This issue of SHOCK compiles another great collection of outstanding research in the areas of infection, sepsis including septic shock and hemorrhage. As usual, the content is well balanced between basic and clinical science and augmented by several state-of-the-art review articles by well-known experts in the field.
Coopersmith and Deutschman (1) summarize the new definitions of sepsis and septic shock after their revision by the Sepsis-3 Task Force and publication earlier in 2016 in a series of papers to JAMA. These papers actually represent the first real revision of the original definitions developed and presented back in 1991. Both the authors were members of the Sepsis-3 Task Force and detail the content of the papers including their opinions on how these changes will impact future sepsis research. The next review by Corrêa et al. (2) represents an excellent summary of vasodilator use together with other interventions to overcome microcirculatory abnormalities in septic shock resuscitation. Microcirculatory blood flow is known to be substantially impaired in septic patients with a clear association between persistent abnormalities, morbidity, and poor outcomes. Therefore, this narrative review may be of particular interest for our clinical readership. The next review (3) is of similar interest for the clinical community as it highlights the link between sepsis and chronic diseases such as diabetes mellitus (DM). A recent study has evaluated over 1,000 patients with sepsis and reported that over 20% had a medical history of DM. The magnitude of this clinical problem is likely to increase in the future as the number of this patient group rises progressively. In their review, Trevelin et al. (3) pick up this challenging association and provide an update on the characteristics of the immune system in diabetic and septic patients. They also expand on the beneficial effects of insulin on the immune response in a glycemic-dependent and independent manner. The last review is extended by a meta-analysis on the association of serum magnesium levels with prognosis of critically sick patients upon intensive care unit (ICU) admission (4). Hypomagnesemia is one of the most common electrolyte disturbances in hospitalized patients but seems to be rather neglected and therefore underdiagnosed. The results by Jiang et al. (4) essentially confirm the strong association between hypomagnesemia and both morbidity and mortality and call for increased vigilance and more research on magnesium therapy for improving outcomes in critically ill patients.
In the first set of clinical articles the tight link between sepsis and coagulation is highlighted. The work by Oh et al. (5) evaluated mean platelet volumes and platelet counts to determine their significance as prognostic markers for early mortality in critically ill patients with suspected sepsis receiving early-goal-directed therapy. As with other markers, both parameters alone did not predict shock and mortality but their ratio at Emergency Department admission and on day 1 was identified as a promising marker for 28-day mortality in patients with severe sepsis. The group by Delabranche et al. (6) picked up on recent evidence indicating Neutrophils Extracellular Traps (NETs) to play an important role in linking inflammation, immunity, and thrombosis as well as shock-induced disseminated intravascular coagulation (DIC). Twenty patients with septic shock were prospectively assessed for NETosis by using two approaches, neutrophil-side fluorescence and DNA-bound myeloperoxidase. All measurements including nucleosome concentrations correlated to DIC indicating that NETosis plays an important role in septic shock-induced DIC. The next set of clinical studies present two new biomarkers for risk assessment and prediction in patients with acute cholangitis and acute respiratory distress syndrome. Kim et al. (7) retrospectively assessed the value of the Delta Neutrophil Index (DNI) in patients with acute cholangitis. The DNI reflects the fraction of circulating immature granulocytes and can be assessed via specific automated blood cell analyzers. Xu et al. (8) sought to determine whether plasma galectin-3 levels were associated with disease severity in acute respiratory distress syndrome patients. Increased levels of both biomarkers correlated with disease severity, hemodynamic instability, and outcome. As with other biomarkers, their clinical value needs to be demonstrated in future studies. The remaining two clinical studies published in this issue of SHOCK originate from France. Guillaume et al. (9) report the results from their retrospective single-center study on risk factors for acute mesenteric ischemia (AMI) among patients requiring ICU admission after cardiac surgery. Over 7 years, almost 5,000 patients were screened with 320 requiring ICU admission for multi-organ failure. Among those, 10% were diagnosed with AMI and extremely poor prognosis. In four of five patients, the principle mechanism underlying AMI was nonocclusive mesenteric ischemia. The authors present a four-component AMI score for risk stratification including coronary artery bypass graft, need for blood transfusion, aspartate aminotransferase >100 UI/L, and the Simplified Acute Physiology Score II >50 at ICU admission. In the last clinical paper, Monneret et al. (10) present a novel diagnostic approach using intracellular staining for the assessment of tumor necrosis factor produced in vitro by monocytes after LPS stimulation. The preliminary results indicate the feasibility of immune functional testing on a routine basis in patients with septic shock but certainly deserve further evaluation and validation in different ICU settings.
