The November issue of SHOCK offers a particularly abundant selection of important reports both in terms of quantity (more papers included to shorten backlog of publication of accepted papers) and in terms of quality. The lead off for the issue by Sayyadioskoie and Schwacha (1) is a mini-review on myeloid-derived suppressor cells (MDSC). These authors summarize the importance of these cells in suppression of inflammation in sepsis and propose a systematic approach to MDSC analysis to enhance the impact of clinical research in this area. On the flip side of myelosuppression is a systematic review by Stolarski et al. (2) addressing the currently very popular term “cytokine storm,” especially in the context of SARS-CoV-2. Based on a review of the current literature, they counter that there is little evidence of such a storm and that the inflammatory response should instead be considered a “cytokine drizzle.” This report should serve as a catalyst to drive investigations into the true mechanisms of this devastating disease. An important contributor to these response are mediators that exert pro- or anti-inflammatory properties that could potentially be used to modulate the inflammatory response. Leite-Avalca et al. (3) provide a review of one class of potentially effective class of mediators – endocannabinoids acting on the cannabinoid receptors. Their review discusses the divergent roles of Cannabinoid receptors 1 and 2 (CB1 and CB2) with CB1 contributing to the cardiovascular dysfunction of sepsis and CB2 providing protection via its anti-inflammatory properties.
The inflammatory response and associated physiological response are highly sensitive to comorbidities. It is has become recently very evident that obesity is an important predisposing factor in severity of COVID-19. However, the effect of obesity in sepsis/trauma in general is complex. The review by Ayalon et al. (4), summarizes the very complicated role of mild to severe obesity which appears to be protective in some pathologies, but increases morbidity and mortality in others. Finally, Cardenas (5) summarizes the central role of thrombin regulation in both normal clotting as well as coagulopathies following trauma.
This month's issue offers four papers focused on heart function, three of those on cardiac arrest. In a clinical study, Maeda et al. (6) examined whether patients who converted from shockable to non-shockable rhythm after cardiac arrest and prior to initiation of extracorporeal cardiopulmonary resuscitation (ECPR) was associated with poorer outcomes than patients did not convert to non-shockable rhythms. Their retrospective analysis showed a significantly higher mortality and poor neurologic outcomes in patients with non-shockable rhythms. These findings should be considered in the decision to initiate resource-intensive ECPR. Another clinical study by Fukuda et al. (7) examines the timing of epinephrine administration during out of hospital cardiac arrest. They examined 119,946 patients in a registry to determine if early (<20 min) vs late (>20 min) time to first administration of epinephrine after out-of-hospital cardiac arrest was associated with poorer outcome. Early epinephrine administration was associated with improved 1 month neurologically favorable survival indicating the importance of early epinephrine administration.
Two basic research studies this month examine mechanisms of injury following cardiac arrest in brain. Li et al. (8) examined the potential role of the XBP1 branch of the unfolded protein response in protecting the brain after resuscitation. In a mouse model, they used both gain of function and loss of function models in both young and aged mice. In both groups, activation of the XBP1 pathway resulted in significant performance in behavioral tests suggesting a potential therapeutic target for neurologic deficits following cardiac arrest. In a rabbit study, Kohlhauer et al. (9) also examined mitochondrial function in brain compared to heart following cardiac arrest. Their results showed that mitochondrial function was altered in both brain and heart following cardiac arrest, but the kinetics did not correlate with functional parameters suggesting that mitochondrial functional impairment may be a secondary event rather than a cause of functional impairment. In the final heart study, Ko et al. (10) used a swine model to evaluate noninvasive electrical impedence tomography (EIT) and the invasive pulse contour analysis (PCA) methods for measurement of cardiac output in various volume states. The found that EIT compared favorably to PCA in beat to beat stroke volume determination both during hypovolemia and with increasing preload suggesting that this noninvasive approach may be an appropriate new tool for fluid management.
