The 2020 March edition of SHOCK features three excellent review articles, and four clinical reports and seven basic science reports that cover a range of topic to include sepsis, myocardial infarction and shock, hemorrhagic shock and ischemia, and acute pancreatitis. The articles are insightful and will help readers understand the current problems encountered in these pathologic states, and possible clinical solutions that come out of both the clinical and basic science realm.
SHOCK begins with a review by Cohen et al. (1). This group discusses the use of single nucleotide polymorphisms (SNPs) as biomarkers to associate outcomes in acute illness like sepsis, burn, and trauma. Gene association studies have recently began using single-nucleotide polymorphisms as novel biomarkers for these pathologies. However, despite fairly extensive studies in other fields, the application of these genetic analyses has lagged in the field of acute illness, due to a lack of accuracy for predicting outcome. These authors suggest that the lack of accuracy could be significantly strengthened if the proper quality controls are met, if the study population is sufficiently large, and if the SNPs are validated by a secondary technique. Readers will find this article of great interest as it presents an excellent review of this new and immerging field.
The second review article by Ho et al. (2) discusses the use of remote ischemic conditioning for improving outcomes after ischemia reperfusion injury. Restriction of blood flow to vital organs for a sufficient period of time leads to reperfusion injury after blood flow returns to normal. This injury can be attenuated by a promising new strategy, remote ischemic conditioning, that includes repetitive inflation and deflation of a cuff on the effected limb. This practical technique is simple, low cost, safe, and effective and has great appeal to the emergency physician. This method has proven efficacy for ST-elevation myocardial infarction, and may also be effective for acute ischemic stroke.
Stansfield et al. (3) have written a review on the Pre-Hospital use of tranexamic acid (TXA) after trauma. The article reviews specific clinically relevant parameters for administration that include how much to use, by what route to use it, and the optimal window of time for use. The article also reviews the safety, effectiveness, and feasibility of use in the prehospital setting. This review article presents a strong case for ambulance services to use, or at least consider the use of TXA as part of their treatment protocol when arriving on the scene of a traumatic injury.
The clinical science article discusses a new biomarker that can potentially predict outcome after sepsis. Feng et al. (4) identified the gene signatures that co-expressed for sepsis survival and for Sphingosine-1-phosphate and its receptor 1 protein (S1PR1). The authors than identified a 62-gene and a 16-gene S1PR1-related molecular signatures that were associated with survival. The two gene signatures, especially the 16-gene signature, have a strong relationship with signaling pathways and protein interactions described in the results. The authors suggest that the S1PR1-related molecular signatures are predictors of clinical outcome in patients with sepsis.
Acute pancreatitis is usually a mild, self-limited disease. However 15% to 25% of these patients show a high mortality due to septic complication. In a retrospective study by Li et al. (5) in Harbin, China, infection with multidrug-resistant pathogens was common in patients with severe acute pancreatitis. These authors found that major pathogens were gram negative, with Acinetobacter baumannii being the most common. These authors also found that both the use of carbapenem, and surgical intervention, were risk factors for producing multidrug-resistant acute pancreatitis.
Patients with myocardial infarction and ST elevation constitute a risk group who suffer in-hospital high-mortality rates. To address this, Klein et al. (6) studied a large cohort of patients with myocardial infarcts, and found an independent association between high levels of neutrophils, and a high neutrophil to leukocyte ratio measured upon admission, with an increased risk of developing late cardiogenic shock and an increased 30-day mortality. Leukocyte count determined upon admission may prove valuable as a simple index for clinicians to target therapeutics before the patients develop fulminant cardiac shock.
The basic science section of SHOCK begins with an interesting article by Fukuda et al. (7) that shows the clinical relevance of using toll-like receptor 4 (TLR4) stimulation to attenuate the development of multiple organ failure. This group showed that prior stimulation of toll-like receptor 4 with monophosphoryl lipid A attenuated the development of acute lung injury from pseudomonas aeruginosa pneumonia in burned sheep. These authors showed that prior infusion of lipid A was well tolerated in the burned sheep, and their data supports the clinical relevance of using TLR4 stimulation to alleviate the pathologies associated with burn.
