Owing to the high quality and clinical relevance of the manuscripts included in the November 2018 issue of SHOCK, writing this commentary was really inspiring, and we therefore wish to thank the editors for giving us this opportunity.
In the first article, Izquierdo-Garcia et al. (1) used nuclear magnetic resonance (NMR) spectroscopy to investigate the metabolomic profile of acute respiratory distress syndrome (ARDS) in patients with H1N1 influenza virus-related pneumonia. In this clinical study, the authors found that the metabolomic profile in the serum can help to identify the presence of ARDS, and they concluded that NMR spectroscopy might represent an interesting method for identifying specific biomarkers in patients with ARDS. In a second clinical study, this time including 227 patients, Vassiliou et al. (2) analyzed the impact of high and low vitamin D levels at the time of hospital admission on the clinical course observed in nonseptic critically ill patients. In general, a high prevalence of low vitamin D levels was found among these patients. In the patients with markedly depressed vitamin D levels, a higher rate of respiratory tract infections was observed. However, the vitamin D levels showed no correlation with mortality, septic complications, or the duration of the intensive care unit (ICU) stay. Therefore, it was postulated that further studies should focus on the potentially beneficial effects of vitamin D substitution in relation to respiratory infection rates and sepsis in critically ill patients.
Cheng et al. (3) focused on the treatment of postoperative vasoplegic shock following cardiac surgery. By comparing the effects of vasopressin or norepinephrine treatment in 1156 patients, they found that vasopressin did not improve the primary and secondary outcome parameters, whereas the application of norepinephrine was associated with a higher cardiac index, lower lactate levels, and less dopamine use. Based on their results, the authors concluded that the application of vasopressin did not improve the postoperative outcomes in patients with preoperative left ventricular dysfunction when compared to norepinephrine. Norepinephrine was therefore recommended to be considered as the first-line vasopressor because of its superior effects on postoperative recovery.
The early C-reactive protein (CRP) levels were measured from the point of hospital discharge for a total of 6 weeks in a study conducted by Grander et al. (4). The CRP levels of patients without either adverse events or rehospitalization constantly decreased over the observation period, whereas steady or increasing CRP concentrations were associated with adverse events and subsequent rehospitalization. Based on their results, the authors suggested the use of CRP levels for postdischarge observation in order to identify those patients at risk of readmission.
Two further clinical trials investigated the relevance of prognostic markers in septic patients. In the retrospective study conducted by Shin et al. (5), which included 946 patients, the prognostic value of the lactate/albumin (L/A) ratio when compared to isolated lactate levels was assessed. The L/A ratio was found to be superior in terms of the prediction of disease progression. Therefore, the authors concluded that the L/A ratio might represent a useful prognostic parameter that also benefits from being independent of both the initial lactate values and potential organ dysfunction. Based on the already proven association between sublingual and intestinal microcirculation, Sekino et al. (6) investigated the relevance of tongue ischemia to the outcome prediction and assessment of intestinal injury in 57 septic patients. The authors found that tongue ischemia was significantly associated with both mortality and enterocyte injury, and they therefore suggested its use as a parameter for the early appraisal of the patient.
Frydland et al. (7) focused on specific endothelial biomarkers in 1414 patients with cardiogenic shock (CS) because of myocardial infarction. They found increased syndecan-1 and soluble thrombomodulin (sTM) serum levels, as well as an association with the temporal onset of cardiac shock. Additionally, the patients with the highest serum concentrations of both biomarkers exhibited significantly increased 30-day mortality. Based on their results, the authors concluded that the biomarkers reflecting endothelial damage represent a promising approach for the identification of patients at risk of developing CS.
The November issue of SHOCK also includes 8 highly interesting experimental studies focusing on lung and brain injury as well as on sepsis. In a murine traumatic brain injury (TBI) model, Martin et al. (8) examined the platelet function in relation to the post-traumatic course. The authors found an initially adenosine diphosphate (ADP)-dependent platelet dysfunction in their TBI model. Furthermore, they observed a rebound phenomenon involving hypercoagulability and hyperaggregation some 6 h after the TBI. It was concluded that the appropriate timing of anticoagulation is a very crucial issue in trauma care if patients are to be prevented from developing venous thromboembolism and thus secondary complications.
