The October 2019 issue of SHOCK showcases a wide range of clinical and basic research studies from around the globe. The clinical studies are focused on sepsis and septic shock, the factors and patient characteristics associated with both short and long-term outcome after sepsis and septic shock, and potential new biomarkers for predicting sepsis-induced end organ damage. The basic science aspects of this month's issue of SHOCK represent a diverse collection of studies providing new insight into potential mechanisms underlying vascular endothelial cell damage and intestinal epithelial cell injury after hemorrhage, large animal modeling of ventilation and oxygenation-induced pathophysiology, new tools for assessing and improving cardiac function after hemorrhage, cardiac arrest, and endotoxemia, as well as a large animal trial of antithrombin III as a potential therapeutic in endotoxin-induced disseminated intravascular coagulation. Perhaps equally as impressive as the quality of the studies is that they come from laboratories and research groups spanning multiple continents, highlighting the global reach of our research community, and our interconnected mission to better understand the biology of trauma, shock, and sepsis.
In the first clinical study by Udy et al. (1), a post hoc analysis of the ARISE trial was performed to examine the association between early vasopressor use and mortality in septic shock. The 2014 Australasian Resuscitation in Sepsis Evaluation (ARISE) trial was a randomized, multicenter, clinical trial that enrolled 1,600 patients with severe sepsis or septic shock to Early Goal Directed Therapy (EGDT) or standard physician care. The trial demonstrated no difference in the primary outcome of all-cause mortality at 90 days. Udy et al. turned to the ARISE data to test the hypothesis that earlier use of vasopressors would be independently associated with differential 90-day mortality. Using three different statistical models the authors made a consistent finding that early vasopressor use was associated with greater 90-day mortality. While the authors acknowledge that early vasopressor use may be a marker of greater illness severity, their study also poses an interesting consideration for the development of future clinical trials.
The next clinical study by Baudry et al. (2) is a long-term observational study of cirrhotic patients admitted to the ICU with septic shock. The authors retrospectively analyzed this cohort to identify potential risk factors for short and long-term outcomes. In doing so, the investigators report on one of the largest cohorts of cirrhotic patients with septic shock in the ICU described in the literature. They found that the early use of organ support other than vasopressors, such as mechanical ventilation and renal replacement therapy, was strongly associated with early ICU mortality whereas the contribution of the underlying liver disease was mainly associated with long-term outcomes. Consistent with the model for end-stage liver disease, the need for renal replacement therapy (RRT) during ICU admission was strongly associated with mortality both early and late with patients RRT demonstrating a 93% 1-year mortality in their cohort.
Nguyen et al. (3) report on a prospective observational study of patients with septic shock. They tested the hypothesis that high plasma renin concentration during the early phase of septic shock would be associated with worse renal outcome. They identified a total of 41 patients admitted to the ICU with septic shock who had sufficient data to calculate plasma renin, aldosterone, and urinary sodium concentrations. The authors found that although plasma renin concentration was not predictive of 28-day mortality, higher plasma renin concentration was associated with adverse renal outcome, shock severity, and delayed shock reversal. While this study confirms that septic shock activates the renin–angiotensin system, it also supports recent data showing that administration of angiotensin II results in better renal outcomes in patients on renal replacement therapy who are in vasodilatory shock.
In another prospective observational study, Treskes et al. (4) describe the effects of enteral nutritional support on hyperglycemia and insulin resistance in patients with septic shock. They report on 24 ventilated patients in septic shock and aimed to determine the early course of insulin resistance in these patients as well as to explore any association between insulin resistance and enteral caloric intake. They found that nearly all of their study population demonstrated stress-induced hyperglycemia requiring exogenous administration of insulin. These exogenous insulin requirements were found to peak at 36 h after ICU admission followed by a gradual decrease over the subsequent 36 h. Additionally, there was a positive correlation between caloric intake and exogenously administered insulin. These data suggest that a strategy of conservative insulin dosing in the early phase of septic shock should be considered until the sepsis-induced insulin resistance resolves. Along the same line, a slow initiation of enteral nutrition during the early phase of septic shock should be considered to avoid worsening hyperglycemia.