Severe smoke inhalation is normally associated with the development of acute lung injury, inflammation, edema, and a high mortality rate. Club cell protein 10-kDa is a potent anti-inflammatory agent shown to decrease airway inflammation in preterm neonates with respiratory distress. In the next article, Lopez et al. (8) found that recombinant Club cell protein 10-kDa infused into sheep subjected to severe smoke inhalation, significantly attenuated the progression ARDS, lung dysfunction, and systemic vascular permeability. These findings suggest that recombinant Club cell protein 10 kDa is a novel therapeutic agent for treatment of smoke inhalation.
Uncontrolled hemorrhage and trauma can result in circulatory shock that can lead to death within the first hour of injury in military and civilian populations. First responders face the challenge of performing effective resuscitation strategies in the prehospital setting. Koons et al. (9) describe a novel noninvasive measurement (compensatory reserve measurement) derived from subtle changes in the arterial waveforms that can be used to guide resuscitation strategies. With this measurement, the group showed that oxygen delivery in hemorrhaged baboons can be restored with less resuscitation (whole blood). The authors suggest that this method could be used by clinicians to restore oxygen delivery with less volume, and avoid over-resuscitation.
Chen et al. (10) have written an article about the interaction between integrin β3 and TLR4. Integrin β3 is a transmembrane receptor on the surface of many cell types, including macrophages. Their data show that integrin β3 interacts with TLR4 through regulation of CD14 expression. CD14 is a coreceptor for TLR4, and allows signal transduction when lipopolysaccharides binds TLR4/CD14 complex. These authors have shown that integrin β3 knockouts loose expression of CD14, and have a higher survival rate after sepsis, and lower signs of acute liver, kidney, and lung damage. These authors suggest that integrin β3/TLR4 may be a good target for sepsis therapy.
The next article also deals with TLR4 signal transduction via lipopolysaccharides released from gram negative pneumonia. Stimulation of TLR4 leads to neutrophil migration in the lungs, breakdown of the alveolar–endothelial barrier, and pulmonary edema. Kasotakis et al. (11) show that gram-negative pneumonia modulates not only the above pathologies, but also changes in expression of histone deacetylase (HDAC) in the lungs. These authors found that selective inhibition of HDAC7 limits the pro-inflammatory effects and significantly improves survival to severe gram-negative pneumonia. Their data suggest that histone deacetylases may be a potential therapeutic targets in the management of gram-negative infection-induced ARDS.
The next article looks at transfusion strategies for improving outcome after hemorrhagic shock. Williams et al. (12) have shown that resuscitation with anaerobically stored RBCs improved outcome, restored cardiac, hemodynamic, and metabolic function with less volume as compared with traditionally stored red cells. Anaerobic storage has been suggested as a way to decrease oxidative changes that occur after storage (RBC deformability, met Hb formation, upregulation of pentose phosphate metabolism) and maintain viability. These data suggest that storing RBCs anaerobically could result in better transfusion outcomes for patients in hemorrhagic shock.
In the next article, Wang et al. (13) discuss calreticulin, a multifunctional protein usually found in the endoplasmic reticulum. Calreticulim regulates a number of cellular functions including calcium binding, regulation of protein folding, molecular chaperone, and regulation of autophagic flux within the cell. Autophagy is important as it is used by the cell to promote nutrient recycling, and the clearance of damaged proteins and organelles. These authors have shown that intraperitoneal injection of calreticulin after ligation of the left coronary artery improved the autophagic flux by inhibiting the excessive formation of autophagosomes, and promoting the clearance of autophagosomes in cardiac tissue. This results in reduced damage to the myocardium after ischemia/reperfusion in the heart.
