“The important thing is not to stop questioning. Curiosity has its own reason for existence. One cannot help but be in awe when he contemplates the mysteries of eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to comprehend a little of this mystery each day.”
—“Old Man's Advice to Youth: ‘Never Lose a Holy Curiosity.”’ LIFE Magazine (2 May 1955) p. 64
— Albert Einstein
As we begin 2021, we are facing a raging global pandemic, political turmoil, social unrest, financial uncertainties, and a backlash against science and reason. Concurrently, we are witnessing the wonders of science, as lifesaving vaccines are developed in record time using completely novel techniques. It is critical during times such as these that we remind ourselves why it is so important to seek the truth, to ask the right questions, to find the answers, and to share the discoveries with others in the spirit of unraveling the “marvelous structure of reality” together.
We feel especially privileged to write this commentary for the first issue of 2021 that offers a number of exciting high-caliber articles, highlighting the steadfast dedication of scientists around the world to advance the field. This issue features 18 articles including 2 letters to the editor, 8 basic science studies, 6 clinical studies, 1 meta-analysis review, and 1 narrative review.
The first two articles are letters to the editor regarding a study that highlighted the role that hydrogen sulfide (H2S) plays in acute lung injury within the context of SARS-CoV-2-coronavirus pneumonia (1–3). To broadly recap a prior study, it was found that higher levels of H2S were identified among survivor patients with SARS-CoV-2-coronavirus pneumonia (1). However, questions were raised regarding the study's high absolute levels of the H2S (2). Welcoming the discussion on their study, the authors offered additional data further supporting their original conclusion that modulation of H2S plays a major role in this viral infection (1, 3).
Remaining on the topic of the impact of hydrogen-based molecules, Xie et al. (4) present their basic science study highlighting the effects that treatment with hydrogen gas (H2) has on sepsis-associated encephalopathy (SAE). Using a preclinical murine model of cecal ligation and puncture, the authors demonstrate that H2 therapy was associated with improved survival, cognitive function, mitochondrial function, and mitochondrial biogenesis parameters. The authors also present mechanistic evidence to suggest that these improved outcomes are due to activation of peroxisome proliferator-activated receptor gamma co-activator 1a (PGC-1a). These are exciting findings that suggest H2 therapy warrants ongoing investigation as a potential strategy for patients suffering from SAE.
Continuing on the topic of sepsis, the next basic science study by Ye et al. (5) sheds light on the mechanistic role of Schwann cells (SCs) in sepsis-induced neuromuscular dysfunction. Using SCs from sepsis mice, the authors report a novel finding that sepsis promotes macrophage infiltration via the toll-like receptor 4 (TLR4)/MyD88 pathway in SCs. Their findings demonstrate that sepsis activates this pathway and triggers the secretion of 2 molecules: IL-1B, which can further stimulate the pathway by binding IL-1R, and macrophage cationic peptide 1 (MCP-1), a macrophage recruitment molecule. This increased secretion of MCP-1 in turn stimulates macrophage infiltration and activates the TLR4/MyD88/ERK pathway which contributes to the consequent neuromuscular dysfunction. This is an important finding that highlights inhibition of this pathway as a potential strategy for preventing sepsis-induced neuromuscular dysfunction.
Sepsis can impact multiple systems. One potential sequalae of sepsis is myocardial dysfunction, referred to as sepsis-induced myocardial dysfunction (SIMD). In the next study, He et al. (6) present a multicenter, randomized, double-blinded, parallel-group trial assessing the impact that Xinmaolong injection (XMLI) has on the progression of myocardial damage to SIMD in sepsis patients. XMLI is a bioactive composite plant extract that is already widely used in China for the treatment of heart failure due to its potential benefits on cardiac function. Although unable to show any mortality benefit in this study, the authors did demonstrate that XMLI treatment resulted in reduced diastolic dysfunction and lower levels of brain natriuretic peptide. In follow-up to these exciting findings, the authors will investigate the effects of XMLI in patients with septic shock, results that we look forward to reviewing.