When moving on to the experimental work published in this issue of SHOCK, two studies focus on the protective role of simvastatin in different settings. Yu et al. (11) have used the classical LPS model in mice to demonstrate the protective effects of simvastatin on acute lung injury by stabilizing cytoskeletons as reflected by circulating cytoskeletal regulating proteins CDC42 and PAK4, endothelial microparticles as well as intracellular adherent junction proteins. These results essentially confirm previous work emphasizing the vascular-protective effects of simvastatin in the lung via augmentation of endothelial barrier function. In the second study, Meireles et al. (12) report on the protective effects of simvastatin in liver cirrhotic animals exposed to hemorrhagic shock and resuscitation. Simvastatin, a drug known for its positive effects on liver microcirculation, was able to prevent shock/resuscitation induced liver endothelial dysfunction thereby attenuating liver injury and inflammation and it may be speculated if this drug has the potential to protect the cirrhotic liver during bleeding complications. A similar model of experimental liver injury was used by Liu et al. (13) to assess the mechanism of corilagin and the possible involvement of the Akt-dependent pathway. Corigalin is a component of the Phyllanthus urinaria extract, which originates from traditional herbal medicine, and has been associated with a number of beneficial effects including hepatoprotection. A set of selected liver parameters including hepatic phospho-Akt expression was studied and most of them were attenuated or increased in corilagin-treated animals following hemorrhagic shock suggesting a protective role and, at least in part, action via the Akt-dependent pathway. The next experimental work by Enderes et al. (14) investigated the effect of FTY720-induced lymphopenia on infectious complications and mortality in a murine sepsis model. This experimental work has clinical relevance as FTY720 is frequently used as an immunosuppressant in chronic relapsing multiple sclerosis (MS). The absence of increased mortality in this study provides experimental evidence that MS patients on this drug and if operated are not likely to have in increased risk for severe forms of postoperative infectious complications. Yao et al. (15) provide some novel insights into the role and regulation of natural killer T (NKT) cells during experimental CPL-sepsis. In their work, the administration of α-lactose blocked the Tim-3 signaling pathway thereby significantly improving survival. Together with a reduced secretion of IL-12 by dendritic cells, reduced Tim-3 expression prevented NKT cell apoptosis and attenuated the “cytokine storm” which was interpreted as a novel and promising immunomodulatory avenue for innovative sepsis treatment. The mechanism of remote ischemic preconditioning (RIPC), which has been identified as one of the most powerful intrinsic cardioprotective strategies, has been challenged in the next work by Ma et al. (16). The question here was to what extent comorbidity may interfere with the protection by RIPC. Hypercholesterolemic rat hearts with and without RIPC were exposed to ischemia and reperfusion and several pathways were assessed. RIPC triggered unique cardioprotective signaling including MG53, phosphorylation of Akt, and glycogen synthetase kinase-3ß (GSK3ß) together with reduced proapoptotic active caspase-3 but failed to reduce myocardial necrosis and apoptosis as well as to increase the phosphorylated Akt and GSK3ß in the hypercholesterolemic myocardium. More importantly, inhibition of GSK reduced myocardial infarct size in both healthy and comorbid hearts but this effect was not augmented when combined with RIPC. Acute GSK3ß inhibition may therefore provide a novel therapeutic strategy for patients with the given comorbidity during acute mayocardial infarction whereas RIPC may be less effective due to signaling adversely affecting GKS3ß. The last experimental contribution to this issue of SHOCK expands on the systemic administration of potassium cyanide and its effect on circulatory failure (17). Intentionally, Haouzi et al. (17) have used a noninhaled modality of intoxication to exclude the breathing pattern to influence the diffusion of CN into the blood and showed that circulatory failure may develop as a direct consequence of CN-induced apnea but in a narrow range of exposure. In this “low range,” maintaining pulmonary gas exchange through ventilation was demonstrated to reverse cardiac depression and restore spontaneous breathing but at higher levels of intoxication, cardiac depression was considered and treated as a specific and irreversible consequence of CN exposure ultimately leading to pulseless electrical activity and death.