Finally a very sobering commentary has been written by Reynolds (14) that concerns the misuse and misunderstanding of the ARRIVE Guidelines. These guidelines were set up to improve reporting on animal research, and as a guide for the inclusion of essential information in the manuscript. The SHOCK society officially endorsed the ARIVE guidelines in 2012. However, our journal (and most others) have shown weak adherence to these guidelines. This commentary briefly describes the problem and points out that only the authors AND reviewers of SHOCK can fix this issue. I strongly recommend that everyone take time to read this commentary. Dr Reynolds will publish a full description of this problem in the near future.
1. Cohen M, Lamparello AJ, Schimunek L, El-Dehaibi F, Namas RA, Xu Y, Kaynar AM, Billiar TR, Vodovotz Y. Quality control measures and validation in gene association studies: lessons for acute illness. Shock
2. Ho AFW, Jun C, Ong MEH, Hausenloy DJ. Remote ischemic conditioning in emergency medicine—–clinical frontiers and research opportunities. Shock
3. Stansfield R, Morris D, Jesuloia E. The use of tranexamic acid (TXA) for the management of hemorrhage in trauma patients in the prehospital environment: Literature review and descriptive analysis of principal themes. Shock
4. Feng A, Rice AD, Zhang Y, Kelly GT, Zhou T, Wang T. S1PR1-associated molecular signature predicts survival in patients with sepsis. Shock
5. Li X, Li L, Liu L, Hu Y, Zhao S, Sun J, Wang G, Hai X. Risk factors of multidrug resistant pathogens induced infection in severe acute pancreatitis. Shock
6. Klein A, Wiberg S, Hassager C, Winther-Jensen M, Frikke-Schmidt R, Bang LE, Lindholm MG, Holmvang L, Moeller-Helgestad O, Ravn HB, et al. Admission leukocyte count is associated with late cardiogenic shock development and all-cause 30-day mortality in patients with ST-elevation myocardial infarction. Shock
7. Fukuda S, Ihara K, Bohannon JK, Hernandez A, Patil NK, Luan L, Stothers C, Stark R, Prough DS, Herndon DN, et al. Monophosphoryl lipid A attenuates multiorgan dysfunction during post-burn pseudomonas aeruginosa
pneumonia in sheep. Shock
8. Lopez E, Fujiwara O, Nelson C, Winn ME, Clayton RS, Cox RA, Hawkins HK, Andersen CR, Wade CE, Hariprakasha H, et al. Club cell protein, CC10, attenuates acute respiratory distress syndrome induced by smoke inhalation. Shock
9. Koons NJ, Nguyen B, Suresh MR, Hinojosa-Laborde C, Convertino VA. Tracking DO2
with compensatory reserve during whole blood resuscitation in baboons. Shock
10. Chen Z, Wang S, Chen Y, Shao Z, Yu Z, Mei S, Li Q. Integrin β3 modulates TLR4-mediated inflammation by regulation of CD14 expression in macrophages in septic condition. Shock
11. Kasotakis G, Kintsurashvili E, Galvan MD, Graham C, Purves JT, Agarwal S, Corcoran DL, Sullenger BA, Palmer SM, Remick DG. Histone deacetylase 7 inhibition in a murine model of gram-negative pneumonia-induced acute lung injury. Shock
12. Williams AT, Jani VP, Nemkov T, Lucas A, Yoshida T, Dunham A, D’Alessandro A, Cabrales P. Transfusion of anaerobically or conventionally stored blood after hemorrhagic shock. Shock
13. Wang J-L, Li Y-Z, Tao T-Q, Wang X-R, Wang Y, Song D-D, Liu X-H. Postconditioning with calreticulin attenuates myocardial ischemia/reperfusion injury and improves autophagic flux. Shock
14. Reynolds PS. Improving reproducibility and transparency in SHOCK
: the ARRIVE
guidelines need better implementation and enforcement. Shock