Transitioning to states of cardiogenic shock, this issue of SHOCK contains several exciting studies on this topic. Debrabant et al. (7) present a clinical study seeking to improve providers’ ability to predict episodes of acute myocardial infarction. They evaluate proteomic data to identify proteins predictive of ST elevation myocardial infarction (STEMI), cardiogenic shock (CS), and mortality in the setting of admission for acute coronary angiography. In their initial association analysis, they identified 4 and 29 proteins to be associated with definitive STEMI or all-cause mortality, respectively. When conducting predictive modeling, the authors found that the addition of proteins did improve the prediction performance for CS and mortality but did not improve prediction performance for STEMI. Overall, these are exciting findings, and their data suggest that proteomics may be able to improve existing prediction models. Expanding on this study could refine providers’ ability to prognosticate patients and more efficiently and accurately triage those requiring immediate coronary interventions.
Remaining on the topic of cardiogenic shock, the next four studies incorporate the scenario of cardiac arrest. In their article, Tabi et al. (8) conducted a clinical study that evaluated patients who had sustained out-of-hospital cardiac arrest, and were treated with targeted temperature management. More specifically, they evaluated the association between lactate levels, mean arterial pressure, and vasopressor/ionotrope dosing with mortality outcomes. Using multivariable logistic regression modeling, the authors demonstrated that a higher degree of shock (higher initial lactate, mean MAP<70 over 24 h, and vasopressor requirements over 24 h) was associated with higher likelihood of mortality. Then after further adjustment, only initial lactate and peak vasoactive-ionotropic score over 24 h were identified as significant predictors of mortality, suggesting that these are important factors that could be used for early prognostication. Although MAP was not determined to be a significant predictor, the authors rightly indicate that their findings of higher mortality among patients with a mean MAP of <70 mm Hg suggest that this might be an appropriate minimum target during early resuscitation efforts. Therefore, this study has both prognostic and therapeutic implications for this patient population.
Cardiac arrest carries a high risk of mortality. Even if one does survive, there is significant risk of neurologic disability. Targeted temperature therapy has been adopted as one measure to mitigate the sequalae of cardiac arrest. Cui et al. (9) present a well-performed study investigating how different targeted temperatures following cardiac arrest mechanistically affect outcomes in a preclinical porcine model. They evaluated two targeted temperature management (TTM) protocols (33°C versus 35°C) in comparison to normothermia. They demonstrate improved survival and neurologic outcomes in the two targeted temperature groups, with the greatest benefit observed in the 33°C group. The authors present data suggesting that these improved outcomes are due to a potential reduction in pro-inflammatory processes (reduced MIF and IL-17F), potential inhibition of brain edema pathways (increased TIMP-1 and TIMP-2), and possible promotion of angiogenesis and vascular stability/maturity (increased VEGF and ANG-1). Similarly, the authors find that the greatest impact on the levels of these biochemical markers occurred in the 33°C group. The authors astutely indicate that current available clinical studies have been unable to identify any significant differences in clinical outcomes between targeted temperatures of 33°C and 36°C. Therefore, the findings in this study highlight that we should continue the efforts to identify the optimal targeted temperature following cardiac arrest.
In the next cardiac arrest study, Xie et al. (10) evaluate remote ischemic postconditioning as a potential therapeutic strategy for improving neurologic outcomes following cardiac arrest. Remote ischemic postconditioning is a transient ischemia-reperfusion treatment that occurs in a remote organ and can have distal effects. The authors employ a preclinical rat model to evaluate the effect that remote ischemic postconditioning has on neuronal apoptosis and mitophagy. The authors detail their exciting findings that demonstrate that remote ischemic postconditioning reduced neuronal apoptosis and improved neurological deficits. It will be especially interesting to determine if combining models of remote ischemic conditioning with models of targeted temperature protocols, such as those described by Cui et al. (9), has synergistic effects.
