanced. Thus, contrary to popular belief, there is no global defect. The authors suggest rather than using the term “immunosuppression,” that we use “reprogramming” to better reflect the immune status of circulating leukocytes in systemic inflammatory response syndrome (SIRS) and septic patients. Both SIRS and sepsis are inflammatory diseases and HMGB1 is a major endogenous mediator. In this issue, Karakike et al. (7) classified patients with SIRS and gram-negative infections into two groups: early and late HMGB1 peak groups. They found that mortality after 28 days was higher in patients with a late peak of HMGB1, and that co-existence of late peak and an inflammatory disease such as diabetes, chronic obstructive pulmonary disease, chronic heart failure, or chronic renal disease synergistically affected mortality. These findings may be of significance for the optimal timeframe and target population in future clinical trial designs concerning therapeutic targeting of HMGB1. Better late than never!
Switching to a younger cohort, this retrospective and observational cohort study by Wu et al. (8), addressed an important challenge for pediatric sepsis care globally by evaluating the ability of the age-adapted sequential organ failure assessment (SOFA) versus the SIRS criteria system to predict in-hospital mortality in China. The two scoring systems were compared in 1,831 patients, 57.8% of whom were less than 1 year of age. The authors showed that when compared with SIRS, age-adapted SOFA was more accurate in predicting both mortality and intensive care unit (ICU) stay ≥7 days. Importantly, varying levels of medical resources in low and middle-income countries presents an additional challenge for the global pediatric sepsis population and this work may allow improved ICU management of these patients, especially in environments where finite medical resources must be considered. Sepsis remains a common and often fatal event following burn injury, in patients of all ages. However, the effect of sepsis on whole body and muscle metabolism in the burn patient remains unclear. In this clinical study, Murton et al. (9) utilized an isotope approach to study muscle protein kinetics. They demonstrated that accelerated muscle proteolysis appears to be the principal metabolic consequence of sepsis in severe burn patients and could be a contributing factor in accelerated loss of muscle mass. Interestingly, these changes do not appear to involve upregulation of traditional atrophy-inducing genes and the authors point to IFNγ as a potential mediator for the additive effect of sepsis on burn-induced muscle breakdown.
Trauma also remains a leading cause of morbidity and mortality among all age groups, with hemorrhagic shock and traumatic brain injury (TBI) responsible for the majority of early deaths. Despite advances in resuscitative strategies, additional therapeutic adjuncts are needed to further improve outcomes. Histone deacetylase inhibitors (HDACis) have shown promise as pharmacologic agents for use in both trauma and sepsis. As reviewed by Williams et al. (10), HDCAis have been shown to improve survival and minimize neurologic injury, coagulopathy, inflammation, and oxidative stress in preclinical models of hemorrhagic shock, TBI, polytrauma, and sepsis. Some HDACis are non-selective, acting on more than one HDAC class while others target individual classes (isoform selective). The non-selective HDACi, Valproic Acid, is being studied in human trials. A phase I, dose-escalation trial has been completed in healthy subjects and a similar study is underway in patients presenting in hemorrhagic shock. More to come on HDACis. To optimize current resuscitation of patients presenting in hemorrhagic shock, many institutions have developed massive transfusion protocols (MTPs) which expedite delivery of predefined ratios of blood products to the patient's bedside in a standardized manner. However, being able to predict which patients will require a massive transfusion is fraught with error and can result in wastage of blood products and increased cost. El-Menyar et al. (11) performed a narrative review with a systematic search method and identified 24 articles that report on scoring systems developed to predict the need for a MTP, 5 from military and 19 from civilian settings. The overall accuracy ranged from AUC 0.618 to 0.905 with both sensitivity and specificity ranging from 53% to 98%. The scoring systems ranged from simple to complex and have unique advantages, disadvantages, and utility. Though the existence of so many scores suggests a lack of agreement, the scores are valid and clinically relevant. With so many choices, which one will you choose?
Moving on to endothelial dysfunction following hemorrhage and trauma, Richter et al. (12) sought to characterize the behavior of angiopoietins (Agpt) and their relationship to the endothelial glycocalyx. They accomplished this in a secondary analysis of prospectively collected data from pediatric trauma patients. Circulating syndecan-1 is considered a biomarker for glycocalyx damage after trauma. The authors found that plasma Agpt-2:Agpt-1 ratio is elevated by 24 h after trauma, higher in patients with shock, and associated with worse outcomes. They also demonstrated a correlation between plasma Agpt-2 levels and plasma syndecan-1 levels, suggesting a relationship between endothelial glycocalyx injury and Agpt-2 release.
In a review by Patterson et al. (13), the authors discuss the gut-microbiota-brain axis as it relates to TBI and propose potential therapeutics. It is known that the microbiota of the healthy gut contribute to intestinal mucosal integrity and immune system regulation. The authors detail how disruption of this system by TBI may lead to dysbiosis, ultimately favoring a pro-inflammatory state that is mediated by T cells and cytokines. Changes in intestinal permeability and the blood–brain barrier may potentiate neuroinflammation and impose secondary brain injury. Early findings suggest that fecal transplant, antibiotics, or targeted immunomodulatory therapies may be future therapeutic targets aimed at modulating the gut–microbiota–brain axis and improving both short and long-term outcomes of TBI.
