Sepsis and infectious/septic shock are the leading causes of mortality in intensive care units (ICU). Although a series of therapeutic measures have been developed, the patient population is still greatly increased in the last decade all over the world. New treatment approaches are badly in need for the life-threatening disease. On-going global pandemic of COVID-19 is severely threatening the life safety of people.
Effective prevention and treatment measures are also badly needed. Accordingly, this issue of SHOCK presented 14 articles about sepsis and COVID-19, in which, six articles are related to the pathogenesis and treatment of sepsis and septic shock, eight articles are related to COVID-19 prevention and treatment. In addition, this issue also comprises of two articles about the application of resuscitative endovascular balloon occlusion in intra-abdominal and pelvic hemorrhage, and the mortality analysis for intraoperative hemorrhagic shock in cancer surgical patients, one article about targeted temperature management for cardiac arrest with non-shockable rhythm, and one article about the beneficial effect of non-thermal atmospheric plasma on bacterial killing and wound disinfection in type 2 diabetes.
Due to the insufficient understanding of its pathophysiology and lack of effective treatment, the morbidity and mortality of COVID-19 are high. Based on the critical role of the unique subpopulation of B lymphocytes, B-1a cells in innate immunity, and immunoregulation, Aziz et al. (1) reviewed the potential effects of B-1a cells in the treatment of COVID19. B-1a cells can spontaneously produce natural IgM, interleukin-10, and granulocyte–monocyte colony stimulating factor, and via these mechanisms B-1a cells can ameliorate influenza virus infection, sepsis, and pneumonia. Since the cytokine storm of these diseases is similar to COVID-19, so B-1a cells may be an important treatment approach for COVID-19. This review provided us with an important research interest and new treatment measure for COVID-19 and related diseases.
Abundant evidences have shown that infectious sepsis both in humans and mice may activate complement system. The major complement activation products involved in sepsis include C5a anaphylatoxin and its receptors (C5aR1 and C5aR2). Fattahi et al. (2) reviewed the role of complement in infectious sepsis. They discussed the role of complement system in innate immune system, early proinflammatory responses, and multiple organ dysfunctions, and pointed out that activated complement can activate neutrophils and macrophages, and induce NLRP3 formation, which can result in strong inflammatory and thrombotic responses and organ damage. Inhibition of complement activation has good beneficial effect on sepsis-induced organ dysfunction. Small molecular blocking agents for C5aRs are in development, which may be the new promise for the treatment of sepsis. Phagocytosis is a complex process by which cells remove pathogen and cell debris. Excessive systemic inflammation of sepsis patients is perhaps closely related to insufficient phagocytosis and cellular clearance of pathogen. Hortova-Kohoutkova et al. (3) reviewed phagocytosis-inflammation crosstalk in sepsis. They systematically outlined the major features of phagocytosis including the main receptors and signaling hallmarks associated with the phagocytosis process. They detailed the process of phagocytosis including the formation of phagosome, cytoskeletal remodeling, and the possible mechanisms. Based on the mechanism and important regulation targets of phagocytosis, newly therapeutic measures for the treatment of sepsis will be developed.
