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What’s New in Shock, August 2014?

Chen, Peter*†; Jeschke, Marc G.*†‡§

doi: 10.1097/SHK.0000000000000206

*Sunnybrook Research Institute; Department of Immunology and Division of Plastic Surgery Department of Surgery, University of Toronto; and §Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

The summer finale of Shock is always exciting, and this August 2014 sepsis-centric edition is certainly no exception, as it features a collection of articles describing various novel approaches in predicting clinical sepsis. In addition, a number of interesting reports pertaining to other clinical diagnostics, intervention procedures, and cardiac surgical maneuver are also incorporated in this issue. Avolio et al. (1) discuss the shortcomings of using blood cultures (BCs) as the conventional diagnosis of sepsis, specifically attributing to its inability to accurately reflect patient status in the clinic because of a lengthy turnaround time in BC assays. Furthermore, they also reiterate that although ample biomarkers have been acknowledged as positive signs for sepsis, they are also widely nonspecific. Avolio et al. offer an alternative to this problem by directly detecting the DNA of the infecting microbe in patient blood through LightCycler SeptiFast, a multipathogen probe-based real-time polymerase chain reaction (PCR) quantification method. The PCR results correlate with the BC outcomes and demonstrate that this PCR method has a specificity and predictive value of 96% and 94%, respectively. This new diagnostic method is an exciting approach for the future of clinical sepsis prediction enabling early, rapid, and accurate diagnosis, which hopefully can change the outcomes of infections and sepsis.

The article by Nadler et al. (2) describes the limited sensitivity of the current triage and monitoring tools to detect life-threatening scenarios, particularly blood loss, in the clinic. To circumvent this problem, Nadler et al. implement the noninvasive Compensatory Reserve Index (CRI) as a novel method to assess the dangers associated with blood loss. Comparisons between area under the curve of CRI to changes in other vital signs (e.g., heart rate, diastolic blood pressure, oxygen saturation) showcase the 2 advantages CRI has to offer: first, it is noninvasive; second, it possesses a far superior sensitivity in contrast to the assessment of vital signs in detecting even minor blood loss. Thus, the use of CRI in combination with the conventional vital sign evaluation may be beneficial in improving the detection of life-threatening scenarios in the clinic.

Ginde et al. (3) bring sepsis back into this Shock issue’s spotlight by showing age-related differences in serum inflammatory biomarkers during the first 72 h of hospitalization due to sepsis. In this study, six biomarkers (chemokine (C-C motif) ligand 23 [CCL-23], C-reactive protein, interleukin 1 receptor antagonist [IL-1ra], neutrophil gelatinase–associated lipocalin, peptidoglycan recognition protein, and tumor necrosis factor receptor 1a [TNFR-1a]) are measured in the serum of a cohort of patients with confirmed infection. It was concluded from the results that older age is associated with higher sepsis severity, and that senescence is associated with greater inflammation at baseline, but this inflammatory state resolved within 72 h. Perhaps the initial inflammatory elevation reported in the older population predisposes them to a disadvantage in combating microbial infections. Further investigation is required, as the six candidate soluble factors surveyed in this study contribute only to a part of this story.

The focus shuffles from the bench back to the clinic, as Liu et al. (4) present their findings on the integration of vital signs and heart rate variability and complexity with computer decision support systems to achieve a more accurate assessment for identifying the need for lifesaving interventions during life-or-death scenarios. In terms of providing a holistic assessment of the patients’ status, it appears the traditional correlation of vital signs and heart rate variability and complexity by using a multivariate logistic regression is far inferior when compared to data that are integrated by a machine learning algorithm. Thus, the improved patient assessment through machine learning–based triage will assist physicians to promptly implement lifesaving interventions to those in need.