Improving therapies following cardiac arrest is an important area of investigation; however, increasing our knowledge on how to prevent cardiac arrest can also have significant implications. In their study, Madurska et al. (11) evaluate cardiac physiology in cases of exsanguination that result in subsequent cardiac arrest. Their study, therefore, provides critical information that bolsters our understanding regarding how providers might prevent cardiac arrest and salvage these patients. As described by the authors, current hemorrhagic shock therapies, such as resuscitative endovascular balloon occlusion of the aorta (REBOA) or intravascular volume replacement, primarily target afterload and preload. This study, however, illustrates that at later stages of hemorrhagic shock, afterload and preload therapies may be ineffective as reduced coronary perfusion results in subsequent failed myocardial contraction. Therefore, the authors’ findings are important regarding patient selection and appropriate timing of therapies in hemorrhagic shock. For example, their findings suggest that REBOA should be used in earlier hemorrhagic stages while other endovascular therapies that affect coronary perfusion should be prioritized in later stages.
To round out the discussion around cardiogenic shock in this issue, the next study is a well-done meta-analysis conducted by Duan et al. (12) to assess the short-term efficacy and safety profile of different interventions for patients with CS or who underwent high-risk percutaneous coronary intervention (HS-PCI). Specifically, the following interventions were evaluated: pharmacotherapy, extracorporeal membrane oxygenation (ECMO), intraaortic balloon pumping (IABP), percutaneous mechanical circulatory support device (pMCS), and ECMO+IABP. Ultimately, following their meta-analysis, the authors suggest that ECMO+IABP may be a more suitable intervention for patients with CS or who underwent HS-PCI. The authors also recommend against routine use of pMCS or ECMO alone as there was no mortality benefit but there was an increased risk of bleeding with these interventions in their study. These findings, therefore, further inform on appropriate patient selection for these various therapies.
The findings presented by Madurska et al. (11) are especially important in the context of increased utilization of endovascular therapies, such as REBOA. In fact, in the next study, Bukur et al. (13) provide a retrospective multicenter analysis evaluating utilization patterns and outcomes associated with use of REBOA as compared with open aortic occlusion. The authors demonstrate that with increased utilization of REBOA, mortality has decreased over the past several years. The authors suggest that there are several explanations for this decrease in mortality including lower threshold to use REBOA (deployed at higher MAPs), increased operator experience, and improved catheter technology. Interestingly, during the earliest years of the registry collection, 100% of REBOA deployments occurred in either the emergency department or the operating room. Then in the most recent year presented, only 78.1% of deployments occurred in the emergency department or operating room. This might suggest that REBOA deployment in the prehospital setting is increasing. When considering the study presented by Maduska et al. (11), it seems also plausible that some of improved mortality observed in this study may be due to earlier deployment of REBOA at earlier stages of hemorrhage when preload and afterload support are most beneficial.
In cases of shock, development of coagulopathy is associated with higher mortality. In the next study, Tang et al. (14) present an important mechanistic study evaluating how modulation of the platelet arachidonic acid-dependent pathway results in the promotion of trauma-induced coagulopathy. The authors use a rat model involving multiple injuries and demonstrate platelet inhibition associated with these injuries, implicating inhibition of the arachidonic acid-dependent pathway as contributary. The authors also suggest that elevated levels of serum Prostaglandin E2 and Prostacyclin contribute to this. Therefore, this study provides potential targets for future therapies developed to reduce risk of coagulopathy in polytrauma patients.
In the setting of traumatic hemorrhage, one currently employed therapy that targets the coagulation pathway is tranexamic acid (TXA). TXA primarily assists with clot stabilization and inhibition of fibrinolysis. However, Richards et al. (15) indicate that it is currently unknown how TXA performs within the context of the three phenotypes of fibrinolysis (fibrinolysis shutdown, physiologic fibrinolysis, and hyperfibrinolysis). Therefore, the authors present a novel study that specifically assesses the effects of TXA within the context of these three phenotypes. In their study, they demonstrate that administration of TXA with the phenotypes of fibrinolysis shutdown and hyperfibrinolysis is actually associated with higher occurrence of multiorgan failure and higher red blood cell transfusion. Although they cannot conclude causation in this study, their findings do suggest that additional studies are needed to further tailor appropriate patient selection for TXA administration.
