What's New in Shock, February 2018?

The February issue of SHOCK continues to build on our understanding of shock's physiologic underpinnings as well as the translation of basic science to clinical practice, led by two reviews. First, Nolt et al. review a problem that has long vexed intensivists treating septic patients: the interpretation and import of serum lactate (1). The authors summarize what is known about lactate as an immunosuppressive metabolite and its potential role in the regulation of the immune cellular response. Such data would support lactate not only as more than as marker of disease severity, resuscitation efficacy, and clinical prognosis, but also as a contributing factor to the evolution of sepsis physiology in and of itself. In a second review, Zhang et al. summarize a body of work investigating potential mechanisms by which an infusion of exogenous atrial natriuretic peptide (ANP) may be protective in shock (2). Already in clinical use for the management of cardiac failure in Asia, ANP seems to impact reactive oxygen species (ROS) production as well as natriuretic peptic receptor-mediated signaling pathways, particularly in intestinal epithelium. The authors speculate that a positive ROS feedback loop, stimulated by exogenous ANP, sustains another wise transient expression of endogenous ANP to effect the organ protection observed in animal models and clinical trials. Four clinical studies are included in the current issue. Distinguishing between causes of shock in the emergency room can be challenging, yet crucial to initiation of timely and effective treatment. Henning et al. performed a secondary analysis of a prospectively collected, observational cohort of persistently hypotensive adults presenting to their institution (3). Using logistic regression analysis, a predictive score utilizing serum troponin, evidence of ECG ischemia, shortness of breath, absence of fever, and a history of heart failure was developed and validated against outcome. Although it may seem obvious that this constellation of clinical history and physical findings would be indicative of a cardiogenic etiology for hypotension, it is not uncommon for such data to initially be dismissed or attributed to something else. Simple screening tools utilizing readily available data put the pieces together early in the patient's presentation and may help prevent delay of timely interventions. Norepinephrine is recommended as the vasopressor of choice for hemodynamic support in sepsis. Given that the gut barrier is considered to play a central role in the evolution of shock and organ failure, Habes’ group explored the impact of norepinephrine infusions on intestinal epithelium in septic patients (4). Logistic regression analysis suggested that early and increasing vasopressor support was a direct contributor to enterocyte damage, as evidenced by circulating intestinal fatty acid-binding protein (I-FABP) levels, but was independent of circulating inflammatory cytokines and translocation. This study emphasizes the pros and cons of any treatment modality—there is always a downside. Acute cardiac dysfunction in sepsis has been an area of interest for many years. Vallabhajosyula et al. asked whether survivors of severe sepsis were at risk for the development of secondary, long-term left ventricular dysfunction (5). They retrospectively studied 434 patients, half of whom showed evidence of cardiac decompensation during their admission for sepsis. With 2 years of follow-up, they documented echocardiographic evidence of persistent LV dysfunction in 28% of patients in the acute decompensation group, although the median decline in ejection fraction was relatively small (4%) and most patients were asymptomatic. Although overall outcomes in this relatively small study of sepsis survivors with and without acute cardiac dysfunction were similar, these data support further examination of the potential long-term impact of an episode of severe sepsis. Finally, Gamal et al. evaluated the precision of a commercially available noninvasive hemoglobin monitoring devise in anemic Caucasian trauma patients, documenting excellent correlation (r = 0.872) to laboratory measurements as low as 5 g/dL (6). Although encouraging, the study, based on finger pulse oximetry technology, was limited by a limited cohort of patients in shock and as well as ethnic diversity, both factors would impact results and require additional study. Ten basic science studies are included this month. First, the complex relationship between trauma and hemodynamic instability due to hemorrhage is dissected by Denk et al. (7). Having developed a mouse model of severe but hemodynamically stable polytrauma, the authors compared hemorrhagic shock alone to polytrauma and polytrauma with hemorrhagic shock. The additive effects of the combined insults on organ injury, both direct and remote, as well as expression of common inflammatory biomarkers will come as no surprise to clinicians. The paper does, however, offer valuable insight into model construction and study design when attempting to emulate the clinical scenario. In a similar vein, Vogt et al. directed their efforts to an assessment of the brain after remote trauma with hemorrhagic shock in a porcine model (8). Although the authors found no evidence of