This subsequent study by Gores et al. (5) explores the pathophysiology induced by high-dose IL-2 (HDIL-2) therapy, which is characterized by systemic inflammation and pulmonary edema. Interestingly, these observations are highly reminiscent to the symptoms reported in patients who have sepsis, specifically referring to the systemic inflammation and sepsis-induced lung injury. Because IL-2 stimulates the production of angiopoietin 2, Gores et al. postulate that patients enrolled in HDIL-2 therapy will exhibit symptoms similar to septic patients, and this pathology is attributed to the induced production of angiopoietin 2 by the HDIL-2 administered. Indeed, a progressive increase in plasma angiopoietin 2 is detected during the course of the HDIL-2 treatment. In contrast, a decrease in forced expiratory volume in 1 s is documented in these same patients who received HDIL-2 therapy. According to the authors, albeit premature, a plausible model for this inverse correlative observation is that the HDIL-2 therapy induces the secretion of angiopoietin 2, and in turn this molecule results in lung damage, consequently leading to a decreased forced expiratory volume in 1 s. Stay tuned for the sequel of this work, as Gores et al. have already alluded to the prospective plans in dissecting the mechanism of this pathophysiologic phenomenon.

Whether a coronary artery bypass graft surgery (on-pump CABG) generates a postoperative systemic inflammatory response and ultimately leading to severe organ failure has been a matter of fervent debate between surgeons. However, there has been emerging evidence suggesting that endothelium activation, in response to inflammatory responses, plays a crucial role in the pathophysiology of organ dysfunction after CABG. Thus, to avoid inflammation, the off-pump CABG was reintroduced into the clinic in the 1990s. Jongman et al. (6) have dedicated this work to investigate if the off-pump approach indeed dampens the inflammatory phenotype and prevents endothelium activation. Interestingly, lower levels of numerous cytokines (TNF-α, IL-10, and myeloperoxidase) are observed in the plasma of patients who received the off-pump surgery relative to the on-pump approach. However, there appear to be no differences in the expression of soluble adhesion molecules. Collectively, these data suggest that off-pump CABG indeed reduces inflammation, but appears to have no differential influence on the activation state of the endothelium in comparison to the conventional on-pump approach.

In Short Communications, Biller et al. (7) describe that the use of serum C-reactive protein and procalcitonin concentration as a predictor for survival in infected patients has been a disappointment, largely because of the false-positive or negative values these assays generate. Realizing the conundrum, Biller et al. propose cholesterol as the next promising candidate that should be incorporated into the list of biomarkers used to predict survival outcomes of hospitalized patient. As lipoproteins, in this case cholesterol, bind to the bioactive lipid A portion of lipopolysaccharide (LPS), it reduces the bioavailability of LPS for pattern recognition receptor expressed by macrophages and other innate leukocytes, thus preventing the activation of inflammation. Biller et al. predict that a decrease in proinflammatory signals as a result of cholesterol-induced inhibition may provide a survival advantage to infected patients, because most of these patients succumb to cytokine storms due to enormous surges of inflammation. Indeed, Biller et al. demonstrate that the cohort of patients who did not survive the infection had a lower cholesterol level of 69 mg/dL, whereas the survivors had 96 mg/dL. This remarkable finding has once again shed light onto the field of biomarkers for predicting survival in infected patients and should be further studied and explored.

Leading off a series of upcoming basic science articles, Rani et al. (8) suggest that γδ T cells promote a wound-healing state at the site of thermal injury by regulating the trafficking of proinflammatory leukocytes. In their article, they showed that γTCR−/− mice (γδ T cells–deficient) have a significant increase in myeloid cells at the site of injury relative to its wild-type counterpart, and several proinflammatory cytokines (TNF-α, macrophage inflammatory protein 1α, macrophage inflammatory protein 1β) are also detected at higher levels in the thermally injured skin of the knockout animals in comparison to the controls. Rani et al. concluded that γδ T cells appear to have a function of promoting a wound healing state at the site of injury by attenuating inflammation, thus making it a very appealing candidate for future investigations in the field of regenerative medicine.

Sumi et al. (9) show that ATP is a danger signal that activates neutrophils in mouse models of sepsis. By implementing the cecal ligation and puncture (CLP) technique in mice, these animals gradually accumulate gut-derived bacteria in their peritoneal cavity and eventually develop sepsis. The innate immune system of these rodents, particularly the neutrophil, is activated during the course of the disease modeling by “danger signals” that are released into the plasma by the invading microbes and the infected cells. Sumi et al. show that ATP is elevated in mice that received CLP and is a danger signal that potently activates polymorphonuclear neutrophils through the purinergic signaling pathway. Importantly, polymorphonuclear neutrophil activation is dampened by suramin, an ATP receptor antagonist that blocks the interaction between ATP and the ATP receptor. This work by Sumi et al. provides yet another promising candidate that can be selected to modulate the immune response of septic patients during the acute phases of their pathology.

