The June 2020 issue of Shock offers two review articles, six clinical science articles, and six articles exploring questions of basic science research. One of the review articles and three of the research articles in this issue address the underlying pathophysiology of the cardiovascular system in shock. The first review article by Tapking et al. (1) synthesizes our current knowledge of the effects of burns on the cardiovascular system. Their review emphasizes the importance of noninvasive monitoring to guide therapy and the potential benefit of pharmacologic agents such as propranalol, insulin, and oxandralone. The clinical article by Cha and Wi (2) investigates association between vitamin D deficiency and cardiogenic shock in patients who have been resuscitated from sudden cardiac arrest. After adjusting for confounding variables, the authors conclude that severe vitamin D deficiency is associated with cardiogenic shock and mortality in this patient population. The basic science article by Guillou et al. (3) aimed to identify the cellular target(s) of the Factor Xa inhibitor rivaroxaban (RIV) since the exact mechanism of Factor Xa inhibitors to attenuate myocardial ischemia-reperfusion (I/R) inury currently remains elusive. The authors used a rat model and found that the RIV-induced protection on myocardial I/R injury is associated with potential direct cytoprotection on cardiomyocytes and not endothelial phenotype modulation. The clinical article by Wang et al. (4) focuses on pulmonary arterial hypertention (PAH). This study investigates the pathological mechanisms of lnc-Ang362, a regulator of several miRNAs that in turn appear to regulate PAH. It was found that Lnc-Ang362 plays an important role in regulating human pulmonary arterial smooth muscle cells via the activation of NFκB and although these studies are limited to cultured cells, they suggest potential therapeutic application to treat PAH.
The second review article by Li et al. (5) and two clinical science articles in this issue address different measurement and treatment techniques for the care of septic intensive care unit (ICU) and emergency department (ED) patients. Li et al. conducted a network meta-analysis to determine and summarize the efficacy and safety of various resuscitation fluids that are routinely used in septic shock patients. The authors rank the outcomes of the different fluids under various conditions including 28-day and 90-day mortality, incidence of acurte kidney injury, and need for renal replacement therapy. They conclude that the balanced solution should be the preferred resuscitation fluid used for septic shock patients while H-HES and L-HES should be avoided. The clinical article by Ronflé et al. (6) assesses the use of the simple measurable venous-to-arterial carbon dioxide partial pressure difference (P(v-a)CO2) as a tool to predict clinical worsening of septic shock. They found that both P(v-a)CO2 and plasma lactate but not ScvO2 significantly correlated with sequential organ failure assessment (SOFA) score. Moreover, P(v-a)CO2 was associated with higher mortality in patients with elevated SOFA score regardless of ScvO2 values. The third article in this grouping by Lafon et al. (7) evaluated the use of focused echocardiography in the ED by recently trained physicians to compare the early hemodynamic profile of patients with acute circulatory failure, a major predictor of patient mortaility in hospitals with sepsis as one of the leading causes. The authors conclude that the profiles obtained by the recently trained physicians were in good agreement with expert assessments, indicating that focused echocardiography may be a reliable tool in the ED setting for early hemodynamic assessment of patients who present with acute circulatory failure.
Several studies in this issue address diagnosis, treatment, and modulation of the immune system for patients of shock. Knaak et al. (8) conducted a retrospective observational study to determine methods to diagnose and treat patients with hemophagocytic lymphohistiocytosis (HLH), an uncontrolled over-activation of the immune response that is often clinically difficult to distinguish from sepsis, in adults. The authors found that infections are the most common trigger of HLH and that ferratin level is an important predictor of mortality and a potentially useful clinical measurement tool. The clinical article by Watanabe et al. (9) examined the pharmacokinetics, pharmacodynamics, and safety of the cancer drug nivolumab, a human programmed death-1 immune checkpoint inhibitor, in patients with immunosuppressive sepsis since immunostimulation may be beneficial in this patient population. They found that nivolumab doses of 480 mg and 960 mg were well tolerated, maintained drug blood concentrations, and increased lymphocyte counts and monocyte human keukocyte antigen-DR subtype expression over time, indicating improved immune function. The basic science article by Chen et al. (10) also studied the effects of an inhibitor on the immune function of sepsis patients. Specifically, they investigated the effects of the soluble epoxide hydrolase inhibitor TPPU since it was previously shown to regulate macrophages and inflammation, two of the major contributing factors to the progression of sepsis. They hypothesized that TPPU may ameliorate cecal ligation and puncture -induced sepsis through macrophage regulation, and found that it does by improving macrophage phagocytosis and reducing the inflammatory response. TPPU may thus be a potential therapeutic target for polymicrobial-induced sepsis.
Two of the basic science articles pertain to aspects of brain injury and hemorrage in shock patients. Spruce et al. (11) point out that while tranexamic acid (TXA) is known to improve survival in traumatic hemorrhage patients, it is incompatible with blood products and intravenous TXA use may therefore be limited. The authors thus sought to examine the bioavailability of intramuscular (IM) TXA and its ability to reverse in vitro hyperfibrinolysis in a swine model of traumatic hemorrhage. By comparing IM to IV routes of administration they found that the pharmacokinetics were similar, with IV resulting in a higher serum concentration during the infusion, but both routes resulting in successful correction of in vitro hyperfibrinolysis and no difference in total body exposure to equal doses of TXA between the two routes. IM TXA may therefore be a useful route of administration when IV use may be limited. Weiss et al. (12) studied neurobehavioral biomarkers of blast-induced mild traumatic brain injury (TBI), often sustained by soldiers injured via explosive device generation of high pressure gas waves, by relating freezing in response to a conditioned stimulus to axonal injury, as a measure of mild TBI. They found that mice with TBI showed increased freezing response when tested in a context associated with the conditioned training, but not when tested in a neutral context. They conclude that contextual freezing may be used as a neurobehavior biomarker for axonal injury in mild TBI and may be used therapeutically to evaluate and treat mild TBI.