As outlined in the review by Ayalon (4), obesity is a complex comorbidity in inflammatory states. In part, adipose tissue serves an important humoral and metabolic function. In a clinical study, Ebihara et al. (11) examined the adipocytokine network in the acute phase of sepsis. They compared adipose-derived cytokines in 37 septic patients to normal controls and related to APACHE scores. Their results showed that the adipokine resistin along with a network including IL-6, IL-8, IL-10, and MCP-1 were elevated in acute sepsis and correlated with APACHE score suggesting their utility as markers of severity and prognosis in sepsis. Adipose function depends, in part on the distribution of white and brown adipose tissue. Knuth et al. (12) examined this distribution in a mouse model of burn injury-induced hypermetabolism. They showed that white adipose browning as evidenced by futile cycles of lipolysis in adipose mitochondria persisted for 60 days after burn injury contributing to fat catabolism, hepatomegaly, and loss of body mass. They suggest that targeting this adipose response may improve outcomes in severe burn injury.
An important regulator of inflammation is inflammasome formation. Pan et al. (13) examined whether the mitochondrial outer membrane protein FUNDC1 regulates autophagy following endotoxin injection via an effect on reactive oxygen (ROS) and NLRP inflammasomes. FUNDC1 knockout mice showed decreased autophagy associated with increased ROS and inflammasome formation. Given that appropriate autophagy is protective in pathologies such as sepsis, they suggest that modulation of FUNDC1 may be a target for therapy development. Inflammation also plays a role in neurodegeneration. Ren et al. (14) developed a model of trigeminal neuralgia (TN) in rats to study contributors to neurodegeneration. NLRP3 accumulated over time following TN which was inhibited by NLRP3 inhibitor MCC950. MCC950 also decrease behavioral changes and protein markers of neurodegeneration suggesting that modulation of inflammasomes may be promising as a therapy for neurodegeneration. Along the theme of neural involvement, this months issue offers two papers focused on the gut/brain axis. Li et al (15) used an LPS model in sepsis to compare different methods of altering the gut microbiome in rats and its impact on proinflammatory cytokines in the cerebral cortex and cortical function. They compared fecal transfer, probiotics, prebiotics, and synbiotics. Fecal transfer was most effective in restoring gut microbial diversity and also most effective in decreasing brain inflammation and improving cortical function. Looking in the reverse direction, Wu et al. (16) studied the effect of vagus nerve stimulation on enterocyte glycocalyx after trauma/hemorrhagic shock. The vagal stimulation is known to protect intestinal permeability following hemorrhage so they tested whether this might be via protection of the glycocalyx. Vagal nerve stimulation preserved the glycocalyx and decreased intestinal permeability. These effects were partly inhibited by and nicotinic receptor antagonist. Increased lung permeability was also inhibited suggesting a correlation between preservation of glycocalyx and prevention of injury. Shedding of glycocalyx is not restricted to enterocytes, but also occurs in vascular endothelial cells. Abdullah et al. (17) addressed the tissue distribution of glycocalyx shedding in blood vessels following hemorrhagic shock. Using a rat hemorrhage/resuscitation model, they found that intestine and lung showed the greatest oxidative stress and this was associated with the greatest glycocalyx shedding compared to muscle, live, and kidney. They suggest that these vascular beds may thus be major contributors to coagulopathies in hemorrhage/resuscitation.
Three other papers this month address aspects of hemorrhage or ischemia/reperfusion. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been recently developed to control lethal bleeding following torso hemorrhage. However, ischemia of distal tissues, especially the splanchnic viscera is a serious limitation. Liu et al. (18) tested whether transrectal cooling of the intestines could mitigate this limitation. REBOA following 50% blood loss with the intestines at 37° resulted in 100% mortality. In contrast, cooling the colon to 10° to 12o abolished mortality and improved blood gasses, abdominal organ injury, and functional deficits at 7 days suggesting the targeted cooling may be an effective adjunct to REBOA. The paper by Proctor et al. (19) addresses another practical problem. Air evacuation following serious trauma results in exposure to hypobaria. They subjected rats to a combination of head trauma and hemorrhage under either sea level (normobaria) or hypobaria equivalent to 8,000 ft of altitude with normoxia or hyperoxia. They found that hypobaria decrease survival and this was potentiated by administering 100% oxygen. Organ inflammation correlated with mortality. They conclude that hypobaria of this degree is deleterious and potentiated by administering high levels of oxygen. The primary cause of injury following hemorrhage is ischemia. Lakshmanan et al. (20) used a natural product, tender coconut water (TCW), which is rich in antioxidants as a treatment for liver ischemia/reperfusion injury and associated lung injury. Mice were drank TCW or placebo for a week before 60 min hepatic ischemia. TCW increase expression of antioxidant genes Hmox1 and Ptgs2 in the liver significantly prevented liver injury and inflammatory markers that correlated with plasma cytokines and lung injury. These effects correlated with decreased macrophage activation suggesting the macrophage as a potential target for TCW actions. A final basic study on inflammation comes from dos Santos et al. (21). Although hydralazine is most commonly used as a potent vasodilator, it is also reported to have antioxidant properties. This study investigated whether it might be protective in a cecal ligation and puncture (CLP) sepsis model. Treatment with hydralazine 4 h after CLP and then every 12 for 48 h resulted in improved survival, decreased sepsis score, and improved metabolic profile. This was associated with decreased oxidative stress and increased activation of the PI3 kinase/Akt pathway suggesting antioxidant actions as its mechanism.