Elaborating on the theme of septic studies by using animal models, Rodríguez-González et al. (10) perform CLP in rats and foster these animals in chambers supplied with differential oxygen concentration to test if hyperoxia worsens the outcomes of these induced-septic animals. Indeed, Rodríguez-González et al. report that CLP animals receiving high oxygen dosage have elevated plasma levels of IL-6, IL-10, TNF-α, and reactive oxygen species relative to hypoxic-fostered rats. This fascinating study suggests that oxygen therapy should be administered with caution for septic patients in the clinic, as it can potentially inflict undesirable effects.

Adding something “sweet” to the field, Kassim et al. (11) propose caffeic acid phenethyl ester (CAPE), an active component of honeybee product, may mitigate the physiological consequences of excessive free radicals produced during sepsis. Peroxynitrite is a free radical generated by macrophages in septic hosts, and this molecule is a potent inducer of cell death and promotes an inflammatory microenvironment. Because the pharmacological function of CAPE is to scavenge peroxynitrite, Kassim et al. hypothesized that by removing peroxynitrite via the use of CAPE during an infectious scenario, it will ameliorate cell death and inflammation, thus improving the outcomes of septic patients. In vitro data where RAW264.7 cells treated with LPS/interferon γ and CAPE showed elevated cell viability and lowered nitric oxide levels relative to its counterpart that did not receive the scavenger molecule. Furthermore, in vivo results demonstrate sepsis-induced mice treated with CAPE have better survival outcomes compared with the control cohort. We believe CAPE is indeed a promising therapeutic approach in treating a variety of inflammatory disease caused by reactive oxygen species, as supported by the elegant combination of in vitro and in vivo evidence presented by Kassim et al.

Liang et al. (12) report that muramyl dipeptide exacerbates the pathophysiology of thermal injury through the use of animal modeling. Muramyl dipeptide is a peptidoglycan, which is a key constituent of both gram-positive and gram-negative bacteria that is recognized by the NOD-like receptors. Upon recognition by NOD-like receptors, the inflammasome is activated, and a myriad of proinflammatory response ensues. By infusing purified muramyl dipeptide into thermally injured rats, these animals show heightened inflammation and poorer survival outcomes. This observation is in line with the clinical observation that opportunistic infection after thermal injury can be detrimental to the patient.

To conclude the sepsis-themed marathon, Ariga et al. (13) show mice primed with LPS before induction of sepsis by CLP display an advantageous outlook in survival compared with the control groups. Also known as “endotoxin tolerance,” mice receiving continuous subcutaneous LPS challenge (5 days) followed by CLP express higher levels of adhesion molecules in the peritoneum compared with the control group. Furthermore, a significantly lower level of pulmonary adhesion molecule expression is detected in the endotoxin tolerant cohort relative to the nontolerant group. These data explain why endotoxin-tolerant mice lack neutrophil recruitment into lung and in turn traffic to the peritoneum, where the bacteria are accumulating after CLP. Albeit an interesting study, further investigation is required to conclude that the survival advantage is indeed attributed to the redirection of neutrophils and not due to the prepriming of the immune system of these animals by the repeated dosing of LPS, thus leading to a more efficient eradication of the microbe.

The August 2014 issue of Shock concludes with the editorial comment by Roesner and Thiemermann (14), deliberating whether the off-pump CABG approach is indeed a more practical and safer surgical approach when compared with the on-pump CABG, echoing the same issue raised by Jongman et al. (6). The authors summarized the findings presented by Jongman and colleagues and presented a rather comprehensive list of “missing links,” which if present may help provide a clearer perception of the pros and cons between the on- and off-pump maneuver. Items on this list include an unknown source of the inflammatory stimuli, the inability to survey tissue samples in patients, and the source of endothelial biomarkers (e.g., heart, lungs, etc.) cannot be tracked. Lastly, Roesner et al. suggest to incorporate more subjects into the study described by Jongman and colleagues’ work (6), as the magnitude of their report, albeit interesting, is still far from conclusive and still possesses huge potential for future in-depth studies.

