What's New in Shock, June 2021?

It is our honor to author the June, “What's New in Shock” commentary as we have the privilege of reviewing an article from a longtime Shock member, Dr Michael Dubick, who recently passed. We thank him for his dedication to Shock as well as his many important contributions to science.

As sepsis remains a disease with high mortality and an important focus of our journal, this month we discuss several articles on sepsis, with an emphasis on innate immunity. Trauma and sepsis are disease states that lead to persistent inflammation, immune suppression, and catabolism syndrome (PICS). While the acute inflammatory response that follows sepsis and trauma is well studied, the mechanisms governing prolonged immunosuppression are largely not understood. In this issue, Bergmann et al. (1) provide an extensive review on the contribution of lymphocytes to the development of PICS. The authors suggest that the imbalance of regulatory T cell (Tregs) subsets determines the development of immunosuppression. They then explain how Tregs, innate lymphoid cells, natural killer T cells, TCR-a CD4 CD8 double-negative T cells, and B cells participate in the development of immune dysfunction in trauma and sepsis. In particular, the contribution of regulatory B cells and the cytokines, interleukin-10 (IL-10), transforming growth factor beta, and IFN-g is discussed. While there is still no approved drug for the treatment of immune dysfunction, the following were suggested as important to therapy development and immune-phenotyping: intensive care unit dynamic immune monitoring, determination of immunologic states using a panel of biomarkers and functional assays, description of patient subgroups based on immune status, and consideration of repurposing autoimmune and cancer drugs for treatment of immune dysfunction following trauma and sepsis.

Sepsis-induced immunosuppression is also associated with the increased expression of programmed cell-death protein 1 (PD-1). PD-1 is expressed predominantly on T cells and binds to its primary ligand, programmed death-ligand 1. Previously, it has been reported that blocking PD-1 or its ligands with antibodies increased survival and alleviated immune suppression but this strategy can lead to hyperactivation of the immune response. Peptide-based therapeutics are an alternative modality that was tested by Phares et al. (2). The authors tested LD01, a linear 22-amino acid peptide antagonist of PD-1, in a cecal-ligation and puncture -induced murine polymicrobial sepsis model and found that this peptide improved survival and decreased bacterial burden (2). The enhanced survival was associated with increased T-cell production of interferon-gamma. This study thus provides an alternative to boost T-cell immunity in sepsis over antibodies against PD-1 and may prove to be a viable therapeutic candidate for mitigating immunosuppression following sepsis. Might it also work in PICS?

Decreased expression of human leukocyte antigen-DR on monocytes (mHLA-DR) is also associated with immune suppression in sepsis. Measuring mHLA-DR is typically performed using flow cytometry; however, its widespread use is limited due to the need for dedicated laboratories because of the pre-analytical constraints. Bourgoin et al. (3) developed a flow cytometry method using whole blood in a one-step procedure that includes red cell lysis, antibodies, and fixative reagents. The one-step method was compared with a standardized routine protocol and demonstrated strong correlation in 24 septic patients. The protocol can even be applied to blood samples collected by finger stick, though further validation is needed. This improved method provides the feasibility of a bedside protocol for flow cytometry measurement of mHLA-DR in critically ill subjects.

Bloch et al. (4) investigated the association between glucagon-like peptide-1 (GLP-1) and the innate immunity markers procalcitonin (PCT) and sCD14 in septic patients. The major function of GLP-1 is to stimulate the inflammatory response and has been implicated in the early dysregulation of innate immunity. Persistently elevated GLP-1 levels after gram-negative sepsis predicted poor long-term outcome. On the other hand, PCT and sCD14 are expressed in gram-negative septic shock and represent markers of early innate immunity response. The current data indicated that elevated GLP-1 in patients with culture-positive gram-negative bacteria was accompanied by a sharp increase in sCD14 and PCT as well as serum lactate. Thus, GLP-1 could be used as a novel marker for rapid diagnosis of gram-negative sepsis and its severity.