In another clinical paper by Kim et al. (5), the pathophysiologic association between immature granulocytes and sepsis-induced acute kidney injury was assessed via the delta neutrophil index (DNI)—a measure of the proportion of circulating immature granulocytes. The authors retrospectively reviewed patients from an institutional sepsis registry to test the hypothesis that DNI could predict a number of clinical endpoints including acute kidney injury, need for renal replacement therapy, and 30-day mortality. Three hundred forty-nine patients met enrollment criteria. They found that DNI at admission and at 12 h post admission were strong independent predictors of severe acute kidney injury, which, in turn, was a strong predictor of 30-day mortality. Given that the DNI can be easily measured from a standard CBC, it may represent a new tool for the ED physician in predicting which septic patients are at a higher risk for adverse outcomes.
The final clinical paper comes from Saran et al. (6) who performed a prospective observational study on 26 patients with Acute Respiratory Distress Syndrome (ARDS). They assessed the ability of trans-esophageal Doppler (TED) to detect hemodynamically significant reduction in cardiac output after prone positioning of patients with ARDS. TED was able to assess cardiac index, peak velocity, corrected flow time, and mean acceleration. No differences in cardiac index were identified after prone positioning. However, corrected flow time showed a trend toward decreased preload by 30 min post-proning. This data suggests that although prone positioning did not affect cardiac index in the study population in aggregate that it may result in decreased preload in patients who are volume down.
From a basic science perspective, this month's issue of SHOCK brings a broad range of investigations spanning across the spectrum of in-vitro, ex-vivo, and in-vivo studies. Three of these studies seek to advance our knowledge of cardiac physiology and monitoring. Bobbia et al. (7) describe a new approach to measuring cardiac output by coupling transthoracic echocardiography with an artificially intelligent algorithm. In this approach the clinician identifies a 5-chamber transthoracic echocardiogram view and defines the left-ventricular outflow tract. The algorithm then interprets the echocardiogram and calculates the cardiac output. The investigators found that the CO calculated by the algorithm was highly correlated with gold-standard measurement by thermodilution and results from the AI algorithm were more strongly correlated with thermodilution than CO measured manually by echocardiography. This novel application of artificial-intelligence technology helps increase the objectivity of the ultrasound-mediated measurement of cardiac output and may help increase both accuracy and precision of TTE as a tool to measure CO.
Two other studies, Xu et al. (8) and Datzmann et al. (9), address the effects of shock and resuscitation on cardiac function. Hypothermia is an important tool in the treatment of post-cardiac arrest patients, and Xu et al. measured the efficacy of continuous renal replacement therapy (CRRT) as a cooling methodology in a large-animal (swine) model of post-cardiac arrest syndrome. These authors found that CRRT more rapidly induced hypothermia as compared with surface cooling, and that the more rapid cooling achieved with CRRT was associated decreased myocardial dysfunction, brain injury, and inflammation. This demonstrates the importance of rapid cooling and the study sets the stage for future comparisons between CRRT with currently available clinical cooling technology such as esophageal cooling probes and indwelling vascular cooling catheters. Datzmann et al. (9) also look to address the issue of myocardial protection after Shock. These authors have previously demonstrated that in the setting of coronary artery disease, hyperoxia can attenuate myocardial injury after hemorrhagic shock. This month in SHOCK, these authors extend these studies to normal hearts without CAD by measuring the effect of hyperoxia on cardiac function and tissue injury after hemorrhagic shock in healthy swine. In contrast to their previous studies, they identified no cardioprotective benefit to hyperoxia during hemorrhagic shock in the healthy animals. Although the increased oxygenation was not beneficial in healthy animals, no deleterious effects were noted, suggesting that in the setting of hemorrhagic shock and unknown coronary perfusion, hyperoxia may be an effective adjunctive therapy with limited risk.