Intra-abdominal and pelvic hemorrhage control is the tough issue in traumatic surgery. Resuscitative endovascular balloon occlusion (REBOA) has been used for several years by acute care surgeons for temporization of intra-abdominal, pelvic, and junctional hemorrhage, while the physiology and outcome of this approach is not determined. Brenner et al. (4) reviewed the technique development of REBOA in recent years and the physiological effects and the complications. They emphasized that more multicentral clinical studies are needed to acquire more data regarding the procedural details, the indications, and the complications of REBOA. Patients suffering from a cardiac arrest face a very high risk of death and severe neurologic damage. Successfully restoring the spontaneous circulation and postresuscitation are the key steps. Barbarawi et al. (5) made a systematic review and meta-analysis about the effect of targeted temperature management (TTM) for cardiac arrest patients with an initial non-shockable rhythm (NSR). The results showed that among patients who survived cardiac arrest with an initial NSR, TTM is associated with a higher rate of survival and favorable neurological outcomes compared with no TTM. But the outcome is only from the observational studies, not from RCT studies, more RCT studies are needed to confirm this conclusion. Sepsis is a complex condition modulated by an array of factors. It is not likely that this multifactorial condition could be ameliorated by a single target-directed intervention. Since millions of dollars have been expended with great disappointment in clinical trials directed at some single targets from the studies using mouse model, blame has been raised on the use of animal models, particularly the rodents. De Maio (6) provided a reasonable opinion that we cannot blame the rodent for the failure of developing sepsis therapies. Rodent model system cannot completely represent the pathophysiology of human because of different genetic background and living environment from human. But we cannot deny the irreplaceable value of rodent in the studies of human diseases including sepsis because of its strong fertility and gene adjustability.
This issue contains seven clinical articles including four articles regarding COVID-19. Renieris et al. evaluated the role of serum hydrogen sulfide (H2S) in the outcome of COVID-19 pneumonia. They found that survivors had significantly higher H2S levels on days 1 and 7 after admission. H2S is a potential marker for severity and final outcome of pneumonia induced by the severe respiratory syndrome coronavirus-2 (SARS-CoV-2) coronavirus. Its correlation with IL- 6 suggests anti-inflammatory properties (7). Song et al. evaluated the role of corticosteroid in COVID-19 patients. They found that corticosteroid had no benefits but potential harms in non-severe cases, and they proposed that corticosteroid should be only used in critically ill patients with 2019-nCoV pneumonia (8). Zhou et al. (9) analyzed the clinical course of 195 critically ill COVID-19 patients and they found most critically ill patients were older with high APACHE II scores. 92.8% patients needed ventilation and circulation supports. ARDS, shock, acute kidney injury, and secondary infection were the common complications of critical COVID-19. A high APACHE II score and low PaO2/FiO2 were the independent risk factor for death.
This study provided an important basis for early identification, triaging, and rational allocation of the health care resources to COVID-19 patients (9). Tatum et al. (10) explored the relationship of neutrophil-to-lymphocyte ratio (NLR) with outcomes in 125 COVID-19 patients from Louisiana. The results showed that the majority patients (88.6%) were African American, and patients with sustained and high NLR level had worse results in almost all measured outcomes. NLR is a good prognostic factor for endotracheal intubation upon hospital admission and an independent predictor for risk of mortality in COVID-19 patients on subsequent hospital days. This study suggested that inhibition of the elevated NLR may be a beneficial measure for the treatment of COVID-19 (10). Perioperative hemorrhagic shock remains a major complication during and after surgery. Hamon et al. (11) evaluated the impact factors of the 30-day mortality and long-term survival after intraoperative hemorrhagic shock with 84 cancer surgical patients. They found that the independent factors associated with the short-term prognosis were the severity of initial clinical status at ICU admission, the worsening of organ dysfunctions during the first 3 days of ICU admission, and intra-operative coagulation disturbance. The long-term mortality was also associated with the worsening of early organ dysfunction, coagulation disturbance, especially with the presence of hepatic dysfunction during the immediate postoperative period and the weight of comorbidities. Therefore, early perioperative bundle strategies should be adopted to improve the patient survival in this situation (11). Polymyxin B hemoperfusion (PMX-HP) is an adjuvant therapy for sepsis or septic shock. However, the expected outcome for PMX-HP has seldom been achieved in randomized trials targeting overall sepsis patients. Nakata et al. conducted a prospective nationwide cohort analysis with severe sepsis (Sepsis-2) to identify the optimal population for PMX-HP in septic patients. The results showed that PMX-HP therapy was not associated with a significant difference in all-cause in-hospital mortality among all patients. However, additional analysis using the multiple interactions of three factors, treatment, severity score, and age, showed that PMX-HP therapy may benefit a limited population with high age and higher disease severity. This study definitively figured out a suitable population for PMX-HP therapy in sepsis patients (12).