Impairment in oxygen utilization by mitochondria has been implicated in the morbidity and mortality in sepsis and, indeed, lactate elevation is a characteristic of septic shock. Hoeyer-Nielsen et al. (5) investigated oxygen consumption (VO2) in septic patients and its association with the patient survival. Their retrospective analysis of 46 septic patients indicated that the VO2:lactate ratio was significantly higher in survivors while there was no association between overall median VO2 alone. The authors suggest that the adequacy of a given number for VO2 may be best interpreted in conjunction with a marker of tissue oxygenation such as lactate and they ask the question if the VO2:lactate ratio could be a treatment target or prognostic tool? Only time and further studies will tell. Although increasing tissue oxygenation is beneficial, commonly used therapies such as infusion of norepinephrine (NE) to sustain blood pressure following sepsis may have just the opposite effect. Using a rabbit model of endotoxic shock, Nakamura et al. (6) confirmed that although NE improved mean arterial blood pressure and superior mesenteric venous blood flow, it decreased jejunal mucosal tissue blood flow and may contribute to nonocclusive bowel necrosis.

Finishing up our discussion of sepsis, in an observational prospective case control study, Hutchings et al. (7) compared microcirculatory disturbances, endothelial cell injury, and inflammation between patients with septic shock and those with COVID. The authors characterized microcirculatory changes by examination of the sublingual microcirculation at a single timepoint. While patients with COVID-19 critical illness had mildly impaired sublingual microcirculatory flow compared with healthy controls, those with septic shock had much more dramatic changes. COVID patients also did not have significant elevations of lactate nor high vasopressor requirements typical of patients in septic shock. What was surprising, is that the authors were unable to demonstrate neither significant endothelial cell injury as measured by shed syndecan-1 nor inflammation as measured by cytokine release. The authors speculate that perhaps there are organ-specific changes rather than systemic changes in these parameters. The mysteries of COVID continue to challenge us.

The COVID pandemic has led to a renewed interest in extracorporeal life support (ECLS), like what was seen after the H1N1 pandemic. Tabatabai et al. (8) present the history of ECLS and data supporting its use, including both veno-venous (VV) and veno-arterial, with an informative explanation of the basic concepts of ECLS. They review ECLS in patients with severe acute respiratory distress syndrome in general and then with specific conditions to include COVID. While the general indications for ECLS are relevant to COVID patients, the authors stress that optimal candidates for VV ECLS with COVID are younger, nonobese and with single-organ pulmonary dysfunction. While data on ECLS after COVID are limited, it remains a viable option for patients who fail conventional therapy.

Tabatabai et al. also touched upon the challenges of anticoagulation in hypercoagulable COVID patients on ECLS, while Goswami et al. (9) expand on the issue of COVID-associated coagulopathy by performing a systematic review of the literature on this important topic. The authors start with a review of the coagulation abnormalities seen with COVID such as increased von Willebrand Factor (VWF) and FVIII, low platelets, and the presence of antiphospholipid antibodies. They then explain the thrombo-elastographic abnormalities seen with COVID as an introduction to the etiology of venous and arterial thrombosis seen in these patients. Finally, a link between inflammation and coagulation is proposed and attributed to a combination of endothelial injury, cytokine storm, complement activation, and neutrophil extracellular traps.

Thromboinflammation is important not only after COVID but also after injury, as discussed in the excellent review by Zeineddin et al. (10). Admittedly as authors of the VWF review article and this commentary, we may be a bit biased! VWF has been widely used as a biomarker of endothelial injury in inflammatory conditions such as diabetes, arteritis, and sepsis but only more recently after injury. When endothelial cells are activated by any inflammatory condition, hyperadhesive ultralarge VWF multimers are released from endothelial cells and platelets and are rapidly cleaved into small multimers by its cleaving enzyme, ADAMTS13, on the surface of endothelial cells. However, during acute injury large amounts of ULVWF multimers are released from the injured endothelium without a corresponding increase in ADAMTS13, resulting in a kinetic and consumptive deficiency of ADAMTS13 and accumulation of pro-thrombotic hyperadhesive VWF multimers on the endothelial surface and in circulation. Additional contributors to coagulopathy arise from extracellular vesicles, at least after traumatic brain injury, that are pro-thrombotic as they express tissue factor and anionic phosphatidylserine on their surface. We hope that elucidation of the mechanism by which the dysregulated VWF-ADAMTS13 axis leads to endothelial dysfunction and coagulopathy after trauma can help identify new targets for therapy and sites for intervention.