Base excess is often used as a prognostic factor in trauma patients; however, such trauma is often associated with high blood alcohol levels which may affect the prognostic value of base excess. Leiblein et al. (22) review data from 11,889 patients, about 25% of whom were positive for blood alcohol (BAL+). They found the BAL+ patients tended to have a more negative base excess, and lower mortality, but both groups showed a similar base excess of −6 as a predictor of poor outcome.
As outlined by Stolarski et al. (2) above, COVID-19 remains somewhat enigmatic and continues to tax health care resources. A hallmark of severe disease is coagulopathy. Vassiliou et al. (23) investigated whether soluble endothelial protein C receptor (sEPCR) shedding might contribute and serve as a marker for patients requiring hospitalization. Multiple logistic regression analysis of 84 hospitalized and 11 non-hospitalized patients showed sEPCR plasma levels to be a significant independent predictor of hospitalization suggesting that sEPCR analysis could be a useful adjunct in determining which patients need to be hospitalized. In a final clinical report, Jiang et al. (24) whether the usual method of indexing urine output to actual body weight (ABW) rather than ideal body weight (IBW) to estimate acute kidney injury (AKI) might lead to misleading results in obese patients. They analyzed records from 14,725 patients and found that using ABW resulted in significantly more patients being deemed to have AKI. Outcome of patients with AKI determined by IBW was similar to those determined by creatinine clearance while those identified by ABW were similar to patients without AKI. This suggests that using ABW to index urine output in obese patients may overestimate the incidence of AKI.
1. Sayyadioskoie SR, Schwacha MG. Myeloid-derived suppressor cells (MDSCs) and the immunoinflammatory response to injury (mini review). Shock 56:658–666, 2021. 2. Stolarski AE, Kim J, Zhang Q, Remick DG. Cytokine drizzle—The rationale for abandoning “cytokine storm.”. Shock 56:667–672, 2021. 3. Leite-Avalca MCG, Zampronio A, Lehmann C. Cannabinoid receptor 1 and 2 signaling pathways involved in sepsis. Shock 56:673–681, 2021. 4. Ayalon I, Bodilly L, Kaplan J. The impact of obesity on critical illnesses. Shock 56:691–700, 2021. 5. Cardenas JC. Thrombin generation following severe trauma: mechanisms, modulators, and implications for hemostasis and thrombosis. Shock 56:682–690, 2021. 6. Maeda K, Inoue A, Kuroda Y, Inoue F, Suga M, Ijuin S, Kai S, Koga T, Igarashi N, Matsuyama S, et al. Association between converting asystole from initial shockable ECG rhythm before extracorporeal cardiopulmonary resuscitation and outcome. Shock 56:701–708, 2021. 7. Fukuda T, Ohashi-Fukuda N, Inokuchi R, Kondo Y, Taira T, Kukita I. Timing of intravenous epinephrine administration during out-of-hospital cardiac arrest. Shock 56:709–717, 2021. 8. Li R, Shen Y, Li X, Lu L, Wang Z, Sheng H, Hoffmann U, Yang W. Activation of the XBP1s/O-GlcNAcylation pathway improves functional outcome after cardiac arrest and resuscitation in young and aged mice. Shock 56:755–761, 2021. 9. Kohlhauer M, Panel M, des Roches MV, Faucher E, Daou YAZ, Boissady E, Lidouren F, Ghaleh B, Morin D, Tissier R. Brain and myocardial mitochondria follow different patterns of dysfunction after cardiac arrest. Shock 56:857–864, 2021. 