What's New in Shock, September 2019? No abstract available

Review of Existing Scoring Systems for Massive Blood Transfusion in Trauma Patients: Where Do We Stand? Background: Uncontrolled bleeding is the main cause of the potential preventable death in trauma patients. Accordingly, we reviewed all the existing scores for massive transfusion posttraumatic hemorrhage and summarized their characteristics, thus making it easier for the reader to have a global view of these scores—how they were created, their accuracy and to which population they apply. Methods: A narrative review with a systematic search method to retrieve the journal articles on the predictive scores or models for massive transfusion was carried out. A literature search using PubMed, SCOPUS, and Google scholar was performed using relevant keywords in different combinations. The keywords used were “massive transfusion,” “score,” “model,” “trauma,” and “hemorrhage” in different combinations. The search was limited for full-text articles published in English language, human species and for the duration from January 1, 1998 to November 30, 2018. Results: The database search yielded 295 articles. The search was then restricted to the inclusion criteria which retrieved 241 articles. Duplicates were removed and full-texts were assessed for the eligibility to include in the review which resulted in inclusion of 24 articles. These articles identified 24 scoring systems including modified or revised scores. Different models and scores for identifying patients requiring massive transfusion in military and civilian settings have been described. Many of these scorings were complex with difficult calculation, while some were simple and easy to remember. Conclusions: The current prevailing practice that is best described as institutional or provider centered should be supplemented with score-based protocol with auditing and monitoring tools to refine it. This review summarizes the current scoring models in predicting the need for MT in civilian and military trauma. Several questions remain open; i.e., do we need to develop new score, merge scores, modify scores, or adopt existing score for certain trauma setting?

Histone Deacetylase Inhibitors: A Novel Strategy in Trauma and Sepsis Trauma remains a leading cause of morbidity and mortality among all age groups in the United States. Hemorrhagic shock and traumatic brain injury (TBI) are major causes of preventable death in trauma. Initial treatment involves fluid resuscitation to improve the intravascular volume. Although crystalloids may provide volume expansion, they do not have any pro-survival properties. Furthermore, aggressive fluid resuscitation can provoke a severe inflammatory response and worsen clinical outcomes. Due to logistical constraints, however, definitive resuscitation with blood products is often not feasible in the prehospital setting—highlighting the importance of adjunctive therapies. In recent years, histone deacetylase inhibitors (HDACis) have shown promise as pharmacologic agents for use in both trauma and sepsis. In this review, we discuss the role of histone deacetylases (HDACs) and pharmacologic agents that inhibit them (HDACis). We also highlight the therapeutic effects and mechanisms of action of HDACis in hemorrhagic shock, TBI, polytrauma, and sepsis. With further investigation and translation, HDACis have the potential to be a high-impact adjunctive therapy to traditional resuscitation.

Immunosuppression is Inappropriately Qualifying the Immune Status of Septic and SIRS Patients Immunosuppression is the most commonly used concept to qualify the immune status of patients with either sterile systemic inflammatory response syndrome (SIRS) or sepsis. In this review we attempt to demonstrate that the concept of immunosuppression is an oversimplification of the complex anti-inflammatory response that occurs in patients dealing with a severe sterile or infectious insult. Particularly, the immune status of leukocytes varies greatly depending on the compartment from where they are derived from. Furthermore, although certain functions of immune cells present in the blood stream or in the hematopoietic organs can be significantly diminished, other functions are either unchanged or even enhanced. This juxtaposition illustrates that there is no global defect. The mechanisms called reprogramming or trained innate immunity are probably aimed at preventing a generalized deleterious inflammatory reaction, and work to maintain the defense mechanisms at their due levels.

Complex Feed-Forward and Feedback Mechanisms Underlie the Relationship Between Traumatic Brain Injury and the Gut–Microbiota–Brain Axis Traumatic brain injury (TBI) contributes to nearly 1 in 3 injury-related deaths in the United States and accounts for a substantial public health burden and cost. The current literature reports that physiologic responses in the gastrointestinal system after TBI include, but are not limited to, epithelial barrier dysfunction, microbiota changes, and immunologic transformations. Recent evidence suggests gut alterations after TBI modify the homeostasis of the bidirectional gut–microbiota–brain axis, resulting in altered immune responses in the periphery and the brain. This cascade possibly contributes to impaired central nervous system (CNS) healing. Although attention to the gut–brain–microbiota axis has been increasing in the literature, the precise mechanisms underlying the changes observed after TBI remain unclear. The purpose of this review are to describe our current understanding regarding alterations to the gut–microbiota–brain axis after TBI, highlight the pathophysiologic changes involved, and evaluate how these variations modify healing in the CNS or even contribute to secondary injury. We also discuss current investigations into potential medical therapies directed at the gut–microbiota–brain axis, which might offer improved outcomes after TBI.