In a further experimental study, Ayalon et al. (9) induced cecal ligation puncture procedure (CLP) in obese and nonobese mice. In this model, they investigated neutrophil infiltration and the mitochondrial density of adipose tissue, as well as the potential browning of white adipose tissue (WAT) before and after the induction of CLP. After CLP, the nonobese animals demonstrated a more distinct breakdown of lipid droplets as well as an increase in the mitochondrial density of the WAT when compared to the obese animals. Furthermore, neutrophil infiltration was almost exclusively found in the nonobese septic mice. The authors concluded that sepsis is associated with signs of WAT browning, which is considered to be an appropriate response to sepsis in nonobese mice. An impairment of browning in obese animals might therefore represent one potential reason for the higher mortality rate seen in obese septic mice. Also focusing on sepsis, Silswal et al. (10) investigated the effects of the nonspecific proteasome inhibitor resveratrol on proteasome activity, as well as on different inflammatory markers, in human blood monocytes following lipopolysaccharide (LPS) incubation. Resveratrol significantly inhibited the expression of LPS-induced biomarkers with less cell toxicity when compared to other more specific proteasome inhibitors (e.g., ONX-0914). It was hence concluded that resveratrol might modulate the inflammatory response after sepsis.
Weaver et al. (11) focused on the relevance of direct peritoneal resuscitation (DPR) in terms of decreasing pulmonary injury and inflammation following lung transplants. Therefore, the cytokines, as well as neutrophil and macrophage recruitment, were assessed in a brain death model in rats. DPR resulted in a significant reduction in the level of cytokines (e.g., tumor necrosis factor, interleukin-6) and adhesion molecules (e.g., intercellular adhesion molecule-1, P-selectin), as well as in a trend toward the decreased pulmonary infiltration of neutrophils and macrophages. The authors concluded that DPR in brain-dead organ donors seems to represent a promising procedure for reducing lung injury and inflammation following lung transplants.
Extrinsic positive end-expiratory pressure (PEEP) is used to prevent alveolar collapse and improve oxygenation. However, its benefits and potential harmful effects remain subject to controversial discussion. Therefore, Andrade et al. (12) mechanically ventilated healthy rats with an extrinsic PEEP of 5 cm H20 and then analyzed the inflammatory changes. The application of PEEP resulted in increased neutrophil recruitment, higher chemokine levels, and a redox imbalance. These changes might represent relevant factors in the pathogeneses of ventilator-induced injuries.
Two other studies focused on the pathogeneses of acute lung injury (ALI) and acute respiratory distress syndrome. In an angiotensin II-induced lung injury mice model, Tao et al. (13) investigated whether soluble epoxide hydrolase (sEH) is involved in angiotensin II-triggered pulmonary inflammation and edema. The angiotensin II treatment resulted in increased sEH activity, a pronounced inflammatory response, and worsened lung damage. sEH gene deficiency and the abolition of sEH induction via the application of losartan significantly mitigated these changes. The authors concluded that angiotensin II-induced inflammation in the lung is partly mediated via sEH. Cao et al. (14) aimed to investigate whether ulinastatin (UTI) alleviates LPS-induced ALI by decreasing toll like receptor (TLR)4 expression. They also aimed to identify the underlying mechanisms. The authors found that UTI significantly protected animals from LPS-induced ALI, reduced the TLR4 levels and NF-kB activation, and attenuated the inflammatory response in lung tissues. Based on these findings, it was postulated that UTI has the potential to ameliorate ALI by reducing the activation of the TLR4/NF-κB pathway.
The final article in this month's issue addresses the nucleotide-binding oligomerization domain (NOD)2/receptor interacting serine/threonine kinase pathway in a thermal injury model in rats. Wu et al. (15) were able to show that muramyl dipeptide (MDP) induces both pro-inflammatory cytokine release via the NOD2/receptor interacting serine/threonine kinase pathway and thermal autophagy. The authors concluded that further studies are required that focus on the effects of the NOD2-downstream signaling pathway, the expression of autophagy-related genes, the degradation of autophagic lysosome, and the relationship between autophagy and inflammation.