Continuing in the realm of injury microenvironment, Walczak et al. (11) expand on their previous work identifying the etiology of anemia following burn injury. Pro-inflammatory cytokines have been implicated in suppression of erythropoeitin (EPO) production and EPO-independent erythrocyte differentiation. This study dives deeper into the mechanism in which cytokines influence late defects in erythrocyte differentiation. Peripheral blood mononuclear cells were isolated from the blood of burn patients as well as human bone marrow cells from healthy donors. Cells were then treated with plasma from burn patients and controls, as well as with different recombinant cytokines and mediators, including IL-6, IL-15, and TNF-alpha. TNF-alpha antibody was also used to examine the effect of TNF-alpha neutralization. The authors exonerated IL-6 and IL-15 of detrimental effects on erythrocyte enucleation and found TNF-alpha to be the primary inhibitory cytokine evidenced by the reversal of the erythrocyte enucleation defect after treatment with TNF-alpha antibody. This reversal, however, was partial leaving part of the mystery to be solved in further experiments.

Inflammatory markers and cytokines can also serve a predictive role which was explored by Shimazui et al. (12), where they assessed the predictive value of seven biomarkers (IL-6, IL-8, IL-10, TNF-alpha, WBC, CRP, and procalcitonin) on the development of multiple organ dysfunction (MOD). In this study, blood was collected from patients presenting with systemic inflammatory response syndrome at three time points (days 0, 1, and 2). The sequential organ failure assessment score was used to identify MOD on days 3 and 7. The authors found IL-6 elevation on day 2 to be the most predictive of MOD on both days 3 and 7 with an area under the curve of 0.84 for both. CRP had the lowest AUC in their analysis.

We shift gears now onto a discussion of hemorrhagic shock and its sequalae. Penn et al. (13) studied a rat model of hemorrhagic shock with tourniquet application and prolonged hypotensive resuscitation to describe different types of decompensation encountered after severe hemorrhagic shock. The authors suggest that decompensation does not seem to be driven by intrinsic cardiac factors but rather of loss of preload from inability of venous vasculature to constrict combined with a loss of oncotic pressure. The authors investigated a new compound, oleic acid saturated albumin (OA-sat BSA), compared with nonesterified fatty acids free BSA (FA-free BSA), and to Plasmalyte. Animals that survived until resuscitation had significantly lower rates of decompensation after treatment with OA-sat BSA than with FA-free BSA or Plasmalyte. The suggested mechanism is maintenance of adequate intravascular oncotic pressure. This analysis provides insight into the mechanisms of decompensation after hemorrhagic shock and proposes possible new therapeutic targets to improve survival. Another therapeutic target in hemorrhagic shock was investigated by Bai et al. (14) who examined the therapeutic effects of carbon monoxide-releasing molecule 3 (CORM-3) on acute lung injury (ALI) following hemorrhagic shock and resuscitation in a rat model. They found that CORM-3 partially alleviated ALI, with a suggested mechanism of preventing apoptosis of lung macrophages, likely by alleviating the activation of the p38MAPK pathway in macrophages. This pathway has been previously implicated in ALI as well as acute liver injury and ischemia-reperfusion injuries. Thus, these findings invite further investigation into the beneficial effects of CORM-3 including that of hemorrhagic shock.

Finally, Piekarski et al. (15) present their findings in an interesting simulated clinical trial of a new device aimed at a more accurate quantification of intraoperative blood loss. Fifty-three anesthesiologists turn to software to improve on their surgical colleagues’ visual estimation of intraoperative blood loss. The simulation scenarios compared the use of a mobile device with software that used colorimetric image correction and analysis for blood loss estimation compared to a gravimetric technique and to standard visual estimation. The new mobile software was found to be the most accurate in the simulated scenarios, independent of dilution effects, followed by the gravimetric technique, while the visual estimation showed the largest deviation from the reference blood volume, overestimating blood loss in most scenarios. I bit surprising as surgeons are notorious for underestimating blood loss. As a surgeon, I’m allowed to say that!