It has been a great honor and pleasure to highlight and comment once more on the valuable contributions to this issue of SHOCK. This is another great collection of outstanding contributions which each single paper worthwhile paying attention to and reading.
1. Coopersmith CM, Deutschman CS. The new sepsis definitions: implications for the basic and translational research communities. Shock
2. Corrêa TD, Filho RR, Assunção MSC, Silva E, Lima A. Vasodilators in septic shock resuscitation: a clinical perspective. Shock
3. Trevelin SC, Carlos D, Beretta M, da Silva JS, Cunha FQ. Diabetes mellitus and sepsis: a challenging association. Shock
4. Jiang P, Lv Q, Lai T, Xu F. Does hypomagnesemia impact on the outcome of patients admitted to the intensive care unit? A systematic review and meta-analysis. Shock
5. Oh GH, Chung SP, Park YS, Hong JH, Lee HS, Chung HS, You JS, Park JW, Park I. Mean platelet volume to platelet count ratio as a promising predictor of early mortality in severe sepsis. Shock
6. Delabranche X, Stiel L, Severac F, Galoisy A-C, Mauvieux L, Zobairi F, Lavigne T, Toti F, Anglès-Cano E, Meziani F, et al. Evidence of NETosis in septic shock-induced disseminated intravascular coagulation. Shock
7. Kim H, Kong T, Chung SP, Hong JH, Lee JW, Joo Y, Ko DR, You JS, Park I. Usefulness of the delta neutrophil index as a promising prognostic marker of acute cholangitis in emergency departments. Shock
8. Xu Z, Li X, Huang Y, Mao P, Wu S, Yang B, Yang Y, Chen K, Liu X, Li Y. The predictive value of plasma galectin-3 for ARDS severity and clinical outcome. Shock
9. Guillaume A, Pili-Floury S, Chocron S, Delabrousse E, De Parseval B, Koch S, Samain E, Capellier G, Piton G. Acute mesenteric ischemia among postcardiac surgery patients presenting with multiple organ failure. Shock
10. Monneret G, Demaret J, Gossez M, Reverdiau E, Malergue F, Rimmelé T, Venet F. Novel approach in monocyte intracellular TNF measurement: application to sepsis-induced immune alterations. Shock
11. Yu Y, Jing L, Zhang X, Gao C. Simvastatin attenuates acute lung injury via regulating CDC42-PAK4 and endothelial microparticles. Shock
12. Meireles CZ, Pasarin M, Lozano JJ, García-Calderó H, Gracia-Sancho J, García-Pagán JC, Bosch J, Abraldes JG. Simvastatin attenuates liver injury in rodents with biliary cirrhosis submitted to hemorrhage/resuscitation. Shock
13. Liu F-C, Chaudry IH, Yu H-P. Hepatoprotective effects of corilagin following hemorrhagic shock are through AKT-dependent pathway. Shock
14. Enderes J, van der Linde J, Müller J, Tran B-T, von Bernstorff W, Heidecke C-D, Schulze T. FTY720-induced lymphopenia does not aggravate mortality in a murine model of polymicrobial abdominal sepsis. Shock
15. Yao Y, Deng H, Li P, Zhang J, Zhang J, Wang D, Li S, Luo Y, Wei Z, Bi G, et al. α-lactose improves the survival of septic mice by blockade of TIM-3 signaling to prevent NKT cell apoptosis and attenuate cytokine storm. Shock
16. Ma L-L, Kong F-J, Guo J-J, Zhu J-B, Shi H-T, Li Y, Sun R-H, Ge J-B. Hypercholesterolemia abrogates remote ischemic preconditioning-induced cardioprotection: role of reperfusion injury salvage kinase signals. Shock
17. Haouzi P, Tubbs N, Rannals MD, Judenherc-Haouzi A, Cabell LA, McDonough JA, Sonobe T. Circulatory failure during noninhaled forms of cyanide intoxication. Shock