Continuing on the theme of trauma, valproic acid (VPA) with fresh frozen plasma (FFP) is one promising strategy that has been shown in preclinical models of traumatic brain injury (TBI) to mitigate neurological injury (16). In their article, Dekker et al. (16) therefore conducted a novel study to provide a mechanistic explanation for these effects. Utilizing a preclinical swine polytrauma model (hemorrhagic shock and TBI), the authors evaluated the effects that VPA and FFP have on the brain transcriptome following injury via computational analyses. Ultimately, the results demonstrated that the neuroprotective effects of VPA result from the creation of a more “pro-survival” transcriptome. This study further validates and adds to the body of literature supporting VPA as an important therapy that is ready for clinical trials.
For those patients who are treated for any form of shock, they are likely to be admitted to an intensive care unit. For critically ill patients, one serious complication that can occur is the onset of intraabdominal hypertension (IAH) which can result in intestinal barrier dysfunction and abdominal sepsis. Since there is currently no well-described therapy IAH, Leng et al. (17) conduct a novel study employing a preclinical rat model of IAH to determine how the microbiome changes and if preemptive supplementation of Lactobacillus species can impact these changes. They first demonstrate that pretreatment with the study's probiotic reduced IAH-induced intestinal barrier damage and then provide evidence regarding how the probiotic modulates the microbiome of the rats. Finally, they detail several theories regarding pathways that may be implicated in these findings, which ultimately requires ongoing evaluation.
Although we discussed several studies on TTM in the setting of cardiac arrest, TTM is also an important therapy following heat stroke and may be informed by improved prognostication. Therefore, the next article by Zhong et al. (18) describes a groundbreaking retrospective case-control study to evaluate the risk factors associated with 90-day mortality following severe heat stroke. The authors ultimately suggest that lower survival is associated with longer cooling duration, faster heart rate, and higher Sequential Organ Failure scores. In particular, the authors emphasize that patients who had a cooling time of less than 2 h had a better prognosis, suggesting that cooling within 2 h is an appropriate target until additional studies are conducted.
The final article in this issue of SHOCK is a review article by Mu et al. (19). Although macrophages have been described as important contributors to inflammation, the authors provide a detailed and critical discussion regarding the more recently identified tissue-resident macrophages (TRM) and their specific role in mediating inflammation, tissue repair, and tissue homeostasis. They present this review within context of the spleen, heart, and lung and discuss how maintaining a stable population of TRMs may be key to restoring homeostasis following injury. Finally, the authors effectively demonstrate the TRMs should continue to be the foci of ongoing investigation as findings related to these cell populations may have broad applications in scenarios involving inflammation and shock.
Once again, this issue of SHOCK exhibits a number of excellent articles with exciting and novel findings. We hope that you enjoy reading these articles. Despite the logistical hurdles likely to be imposed by the pandemic during 2021, we urge you all to remember: “The important thing is not to stop questioning.”