Does Fenoldopam Protect Kidney in Cardiac Surgery? A Systemic Review and Meta-Analysis With Trial Sequential Analysis Purpose: To assess the benefits and harms of fenoldopam for nephroprotective effects in adult patients undergoing cardiac surgery. Methods: We conducted a systematic review with meta-analysis of randomized controlled trials (RCTs) comparing fenoldopam with placebo in cardiac surgery. Trials were systematically searched from PubMed, EMBASE, CENTRAL, and CNKI databases, up to July 30, 2018. A trial sequential analysis (TSA) was used to determine whether the present evidence was valid and conclusive for the primary outcomes. Results: A total of seven randomized controlled trials involving 1,107 adult patients undergoing cardiac surgery fulfilled the inclusion criteria. The pooled analysis suggested that the use of fenoldopam was associated with a reduction in the incidence of AKI (18 of 216 [8.3%] in the fenoldopam group versus 45 of 222 [20.3%] in the placebo group, RR = 0.42 [0.26, 0.69], P = 0.0006) and with a higher rate of hypotension (92/357 [25.8%] versus 51/348 [14.7%], RR = 1.76 [1.29, 2.39], P = 0.0003). There was no significant effect on renal replacement therapy requirement (77 of 540 [14.3%] versus 75 of 536 [14.0%], P = 0.96) or hospital mortality (87/392 [22.2%] versus 83/383 [21.7%], P = 0.86). TSA supported the results of the conventional analysis on AKI. Conclusions: Low-dose dopamine offers transient improvements in renal physiology, but no good evidence shows that it offers important clinical benefits to patients with or at risk for acute renal failure. Among patients treated with fenoldopam, there was a decrease in AKI and an increased incidence of hypotension, had no significant effect on RRT or mortality. Given that most studies were small and the definition of AKI was variable between studies, there is not enough evidence to support the systematic use of fenoldopam in cardiac surgery.

Late Peaks of HMGB1 and Sepsis Outcome: Evidence For Synergy With Chronic Inflammatory Disorders High mobility group box 1 (HMGB1) is released from macrophages as a late biomarker of sepsis. Conditions associated with pre-existing macrophage activation may modify HMGB1 expression. This study aimed to assess the impact of HMGB1 kinetics on 28-day mortality. In a sub-study of a previous randomized clinical trial among patients with systemic inflammatory response syndrome and gram-negative infections, patients were classified in early and late HMGB1 peak groups. Serial measurements of HMGB1, ferritin and interferon-gamma (IFNγ) were performed in all available sera. Two hundred ten patients were included; 118 (46.5%) had at least one inflammatory disease (diabetes, chronic obstructive pulmonary disease, chronic heart failure, or chronic renal disease). Mortality after 28 days was higher among patients with a late peak of HMGB1 (OR 2.640; P = 0.026). Co-existence of late peak and inflammatory disease synergistically impacted mortality (odds ratio of logistic regression analysis 3.17; P: 0.027). Late peak was concomitantly associated with higher values of ferritin (P = 0.035), and IFNγ (P = 0.002) among patients with hyperferritinemia. It is concluded that late HMGB1 peak was associated with worse prognosis, especially in patients with underlying chronic inflammatory conditions.

Plasma Angiopoietin-2/-1 Ratio is Elevated and Angiopoietin-2 Levels Correlate With Plasma Syndecan-1 Following Pediatric Trauma Background: Angiopoietin-1 (Agpt-1) and Agpt-2 are cytokine regulators of vascular endothelial integrity. Elevated plasma Agpt-2 levels and ratios of Agpt-2:Agpt-1 are associated with adverse outcomes in adult trauma and pediatric sepsis populations. However, the behavior of the angiopoietins after pediatric trauma has not been characterized, and their relationship to endothelial glycocalyx damage, indicated by plasma syndecan-1 (Syn-1) levels, has not been established. Methods: We performed a secondary analysis of prospectively collected data from 52 pediatric trauma patients and 12 control patients at a level one pediatric trauma center from 2013 to 2016. We measured Agpt-1, Agpt-2, and Syn-1 levels from plasma taken upon hospital arrival and 24 h after admission. Angiopoietin levels were compared to controls, and the correlation between Agpt-2 and Syn-1 was assessed. Results: Plasma Agpt-1 and Agpt-2 levels are elevated immediately after pediatric trauma compared with controls. At 24 h, trauma patients demonstrated significantly elevated plasma Agpt-2:Agpt-1 ratios relative to controls due to decline of Agpt-1 levels to near that of controls. Higher 24-h Agpt-2 levels are associated with more hypoperfusion, and elevated 24-h Agpt-2:Agpt-1 ratios are associated with adverse clinical outcomes. Significant positive correlations between Agpt-2 and Syn-1 upon admission and at 24 h after injury were identified. Conclusion: Our findings suggest dysregulation of circulating angiopoietins after pediatric trauma that may be linked to endothelial glycocalyx injury. Larger prospective studies are needed to validate these findings and determine the relationship of Agpt-2 with other markers of endotheliopathy.