Infection is a frequent complication following trauma but can be difficult to differentiate from SIRS. In this issue, Kang et al. (14) evaluated the diagnostic value of plasma presepsin (a soluble form of CD14), procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBCs) on the infection in trauma patients. They found that plasma presepsin levels were increased within the first 3 days of admission in infected, but not in noninfected trauma patients. The pro-inflammatory response of trauma led to an increase in plasma PCT, CRP, and WBCs in both the infected and noninfected trauma patients. Their study therefore identified that presepsin may be a biomarker for the early diagnosis of infection in trauma patients. Continuing on the theme of inflammation, Wang et al. (15) revealed an important role of autophagy in the degradation of NLRP3 inflammasomes in mice subjected to intestinal ischemia/reperfusion injury. NLRP3 is a member of the NLR (NOD-like receptors) family, which are cytosolic pattern recognition receptors that detect a variety of pathogen-associated molecular patterns and damage-associated molecular patterns signals to trigger the formation of the inflammasome. The NLRP3 inflammasome modulates intestinal inflammation while autophagy has been implicated in the alleviation of inflammation. The authors measured the adaptor protein, ASC, caspase-1 activity, and interleukin-1β (IL-1β) to determine the extent of injury. Their results first indicated that NLRP3 knockdown decreased pro-inflammatory cytokine production and improved hypoxia/reoxygenation (H/R)-triggered inflammation in intestinal epithelial cells in-vitro. Their study further demonstrated autophagy suppressed intestinal I/R-induced NLRP3 inflammasome activation in vivo because loss of autophagy enhanced inflammasome-mediated IL-1β secretion and aggravated intestinal injury. Collectively, these results directly implicated the homeostatic process of autophagy and NLRP3 inflammasome following intestinal I/R and identified a novel pathway for potential therapeutic intervention.
In summary, this month's edition of Shock stayed true to our Society's mission to improve the care of victims of trauma, shock, and sepsis through clinically relevant research into the basic science of injury, inflammation, and sepsis.
1. Xu J, Shen P, Gao Y, Xia S, Liu S, Li Z, Zhou G, Xu Y, Zhang M. The effects of the duration of aortic balloon occlusion on outcomes of traumatic cardiac arrest in a porcine model. Shock
2. Takase B, Higashimura Y, Hashimoto K, Asahina H, Ishihara M, Sakai H. Myocardial electrical remodeling and the arrhythmogenic substrate in hemorrhagic shock-induced heart: Anti-arrhythmogenic effect of liposome-encapsulated hemoglobin (HBV) on the myocardium. Shock
3. Sun H, Xie Q, Peng Z. Does fenoldopam protect kidney in cardiac surgery? A systemic review and meta-analysis with trial sequential analysis. Shock
4. Holm FS, Sivapalan P, Seersholm N, Itenov TS, Christensen PH, Jensen J-US. Acute lung injury in critically ill patients: actin-scavenger gelsolin
signals prolonged respiratory failure. Shock
5. Ding X, Jin S, Shao Z, Xu L, Yu Z, Tong Y, Chen Z, Turnquist H, Pitt BR, Billiar TR, et al. The IL-33-ST2 pathway contributes to ventilator-induced lung injury in septic mice in a tidal volume-dependent manner. Shock
6. Cavaillon J-M, Giamarellos-Bourboulis EJ. Immunosuppression is inappropriately qualifying the immune status of septic and SIRS patients. Shock
7. Karakike E, Adami M-E, Lada M, Gkavogianni T, Koutelidakis IM, Bauer M, Giamarellos-Bourboulis EJ, Tsangaris I. Late peaks of HMGB1 and sepsis outcome: Evidence for synergy with chronic inflammatory disorders. Shock
8. Wu Z, Liang Y, Li Z, Liu G, Zheng J, Zuo Y, Li L, Cao X, Zhang J, Liang H. Accuracy comparison between age-adapted SOFA and SIRS in predicting in-hospital mortality of infected children at China's PICU. Shock
9. Murton A, Bohanon FJ, Ogunbileje JO, Capek KD, Tran EA, Chao T, Sidossis LS, Porter C, Herndon DN. Sepsis increases muscle proteolysis in severely burned adults, but does not impact whole-body lipid or carbohydrate kinetics. Shock
10. Williams AM, Dennahy IS, Bhatti UF, Biesterveld BE, Graham NJ, Li Y, Alam HB. Histone deacetylase inhibitors: a novel strategy in trauma and sepsis. Shock
11. El-Menyar A, Mekkodathil A, Abdelrahman H, Latifi R, Galwankar S, Al-Thani H, Rizoli S. Review of existing scoring systems for massive blood transfusion in trauma patients: where do we stand? Shock
12. Richter RP, Russell RT, Hu PJ, Uhlich RM, Swain TA, Kerby JD, Pittet J-F, Richter JR. Plasma angiopoietin-2/-1 ratio is elevated and angiopoietin-2 levels correlate with plasma syndecan-1 following pediatric trauma. Shock
13. Patterson TT, Nicholson S, Wallace D, Hawryluk GWJ, Grandhi R. Complex feed-forward and feedback mechanisms underlie the relationship between traumatic brain injury and the gut–microbiota–brain axis. Shock
14. Kang J, Gong P, Zhang X-D, Wang W-J, Li C-S. Early differential value of plasma presepsin on infection of trauma patients. Shock
15. Wang Z, Li Z, Feng D, Zu G, Li Y, Zhao Y, Wang G, Ning S, Zhu J, Zhang F, et al. Autophagy induction ameliorates inflammatory responses in intestinal ischemia–reperfusion through inhibiting NLRP3 inflammasome activation. Shock