Optimal biomarkers can greatly enhance the diagnostic and prognostic capability for clinical illness including severe sepsis. Vassalli et al. investigated the behavior of pentraxin-3 (PTX3), troponin T (hsTnT), N-terminal pro-B type Natriuretic Peptide (NT-proBNP) in sepsis and their diagnostic and prognostic prediction value with 958 septic patients in intensive care units. Their results showed that different biomarkers reflected different mechanisms and clinical presentation. PTX3 mainly reflects the severity of sepsis, which is closely associated with the lactate level and mortality. hsTnT mainly reflects the impaired oxygen transport, which is associated with ScvO2 level. NTproBNP reflects both the impaired oxygen transport and the severity of sepsis, and possibly reflects inappropriate fluid administration. The clinical application value of these biomarkers needs further confirmation (13).
Wound bioburden, including biofilm formation, is an important impact factor in wound infection. Cooney et al. (14) observed the efficacy and safety of a novel atmospheric plasma device—indirect non-thermal plasma (INTP) device on wound disinfection in animal wounds. The results showed that the indirect convection technology displayed good bactericidal capabilities toward P aeruginosa biofilm both in vitro and in diabetic murine wound beds. The INTP device may be a promising adjunct treatment measure for infected wounds (14). In recent years, the clinical relevance of mouse models of sepsis has been heavily scrutinized due to the translational failures of many promising preclinical studies. As most frequently used model, cecal ligation and puncture (CLP), also needs improvement to increase its clinical relevance. Carpenter et al. (15) compared the effects of 22°C or 30°C housing temperature on the survival of CLP mice. This study demonstrated that thermoneutral housing (30°C) improved the survival outcome of the CLP mice and reduced the bacterial load by enhancing the phagocytosis. These results reinforced the importance of reporting housing temperature and related factors such as housing density, nesting materials, and relative humidity to improve reproducibility of animal models. Also, the effects of cold stress must be considered when interpreting the results of current mouse studies. Therefore, housing temperature must take as an important referred factor for preclinical studies with animal models and for the treatment of septic patients in intensive care settings. Since the understanding of the novel strain of SARS-CoV-2 is escalating, the speculation of the potential therapies continues to outpace what we know. Because SARS-CoV-2 relies heavily on the angiotensin-converting enzyme (ACE) 2 pathway, many investigators tried to augment this system as a potential treatment option. But clinical outcomes were not satisfactory. Based on the role and modulation mechanism of ACE and ACE2 in COVID-19 development and available results of AngII used in COVID-19 patients, Ferreira and Cearcy et al. made a minute commentary and pointed out that Ang II is harmful for COVID-19 patients, it not suitable for COVID-19 patients. This commentary provided us a theoretic and experimental basis for use or not Ang II in the treatment of COVID-19 (16).
Cytokine storm is one of the main clinical features of COVID-19. No effective measures are available to control bacteria or virus-induced cytokine storm including severe COVID-19. Napp and Bauersachs recommended extracorporeal hemoadsorption for COVID-19-associated cytokine storm. This recommendation is reasonable and valuable. Available clinical data have proven extracorporeal hemoadsorption (Cytosorb) could effectively remove excessive amounts of small hydrophobic molecules from the circulation. It has already been used in COVID-19 patients in China and Europe (17). Based on clinical trial and basic study results, Bertolini and Noera (18) recommended melanocortin peptides (ACTH 1–24 and alpha-MSH) can be used in the treatment of COVID-19 patients. They found ACTH1–24 and alpha—MSH may dose-dependently reverse the hypotension, unveil the respiratory depression, and restore the cardiac output in hemorrhagic shock, respiratory arrest, and cardiac arrest animal models. Clinical trials showed ACTH1–24 obtained the life-saving effect in a phase II and phase III clinical study, one is for 32 type A aortic dissection complicated by aortic rupture and cardiac tamponade and with severe shock, another is for 100 critically ill in shock patients. Based on these results, Bertolini and Noera (18) provided a detailed protocol of ACTH 1–24 in the treatment of COVID-19. However, when and how to use this protocol, especially how to combine the critical severity of COVID-19 need further investigation and confirmation.