In the next basic science paper, Breuer et al. (10) look to the diaphragm as a driver of the systemic inflammatory response during trauma and critical illness. Using a piglet model of ventilated respiratory failure, they found that mechanical ventilation alone or ventilation after trauma was associated with increased levels of activated caspase-3 (the executioner protease of apoptosis) in the diaphragm as compared with control animals. These data suggest a mechanism by which prolonged ventilation could exacerbate respiratory failure by inducing cell death in the diaphragm. After trauma, they found signs of increased inflammation in the diaphragm as compared to control, but no difference between animals subjected to mechanical ventilation versus mechanical ventilation after trauma. These results suggest that after trauma, mechanical ventilation can serve as a “second hit” to the diaphragm, amplifying the inflammatory response. Future studies will be required to parse out the implications of these results.
Two articles this month look at the role of the sphingosine-1 phosphate (S1P) during shock. S1P is a well-defined lipid signaling molecule that recruits leukocytes into the tissue out of the circulation, and there is intense interest in defining the role of S1P during shock as there are several drugs currently available to modulate interaction between S1P and its cognate receptors. Kuai et al. (11) describe a role for an S1P receptor agonist in modulating the effects of endotoxin on cardiomyocytes in an in-vitro cell culture assay. They find that in-vitro, S1P analogs can protect cultured cells from the cytotoxic effects of LPS, downregulating proapoptotic caspase-3 and upregulating ERK and AKT signaling, which could have a pro-survival effect. Meanwhile, detailed work from Alves et al. (12) at the University of South Florida sheds light on the potential mechanisms of these results. These investigators examined the interaction between S1P and the endothelia in a rodent model of resuscitated hemorrhagic shock. Using an elegant application of intravital microscopy, they find that S1P can protect the mesenteric microcirculation, decreasing shock-induced changes in permeability. They extend this work ex vivo to establish a role for S1P in protecting the endothelial glycocalyx and adherens junctions as a mechanism of preserving the endothelial integrity, and link these effects of S1P on the endothelia to mitochondrial dysfunction. These important results describe a novel mechanistic role for S1P in the pathogenesis of shock and lay the groundwork for future translational studies.
Reports from Wrba et al. (13) and Chen et al. (14) shed light on intestinal injury after trauma and sepsis. Wrba et al. present data demonstrating that trauma and hemorrhagic shock increase intestinal permeability and that in the setting of shock this was associated with a decrease in the tight-junction protein ZO-1. Chen et al. undertake detailed analysis of the role of the dendritic cell surface receptor DC-SIGN in intestinal injury after shock. DC-SIGN is a receptor for pathogen-associated molecular patterns that is specifically expressed on the surface of dendritic cells and recognizes mannose-containing carbohydrates. In a well-controlled and technically meticulous study, these authors find that siRNA knockdown of DC-SIGN attenuated the inflammatory response after cecal ligation and puncture induced sepsis, and linked this back to decreased activation of the ERK and NF-kB pathways. They translate these observations into human in-vitro studies where they demonstrated that LPS upregulates DC-SIGN in a human intestinal epithelial cell line. In analogy to their in-vivo murine studies, they found that DC-SIGN drives LPS-induced inflammation. Taken together, these results define a new pathway of intestinal injury after sepsis and suggest that the dendritic cells/DC-SIGN may be providing fuel for the “motor of sepsis.”
Last, Duburcq et al. (15) describe negative study on recombinant human antithrombin (ATryn) in a swine model of endotoxin-induced disseminated intravascular coagulation. Although they did find that ATryn was able to increase circulating antithrombin levels, they detected no difference in clinical or microcirculatory metrics.
Taken together, this month's issue of SHOCK provides the readership with a myriad of quality clinical and basic science studies ranging from sepsis to hemorrhage in both human patients and animal models from laboratories around the globe. Each provides novel insight into the biology of trauma, infection, and inflammation while bringing our research community one step closer to improving the care of the injured and infirmed around the world.