Accuracy Comparison Between Age-Adapted SOFA and SIRS in Predicting in-Hospital Mortality of Infected Children at China's PICU Objectives: Sepsis-3 consensus suggests “the need to develop similar updated definitions for pediatric populations.” Sequential organ failure assessment (SOFA) and systemic inflammatory response syndrome (SIRS) criteria are two systems widely used to define the status of infection. However, it is still unclear whether SOFA is more accurate than SIRS in predicting children mortality in low- and middle-income countries. Thus, we validated the accuracy of age-adapted SOFA and SIRS in predicating the poor prognosis of infected children in China's pediatric intensive care unit (PICU). Methods: We performed a retrospective and observational cohort study of children admitted for infection to PICU in the hospital between January 1, 2009 and December 31, 2017. The indexes within 24 h after intensive care unit (ICU) admission were analyzed according to age-adapted SOFA and SIRS, and all data were sourced from the hospital's electronic health record database. The prognosis was illustrated with primary outcome and secondary outcome. Primary outcome referred to in-hospital mortality, and secondary outcome to in-hospital mortality or ICU length of stay ≥ 7 days. The predictive power of age-adapted SOFA and SIRS was compared using crude and adjusted area under the receiver operating characteristic curve (AUROC). Results: Of 1,831 PICU-admitted children due to infection, 164 (9.0%) experienced primary outcome, and 948 (51.8%) secondary outcome. Of 164 deaths, 65.9% were males (median age of 7.53 months, range of 2.67–41.00 months). Children who scored ≥ 2 in age-adapted SOFA or met two SIRS criteria accounted for 92.5% and 73.3%, respectively. In addition, age-adapted SOFA score of ≥2 predicted adverse outcome more accurately than pediatric SIRS (adjusted AUROC, 0.753; 0.713–0.796 vs. 0.674; 0.631–0.702; P < 0.001). Conclusion: Compared with SIRS criteria, age-adapted SOFA score of ≥ 2 enjoys a more accuracy in predicting in-hospital mortality of PICU-admitted children, and a higher sensitivity in identifying children with severe infection.

Sepsis Increases Muscle Proteolysis in Severely Burned Adults, but Does not Impact Whole-Body Lipid or Carbohydrate Kinetics Sepsis is a common and often fatal consequence of severe burn injury, but its exact effects on whole body and muscle metabolism in the burn patient is unclear. To address this, 13 septic and 11 nonseptic patients (age: 36.9 ± 13.0 years) with burns encompassing >30% of their total body surface area underwent muscle protein kinetic studies under postabsorptive conditions using bolus injections of ring-13C6 and 15N phenylalanine isotopes. In parallel, whole-body lipid and carbohydrate kinetics were assessed using constant infusions of [U-13C6]palmitate, [6,6-2H2]glucose, and [2H5]glycerol, and during a 2-h hyperinsulinemic euglycemic clamp. Muscle mRNA levels of genes implicated in the development of muscle cachexia were assessed by qPCR. Fractional breakdown rates of mixed-muscle proteins were found to be 2.4-fold greater in septic versus nonseptic patients (P < 0.05). No discernable differences in fractional synthetic rate of mixed-muscle proteins or rate of appearance of plasma free fatty acids, glycerol, or glucose could be observed between patient groups, although the latter was significantly associated with burn size (P < 0.05). Hyperinsulinemia stimulated whole-body glucose uptake and suppressed endogenous glucose production and whole-body lipolytic rate to equivalent degrees in both groups. Muscle mRNA levels of genes spanning autophagy, lysosomal, and ubiquitin proteasome-mediated proteolysis were not enhanced in septic versus nonseptic patients. Our results demonstrate that accelerated muscle proteolysis appears to be the principal metabolic consequence of sepsis in severe burn patients and could be a contributing factor to the accelerated loss of muscle mass in these individuals. The exact mechanistic basis for these changes remains unclear.