1. Aziz M, Brenner M, Wang P. Therapeutic potential of B-1A cells in COVID-19. Shock
2. Fattahi F, Zetoune FS, Ward PA. Complement as a major inducer of harmful events in infectious sepsis. Shock
3. Hortová-Kohoutková M, Tidu F, De Zuani M, Šrámek V, Helán M, Frič J. Phagocytosis–inflammation crosstalk in sepsis: new avenues for therapeutic intervention. Shock
4. Brenner M, Moore L, Dubose J, Scalea J. Resuscitative endovascular balloon occlusion of the aorta (REBOA) for use in temporizing intra-abdominal and pelvic hemorrhage: physiologic sequelae and considerations. Shock
5. Barbarawi M, Alabdouh A, Barbarawi O, Lakshman H, Alkasasbeh M, Rizk F, Bachuwa G, Alkotob ML. Targeted temperature management in cardiac arrest patients with an initial non-shockable rhythm: a systematic review and meta-analysis. Shock
6. De Maio A. Invited opinion do not blame the rodent for the failure of developing sepsis therapies. Shock
7. 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
8. Yuan M, Xu X, Xia D, Tao Z, Yin W, Tan W, Hu Y, Song C. Effects of corticosteroid treatment for non-severe COVID-19 pneumonia: a propensity score-based analysis. Shock
9. Zhou S, Yang Y, Zhang X, Li Z, Liu X, Hu C, Chen C, Wang D, Peng Z. Clinical course of 195 critically ill COVID-19 patients: a retrospective multicenter study. Shock
10. Tatum D, Taghavi S, Houghton A, Stover J, Toraih E, Duchesne J. Neutrophil-to-lymphocyte ratio and outcomes in Louisiana COVID-19 patients. Shock
11. Hamon A, Mokart D, Pouliquen C, de Guibert JM, Cambon S, Duong LN, Lambaudie E, Sannini A, Chow-Chine L, Bisbal M, et al. Intraoperative hemorrhagic shock in cancer surgical patients: short and long-term mortality and associated factors. Shock
12. Nakata H, Yamakawa K, Kabata D, Umemura Y, Ogura H, Gando S, Shintani A, Shiraishi A, Saitoh D, Fujishima S, et al. Identifying septic shock populations benefiting from polymyxin B hemoperfusion: a prospective cohort study incorporating a restricted cubic spline regression model. Shock
13. Vassalli F, Masson S, Meessen J, Pasticci I, Bonifazi M, Vivona L, Caironi P, Busana M, Giosa L, Macri MM, et al. Pentraxin-3, troponin T, N-terminal pro-B-type natriuretic peptide in septic patients. Shock
14. Cooley CR, McLain JM, Dupuy SD, Eder AE, Wintenberg M, Kelly-Wintenberg K, Wintenberg A, Collier JJ, Burke SJ, Karlstad MD. Indirect, non-thermal atmospheric plasma promotes bacterial killing in vitro
and wound disinfection in vivo
using monogenic and polygenic models of type 2 diabetes (without adverse metabolic complications). Shock
15. Carpenter KC, Zhou Y, Hakenjos JM, Fry CD, Nemzek JA. Thermoneutral housing temperature improves survival in a murine model of polymicrobial peritonitis. Shock
16. Ferreira JA, Mcmanus J, Jankowski CA, Searcy R. Why the use of angiotensin II may be a fatal mistake in COVID-19. Shock
17. Napp LC, Bauersachs J. Extracorporeal hemoadsorption: an option for COVID-19-associated cytokine storm syndrome. Shock
18. Bertolini A, Noera G. ACTH 1-24 and other melanocortins for COVID-19 treatment. Shock