That sums up this month's What's New in Shock, with topics of sepsis, shock, and of course COVID. Hopefully, one day soon we will see a COVID-free issue and a COVID-free society!

1. Bergmann CB, Beckmann N, Salyer CE, Crisologo PA, Nomellini V, Caldwell CC. Lymphocyte immunosuppression and dysfunction contributing to persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Shock 55:723–741, 2021. 2. Phares TW, Kotraiah V, Chung C-S, Unsinger J, Mazer M, Remy KE, Browne CD, Buontempo P, Mansour M, Pannucci J, et al. A peptide-based checkpoint immunomodulator alleviates immune dysfunction in murine polymicrobial sepsis. Shock 55:806–815, 2021. 3. Bourgoin P, Taspinar R, Gossez M, Venet F, Delwarde B, Rimmelé T, Morange P-E, Malergue F, Monneret G. Toward monocyte HLA-DR bedside monitoring: a proof-of-concept study. Shock 55:782–789, 2021. 4. Bloch O, Perl SH, Lazarovitch T, Zelnik-Yovel D, Love I, Mendel-Cohen L, Goltsman G, Flor H, Rapoport MJ. Hyper-activation of endogenous GLP-1 system to gram-negative sepsis is associated with early innate immune response and modulated by diabetes. Shock 55:796–805, 2021. 5. Hoeyer-Nielsen AK, Holmberg MJ, Grossestreuer AV, Yankama T, Branton J-P, Donnino MW, Berg KM. Association between the oxygen consumption: lactate ratio and survival in critically ill patients with sepsis. Shock 55:775–781, 2021. 6. Nakamura F, Muroya T, Onoe A, Ikegawa H, Kuwagata Y. Effects of norepinephrine on the intestinal vascular system in rabbits with endotoxic shock. Shock 55:827–831, 2021. 7. Hutchings SD, Watchorn J, Trovato F, Napoli S, Mujib SF, Hopkins P, McPhail M. Microcirculatory, endothelial, and inflammatory responses in critically ill patients with COVID-19 are distinct from those seen in septic shock: a case control study. Shock 55:752–758, 2021. 8. Tabatabai A, Galvagno SM Jr, O’Connor JV, Scalea TM, Deatrick KB. Extracorporeal life support (ECLS): a review and focus on considerations for COVID-19. Shock 55:742–751, 2021. 9. Goswami J, MacArthur TA, Sridharan M, Pruthi RK, McBane RD II, Witzig TE, Park MS. A review of pathophysiology, clinical features, and management options of COVID-19 associated coagulopathy. Shock 55:700–716, 2021. 10. Zeineddin A, Dong J-F, Wu F, Terse P, Kozar RA. Role of Von Willebrand factor after injury: it may do more than we think. Shock 55:717–722, 2021. 11. Walczak J, Hasan S, Shoaee N, Tromblay D, Muthumalaiappan K. Plasma TNFα and unknown factor/s potentially impede erythroblast enucleation obstructing terminal maturation of red blood cells in burn patients. Shock 55:766–774, 2021. 12. Shimazui T, Nakada T-a, Yazaki M, Mayumi T, Takasu O, Matsuda K, Sasaki J, Otsubo H, Teshima Y, Nabeta M, et al. Blood interleukin-6 levels predict multiple organ dysfunction in critically ill patients. Shock 55:790–795, 2021. 13. Penn AH, Dubick MA, Torres Filho IP. Albumin saturated with fatty acids prevents decompensation in a rat hemorrhagic shock trauma model with tourniquet and hypotensive resuscitation. Shock 55:832–841, 2021. 14. Bai J, Bai Y, Wang X-P, Zheng W-C, Zhang L-M. Carbon monoxide-releasing molecule-3 ameliorates acute lung injury in a model of hemorrhagic shock and resuscitation: roles of P38MAPK signaling pathway. Shock 55:816–826, 2021. 15. Piekarski F, Gerdessen L, Schmitt E, Friedrichson B, Neef V, Meybohm P, Zacharowski K, Raimann FJ, Wunderer F. Quantification of intraoperative blood loss in a simulated scenario using a novel device. Shock 55:759–765, 2021.

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