Finally, we would again like to thank the editors of SHOCK for giving us the opportunity to write this commentary.
1. Izquierdo-Garcia JL, Nin N, Jimenez-Clemente J, Horcajada JP, Arenas-Miras MDM, Geo J, Esteban A, Ruiz-Cabello J, Lorente JA. Metabolomic profile of ARDS by nuclear magnetic resonance spectroscopy in patients with H1N1 influenza virus pneumonia. Shock
2. Vassiliou AG, Jahaj E, Mastora Z, Stagaki E, Orfanos SE, Kotanidou A. Serum admission 25-hydroxyvitamin D levels and outcomes in initially non-septic critically-ill patients. Shock
3. Cheng Y, Pan T, Ge M, Chen T, Ye J, Lu L, Chen C, Zong Q, Ding Y, Wang D. Evaluation of vasopressin for vasoplegic shock in patients with preoperative left ventricular dysfunction after cardiac surgery: a propensity-score analysis. Shock
4. Grander W, Koller B, Ludwig C, Dünser MW, Gradwohl-Matis I. High CRP levels after critical illness are associated with an increased risk of rehospitalization. Shock
5. Shin J, Hwang SY, Jo IJ, Kim WY, Ryoo SM, Kang GH, Kim K, Jo YH, Chung SP, Joo YS, et al. for the Korean Shock Society (KoSS) Investigators. Prognostic value of the lactate/albumin ratio for predicting 28-day mortality in critically ill sepsis patients. Shock
6. Sekino M, Funaoka H, Sato S, Okada K, Inoue H, Yano R, Matsumoto S, Ichinomiya T, Higashijima U, Matsumoto S, et al. Association between macroscopic tongue ischemia and enterocyte injury and poor outcome in patients with septic shock: a preliminary observational study. Shock
7. Frydland M, Ostrowski SR, Møller JE, Hadziselimovic E, Holmvang L, Ravn HB, Jensen LO, Pettersson AS, Kjaergaard J, Lindholm MG, et al. Plasma concentration of biomarkers reflecting endothelial cell- and glycocalyx damage are increased in patients with suspected ST-elevation myocardial infarction complicated by cardiogenic shock. Shock
8. Martin GE, Xia B, Kim Y, Johnson MD, Veile R, Friend LA, Makley AT, Caldwell CC, Goodman MD. Platelet function changes in a time-dependent manner following traumatic brain injury in a murine model. Shock
9. Ayalon T, Shen H, Williamson L, Stringer K, Zingarelli B, Kaplan JM. Sepsis induces adipose tissue browning in nonobese mice but not in obese mice. Shock
10. Silswal N, Reddy NS, Qureshi AA, Qureshi N. Resveratrol downregulates biomarkers of sepsis via
inhibition of proteasome's proteases. Shock
11. Weaver JL, Matheson PJ, Matheson A, Downard CD, Garrison RN, Smith JW. Direct peritoneal resuscitation alters leukocyte infiltration in the lung after acute brain death. Shock
12. Andrade MC, de Souza ABF, Horta JG, de Paula Costa G, Talvani A, Cangussú SD, de Menezes RCA, Bezerra FS. Applying positive end-expiratory pressure during mechanical ventilation causes pulmonary redox imbalance and inflammation in rats. Shock
13. Tao W, Li P-S, Xu G, Luo Y, Shu Y-S, Tao Y-Z, Yang L-Q. Soluble epoxide hydrolase plays a vital role in angiotensin II-induced lung injury in mice. Shock
14. Cao C, Yin C, Shou S, Wang J, Yu L, Li X, Chai Y. Ulinastatin protects against LPS-induced acute lung injury by attenuating TLR4/NF-κB pathway activation and reducing inflammatory mediators. Shock
15. Wu X-J, Liang H, Zhang Y, Yang X-M, Wang H-Y, Li H, Li X-Y, Chen K, Wang Y-L, Li J-G, et al. Muramyl dipeptide enhances thermal injury-induced autophagy and inflammatory cytokine response of lungs via activation of NOD2/RICK signaling pathway in rats. Shock