gross cerebral damage or sustained alterations in neuromonitoring parameters when resuscitation was initiated within 2 h, microglial and astrocyte activation was observed, despite the absence of direct traumatic brain injury. This activation was enhanced with mild hypothermia, although meningeal inflammation was reduced. The import of this microglial and astrocyte activation certainly warrants further study. Graded polytrauma combined with severe hemorrhagic shock is also the focus of the Sheppard group. In their quest to develop a nonhuman primate model that would reliably emulate the severely injured trauma patient, they offer a detailed comparison of five different models, summarizing observed hemodynamics, blood gas analyses, cell counts, coagulation, blood chemistry and serum biomarker profiles as well as pathology (9). The inclusion of such comprehensive descriptive work in SHOCK emphasizes the importance of tailoring study designs to take advantage of expected patterns of injury response inherent to a specific model; reliable assessment of future therapeutics demands experimental fidelity. The next two articles focus on acute lung injury. Bian et al. build on previous work, exploring the underlying mechanisms responsible for their observation that hydrogen gas (H2) inhalation improves survival and is protective for multiple organs in a mouse cecal ligation and puncture model (10). Using isobaric tags coupled with liquid chromatography-tandem mass spectroscopy, they compared proteomic analyses on lung lysates from septic treated and untreated mice. A true tour-de-force, they identified 192 proteins of interest and applied techniques of functional enrichment analysis to narrow their focus to four pathways responsible for coagulation, plasminogen activation, nicotinic receptor signaling, and chemokine/cytokine-mediated inflammation. The power of these technologies is truly impressive—clearly this is only the beginning for this group. We continue to search for treatment regimens that will alter the course of ARDS. Ji et al. explored the use of Indinavir, an antiviral medication used for the treatment of AIDS that modulates HMGB1/TLR4-mediated inflammation, in combination with corticosteroids as a means of altering the evolution of LPS activation of human pulmonary microvascular endothelial cell activation and acute lung injury in a rat (11). Interestingly, although the combined therapies were additive with regard to overall evidence of protection after LPS-induced acute lung injury, the addition of Indinavir reduced the necessary steroid dosage required to achieve that protection. As steroids are generally used as a rescue therapy in severe ARDS, it would be interesting to investigate whether such a combined treatment would be effective in more advanced lung injury. Several papers in this issue of SHOCK focus on the development of a model to solve a challenging problem. Babini et al. identified a need for a clinically relevant model to study postcardiac arrest syndrome, and developed an porcine LAD occlusion model of variable duration cardiac arrest, resuscitation, and postarrest neurologic assessment (12). Although their study confirmed the expected (a linear relationship between arrest time with lower survival and worse myocardial and neurologic dysfunction), their work provides a framework to address a poorly studied clinical problem that devastates thousands of patients every day. Kudos. Glas et al. also focused on neurologic complications of cardiac arrest (13). Drawing on other studies that have shown promising improvements in neurologic function after stroke and hypoxic-ischemic brain injury, they hypothesized that blocking the p53 pathway, central to delayed cell death and apoptosis, would reduce hippocampal cellular degeneration in a rat model of cardiac arrest. They found that a single dose of the antiapoptotic small molecule pifithrin-μ, given after return of spontaneous circulation, decreased cell death by 25%. We will eagerly await further investigation from both of these groups as they venture to identify interventions that may improve neurologic outcome after cardiac arrest. Dissection and manipulation of inflammatory and apoptotic pathways that are activated during sepsis remain areas of interest and study. Zou et al. observed over-expression of Fn14 (TWEAK/Fn14 pathway) in the pulmonary microvasculature of mice with acute lung injury after CLP, and amelioration of the associated inflammation through reduced ICAM-1 and MCP-1 expression with Fn14 blockade (14). Interestingly, the effects of Fn14 blockade were not limited to acute injury as pulmonary fibrosis scores were also reduced. This alone deserves further investigation. Finally, muscle dysfunction is an underappreciated and poorly understood consequence of sepsis. Balboa's group identified de novo expression of four proteins (three connexins and P2X2R) that have been linked to the channelopathy characteristic of muscle dysfunction in late sepsis (15). These poorly selective channel proteins increase the permeability of the sarcolemma and may be key to alterations in calcium flux and mitochondrial function that lead to the persistent muscle weakness observed in septic patients. As usual, SHOCK and its contributors continue to report provocative and thoughtful science.