1. Renieris G, Katrini K, Damoulari C, Akinosoglou K, Psarrakis C, Kyriakopoulou M, Dimopoulos G, Lada M, Koufargyris P, Giamarellos-Bourboulis EJ. Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the SARS-CoV-2 Coronavirus. Shock
2. Radermacher P, Calzia E, McCook O, Wachter U, Szabo C. Letter to the editor. Shock
3. Renieris G, Katrini K, Giamarellos-Bourboulis EJ. Reply to Radermacher et al. on “Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the SARS-CoV-2 Coronavirus”. Shock
4. Xie K, Wang Y, Yin L, Wang Y, Chen H, Mao X, Wang G. Hydrogen gas alleviates sepsis-induced brain injury by improving mitochondrial biogenesis through the activation of PGC-α in mice. Shock
5. Ye W, Liu X, Bai Y, Tang N, Wu G, Wang X, Cheng J, Liu L. Sepsis activates the TLR4/MYD88 pathway in schwann cells to promote infiltration of macrophages, thereby impeding neuromuscular function. Shock
6. He J, Zhao X, Lin X, Yang Z, Ma M, Ma L, Liang Q, Li L, Ye Y, Wen Z, et al. The effect of Xinmailong infusion on sepsis-induced myocardial dysfunction: a pragmatic randomized controlled trial. Shock
7. Debrabant B, Halekoh U, Soerensen M, Møller JE, Hassager C, Frydland M, Palstrøm N, Hjelmborg J, Beck HC, Rasmussen LM. STEMI, cardiogenic shock, and mortality in patients admitted for acute angiography: associations and predictions from plasma proteome data. Shock
8. Tabi M, Burstein BJ, Ahmed A, Dezfulian C, Kashani KB, Jentzer JC. Shock severity and hospital mortality in out of hospital cardiac arrest patients treated with targeted temperature management. Shock
9. Cui H, Yang Z, Xiao P, Shao F, Zhao S, Tang Z. Effects of different target temperatures on angiogenesis and neurogenesis following resuscitation in a porcine model after cardiac arrest. Shock
10. Xie B, Gao X, Huang Y, Zhang Y, Zhu S. Remote ischemic postconditioning inhibits hippocampal neuronal apoptosis and mitophagy after cardiopulmonary resuscitation in rats. Shock
11. Madurska MJ, Abdou H, Leung LY, Richmond MJ, Elansary NN, Scalea TM, Hu P, Morrison JJ. The cardiac physiology underpinning exsanguination cardiac arrest: targets for endovascular resuscitation. Shock
12. Duan J, Shi Y, Luo G, Peng Y, Duan B, Zhang Z. Short-term efficacy and safety of different mechanical hemodynamic support devices for cardiogenic shock or high-risk PCI: a network meta-analysis of thirty-seven trials. Shock
13. Bukur M, Gorman E, DiMaggio C, Frangos S, Morrison JJ, Scalea TM, Moore LJ, Podbielski J, Inaba K, Kauvar D, et al. and the AAST AORTA Study Group. Temporal changes in REBOA utilization practices are associated with increased survival: an analysis of AORTA registry. Shock
14. Tang Y, Huang S, Lin W, Wen K, Lin Z, Han M. Arachidonic acid-dependent pathway inhibition in platelets: Its role in multiple injury-induced coagulopathy and the potential mechanisms. Shock
15. Richards JE, Fedeles BT, Chow JH, Morrison JJ, Renner C, Trinh AT, Schlee CC, Koerner K, Grissom TE, Betzold RD, et al. Is tranexamic acid associated with mortality or multiple organ failure following severe injury? Shock
16. Dekker SE, Biesterveld BE, Bambakidis T, Williams AM, Tagett R, Johnson CN, Sillesen M, Liu B, Li Y, Alam HB. Modulation of brain transcriptome by combined histone deacetylase inhibition and plasma treatment following traumatic brain injury and hemorrhagic shock. Shock
17. Leng Y, Jiang C, Xing X, Tsai M-S, Snyder M, Zhai A, Yao G. Prevention of severe intestinal barrier dysfunction through a single-species probiotics is associated with the activation of microbiome-mediated glutamate–glutamine biosynthesis. Shock
18. Zhong L, Wu M, Liu Z, Liu Y, Ren G, Su L, Liu Z. Risk factors for the 90-day prognosis of severe heat stroke: a case-control study. Shock
19. Mu X, Li Y, Fan G-C. Tissue-resident macrophages in the control of infection and resolution of inflammation. Shock