10. Ko RE, Jang GY, Chung CR, Lee JY, Oh TI, Suh GY, Kim Y, Woo EJ. Noninvasive beat-to-beat stroke volume measurements to determine preload responsiveness during mini-fluid challenge in a swine model: a preliminary study. Shock 56:850–856, 2021. 11. Ebihara T, Matsumoto H, Matsubara T, Matsuura H, Hirose T, Shimizu K, Ogura H, Kang S, Tanaka T, Shimazu T. Adipocytokine profile reveals resistin forming a prognostic-related cytokine network in the acute phase of sepsis. Shock 56:718–726, 2021. 12. Knuth CM, Auger C, Chi L, Barayan D, Abdullahi A, Jeschke MG. Thermal stress induces long-term remodeling of adipose tissue and is associated with systemic dysfunction. Shock 56:744–754, 2021. 13. Pan P, Chen J, Liu X, Fan J, Zhang D, Zhao W, Xie L, Su L. FUNDC1 regulates autophagy by inhibiting ROS-NLRP3 signaling to avoid apoptosis in the lung in a lipopolysaccharide-induced mouse model. Shock 56:773–781, 2021. 14. Ren C, Chen M, Mu G, Peng S, Liu X, Ou C. NLRP3 inflammasome mediates neurodegeneration in rats with chronic neuropathic pain. Shock 56:840–849, 2021. 15. Li S, Guo H, Xu X, Hua R, Zhao Q, Li J, Lv J, Li J. Therapeutic methods for gut microbiota modification in lipopolysaccharide-associated encephalopathy. Shock 56:824–831, 2021. 16. Wu J, Yin Y, Qin M, Li K, Liu F, Zhou X, Song X, Li B. Vagus nerve stimulation protects enterocyte glycocalyx after hemorrhagic shock via the cholinergic anti-inflammatory pathway. Shock 56:832–839, 2021. 17. Abdullah S, Karim M, Legendre M, Rodriguez L, Friedman J, Cotton-Betteridge A, Drury R, Packer J, Guidry C, Duchesne J, et al. Hemorrhagic shock and resuscitation causes glycocalyx shedding and endothelial oxidative stress preferentially in the lung and intestinal vasculature. Shock 56:803–812, 2021. 18. Liu C, Yuan D, Crawford R, Sarkar R, Hu B. Directly cooling gut prevents mortality in the rat model of REBOA management of lethal hemorrhage. Shock 56:813–823, 2021. 19. Proctor JL, Medina J, Rangghran P, Tamrakar P, Miller C, Puche A, Quan W, Coksaygan T, Drachenberg CB, Rosenthal RE, et al. Air-evacuation-relevant hypobaria following traumatic brain injury plus hemorrhagic shock in rats increases mortality and injury to the gut, lungs, and kidneys. Shock 56:793–802, 2021. 20. Lakshmanan J, Zhang B, Wright K, Motameni AT, Herbst JL, Harbrecht BG. Tender coconut water protects mice from ischemia-reperfusion-mediated liver injury and secondary lung injury. Shock 56:762–772, 2021. 21. dos Santos DM, Da Silva EAP, Oliveira JYS, de Menezes Marinho YY, de Santana IR, Heimfarth L, Pereira EWM, Júnior LJQ, Assreuy J, Menezes IAC, et al. The therapeutic value of hydralazine in reducing inflammatory response, oxidative stress, and mortality in animal sepsis: involvement of the P13K/AKT pathway. Shock 56:782–792, 2021. 22. Leiblein M, Sturm R, Franz N, Mühlenfeld N, Relja B, Lefering R, Marzi I, Wagner N. The influence of alcohol on the base excess parameter in trauma patients. Shock 56:727–732, 2021. 23. Vassiliou AG, Keskinidou C, Jahaj E, Gallos P, Zacharis A, Athanasiou N, Tsipilis S, Mastora Z, Dimopoulou I, Kotanidou A, et al. Could soluble endothelial protein C receptor levels recognize SARS-CoV2-positive patients requiring hospitalization? Shock 56:733–736, 2021. 24. Jiang J, Zhang J, Liu Y, Xu D, Peng Z. Urine output calculated using actual body weight may result in overestimation of acute kidney injury for obese patients. Shock 56:737–743, 2021.
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