With the numerous exciting articles featured in this issue of Shock, it will undoubtedly stimulate novel ideas leading to great experiments and scientific progression.

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1. Avolio M, Diamante P, Modolo ML, De Rosa R, Stano P, Camporese A: Direct molecular detection of pathogens in blood as specific rule-in diagnostic biomarker in patients with presumed sepsis—our experience on a heterogeneous cohort of patients with signs of infective SIRS. Shock 42: 86–92, 2014.
2. Nadler R, Convertino VA, Gendler S, Lending G, Lipsky AM, Cardin S, Lowenthal A, Glassberg E: The value of noninvasive measurement of the compensatory reserve index in monitoring and triage of patients experiencing minimal blood loss. Shock 42: 93–98, 2014.
3. Ginde AA, Blatchford PJ, Trzeciak S, Hollander JE, Birkhahn R, Otero R, Osborn TM, Moretti E, Nguyen HB, Gunnerson KJ, et al.: Age-related differences in biomarkers of acute inflammation during hospitalization for sepsis. Shock 42: 99–107, 2014.
4. Liu NT, Holcomb JB, Wade CE, Darrah MI, Salinas J: Utility of vital signs, heart-rate variability and complexity, and machine learning for identifying the need for life-saving interventions in trauma patients. Shock 42: 108–114, 2014.
5. Gores KM, Delsing AS, Kraus SJ, Powers L, Vaena DA, Milhem MM, Monick M, Doerschug KC: Plasma angiopoietin-2 concentrations are related to impaired lung function, and organ failure in a clinical cohort receiving high dose interleukin-2 therapy. Shock 42: 115–120, 2014.
6. Jongman RM, Zijlstra JG, Kok WF, van Harten AE, Mariani MA, Moser J, Struys MMRF, Absalom AR, Molema G, Scheeren TWL, et al.: Off pump CABG surgery reduces systemic inflammation compared with on pump surgery but does not change systemic endothelial response: a prospective randomized study. Shock 42: 121–128, 2014.
7. Biller K, Fae P, Germann R, Drexel H, Walli AK, Fraunberger P: Cholesterol rather than PCT or CRP predicts mortality in patients with infection. Shock 42: 129–132, 2014.
8. Rani M, Zhang Q, Schwacha MG: Gamma delta T cells regulate wound myeloid cell activity after burn. Shock 42: 133–141, 2014.
9. Sumi Y, Woehrle T, Chen Y, Bao Y, Li X, Yao Y, Inoue Y, Tanaka H, Junger WG: Plasma ATP is required for neutrophil activation in a mouse sepsis model. Shock 42: 142–147, 2014.
10. Rodriguez-Gonzalez R, Martin-Barrasa J, Ramos-Nuez A, Canas-Pedrosa AM, Martinez-Saavedra MT, Garcia-Bello MA, Lopez-Aguilar J, Baluja A, Alvarez J, Slutsky AS, et al.: Multiple system organ response induced by hyperoxia in a clinically relevant animal model of sepsis. Shock 42: 148–153, 2014.
11. Kassim M, Mansor M, Kamalden TA, Shariffuddin II, Hasan MS, Ong G, Sekaran SD, Suhaimi A, Al-Abd N, Yusoff KM: Caffeic acid phenethyl ester (CAPE): scavenger of peroxynitrite in vitro and in sepsis models. Shock 42: 154–160, 2014.
12. Liang H, Song X-M, Wu X-J, Li J-G, Han Y, Wang Y-L, Li H, Zhang Z-Z, Le L-L, Xu Y: Muramyl dipeptide enhances thermal injury-induced inflammatory cytokine production and organ function injury in rats. Shock 42: 161–167, 2014.
13. Ariga SK, Abatepaulo FB, Sant anna Melo E, Velasco IT, da Silva FP, de Lima TM, Soriano FG: Endotoxin tolerance drives neutrophil to infectious site. Shock 42: 168–173, 2014.
14. Roesner JP, Thiemermann C: Mirror, mirror on the wall, is off-pump better than on-pump at all? Shock 42: 174–175, 2014.
© 2014 by the Shock Society