The final two articles are basic science papers that evaluate and further elucidate important mechanistic pathways in septic shock and ischemic injury. Baptiste et al. (13) examined the potentially beneficial effects of TGF-β inhibitor LY364947 on the diaphram during chronic sepsis since TGF-β has been reported to trigger the protein breakdown cascade involved in muscle wasting. The inhibitor was found to only abolish diaphram wasting in the group given inhibitor on day 1 (as opposed to day 0) in the rat model. Over-expression of SMAD3 in septic rats was reversed and over-expression of calpain-1 and MAFbx were decreased by LY364947. They conclude that inhibition of TGF-β protects the diaphram from wasting and weakness during chronic sepsis as early as 1 day postinfection, which could prove to be a highly beneficial theraputic target for ICU patients with sepsis. Lastly, but certainly not the least, Jensen et al. (14) investigated whether hydrogen sulfide (H2S) plays a vital role in cell-mediated intestinal protection after ischemic injury, since H2S is a vasodilator that is released from stem cells and increased in hypoxic conditions. Their hypothesis was tested in a cell model using human bone marrow-derived mesenchymal stem cells subjected to knockdown of H2S-producing enzymes CBS, MPST, and CTH. The authors found that knockdown of these conventional enzymes only impacted H2S gas production in normoxic conditions (i.e., not in hypoxic conditions), and that perfusion and indicators of histological injury were unchanged compared with their control. The data therefore indicate that alternative H2S production pathways may be initiated during hypoxic or ischemic conditions.
1. Tapking C, Popp D, Herndon DN, Branski LK, Hundeshagen G, Armenta AM, Busch M, Most P, Kinsky MP. Cardiac dysfunction in severely burned patients: current understanding of etiology, pathophysiology, and treatment. Shock
2. Cha J-J, Wi J. Association of vitamin D deficiency with profound cardiogenic shock in patients resuscitated from sudden cardiac arrest. Shock
3. Guillou S, Beaumont J, Tamareille S, Giraud S, Mirebeau-Prunier D, Prunier F, Macchi L. Direct rivaroxaban-induced factor Xa inhibiton proves to be cardioprotective in rats. Shock
4. Wang H, Qin R, Cheng Y. LncRNA-Ang362 promotes pulmonary arterial hypertension by regulating miR-221 and miR-222. Shock
5. Li B, Zhao H, Zhang J, Yan Q, Li T, Liu L. Resuscitation fluids in septic shock: a network meta-analysis of randomized controlled trials. Shock
6. Ronflé R, Lefebvre L, Duclos G, Rambaud R, Baumstarck K, Boucekine M, Daviet F, Baldesi O, Papazian L, Leone M. Venous-to-arterial carbon dioxide partial pressure difference: predictor of septic patient prognosis depending on central venous oxygen saturation. Shock
7. Lafon T, Appert A, Hadj M, Bigrat V, Legarcon V, Claveries P, Goudelin M, Evrard B, Hernandez Padilla AC, Baisse A, et al. Comparative early hemodynamic profiles in patients presenting to the emergency department with septic and nonseptic acute circulatory failure using focused echocardiography. Shock
8. Knaak C, Schuster FS, Spies C, Vorderwülbecke G, Nyvit P, Schenk T, Balzer F, La Rosée P, Janka G, Brunkhorst FM, et al. Hemophagocytic lymphohistiocytosis in critically ill patients. Shock
9. Watanabe E, Nishida O, Kakihana Y, Odani M, Okamura T, Harada T, Oda S. Pharmacokinetics, pharmacodynamics, and safety of Nivolumab in patients with sepsis-induced immunosuppression: a multicenter, open-label phase 1/2 study. Shock
10. Chen Z, Tang Y, Yu J, Dong R, Yang Y, Fu M, Luo J, Hu S, Wang DW, Tu L, et al. sEH inhibitor TPPU ameliorates cecal ligation and puncture-induced sepsis by regulating macrophage functions. Shock
11. Spruce MW, Beyer CA, Caples CM, DeSoucy EK, Kashtan HW, Hoareau GL, Grayson JK, Johnson MA. Pharmacokinetics of tranexamic acid given as an intramuscular injection compared to intravenous infusion in a swine model of ongoing hemorrhage. Shock
12. Weiss C, Lendacki FR, Rigby PH, Wyrwicz AM, Disterhoft JF, Spiess J. Conditioned contextual freezing is a neurobehavioral biomarker of axonal injury indicated by reduced fractional anisotropy in a mouse model of blast-induced mild traumatic brain injury. Shock
13. Jensen AR, Drucker NA, Olson KR, Markel TA. Stem cell therapy and hydrogen sulfide: conventional or nonconventional mechanisms of action? Shock
14. Jude B, Tissier F, Dubourg A, Droguet M, Castel T, Karelle L, Giroux-Metges M-A, Pennec J-P. TGF-β pathway inhibition protects the diaphragm from sepsis-induced wasting and weakness in rat. Shock