1. Udy AA, Finnis M, Jones D, Delaney A, Macdonald S, Bellomo R, Peake S. for the ARISE Investigators. Incidence, patient characteristics, mode of drug delivery, and outcomes of septic shock patients treated with vasopressors in the ARISE trial. Shock
2. Baudry T, Hernu R, Valleix B, Jahandiez V, Faucher E, Simon M, Cour M, Argaud L. Cirrhotic patients admitted to the ICU with septic shock: factors predicting short and long-term outcome. Shock
3. Nguyen M, Denimal D, Dargent A, Guinot P-G, Duvillard L, Quenot J-P, Bouhemad B. Plasma renin concentration is associated with hemodynamic deficiency and adverse renal outcome in septic shock. Shock
4. Treskes N, Koekkoek WAC, van Zanten ARH. The effect of nutrition on early stress-induced hyperglycemia, serum insulin levels, and exogenous insulin administration in critically ill patients with septic shock: a prospective observational study. Shock
5. Kim JH, Park YS, Yoon C-Y, Lee HS, Kim S, Lee JW, Kong T, You JS, Park JW, Chung SP. Delta neutrophil index for the prediction of the development of sepsis-induced acute kidney injury in the emergency department. Shock
6. Saran S, Gurjar M, Azim A, Mishra P, Ghosh PS, Baronia AK, Poddar B, Singh RK. Trans-esophageal Doppler assessment of acute hemodynamic changes due to prone positioning in acute respiratory distress syndrome patients. Shock
7. Bobbia X, Muller L, Claret P-G, Vigouroux L, Perez-Martin A, de La Coussaye JE, Lefrant JY, Louart G, Roger C, Markarian T. A new echocardiographic tool for cardiac output evaluation: an experimental study. Shock
8. Xu J, Chen Q, Jin X, Wu C, Li Z, Zhou G, Xu Y, Qian A, Li Y, Zhang M. Early initiation of continuous renal replacement therapy induces fast hypothermia and improves post-cardiac arrest syndrome in a porcine model. Shock
9. Datzmann T, Wepler M, Wachter U, Vogt JA, McCook O, Merz T, Calzia E, Gröger M, Hartmann C, Asfar P, et al. Cardiac effects of hyperoxia during resuscitation from hemorrhagic shock in swine. Shock
10. Breuer T, Bruells CS, Horst K, Thiele C, Hildebrand F, Linnartz S, Siegberg T, Frank N, Gayan-Ramirez G, Martin L, et al. Effect of long-term polytrauma on ventilator-induced diaphragmatic dysfunction in a piglet model. Shock
11. Kuai F, Wang L, Su J, Wang Y, Han Y, Zhou S. Exploring the protective role and the mechanism of sphingosine 1 phosphate in endotoxic cardiomyocytes. Shock
12. Alves NG, Trujillo AN, Breslin JW, Yuan SY. Sphingosine-1-phosphate reduces hemorrhagic shock and resuscitation-induced microvascular leakage by protecting endothelial mitochondrial integrity. Shock
13. Wrba L, Ohmann JJ, Eisele P, Chakraborty S, Braumüller S, Braun CK, Klohs B, Schultze A, von Baum H, Palmer A, et al. Remote intestinal injury early after experimental polytrauma and hemorrhagic shock. Shock
14. Chen W, Ma L, Li R, Huang S, Xie R, Chen Y, Zhao B, Fei J, Qu H, Chen H, et al. DC-SIGN expression in intestinal epithelial cells regulates sepsis-associated acute intestinal injury via activating ERK1/2-NF-κB/P65 signaling. Shock
15. Duburcq T, Durand A, Tournoys A, Gnemmi V, Bonner C, Gmyr V, Hubert T, Pattou F, Jourdain M. Single low dose of human recombinant antithrombin (ATryn) has no impact on endotoxin-induced disseminated intravascular coagulation: an experimental randomized open label controlled study. Shock