This issue of Shock provides another excellent selection of 16 manuscripts spanning the basic sciences and clinical outcomes of shock, injury, inflammation, and sepsis. An important theme this month is organ dysfunction in sepsis. Neutrophil dysregulation is a critical step early in the development of septic organ dysfunction. Soroush et al. (1) previously identified protein kinase C-delta (PKC-∂) as a key regulator of neutrophil activation and now searched for a site-specific target for future anti-inflammatory therapies. They demonstrated that PKC-∂ tyrosine 155 is a key phosphorylation site involved in PKC-∂'s regulation of neutrophil activation and migration. These studies provide mechanistic insight into the regulation of inflammation and earned the authors the new investigator award. Future studies will be aimed at identifying novel targets for treating inflammation.
Continuing on the theme of neutrophil dysregulation in sepsis, Jin et al. (2) investigated extracellular cold-inducible RNA-binding protein (CIRP) related acute lung injury in a murine model of septic shock. They found CIRP stimulates neutrophil reverse transendothelial migration and increase local pulmonary inflammation in a dose-dependent fashion. Yu et al. (3) also studied inflammatory mediators of acute lung injury in sepsis. They examined the role of NLRP3 inflammasomes and NF-kB signaling proteins in a mouse model of severe acute pancreatitis. They found surfactant protein D exerts protective effects against acute lung injury by suppressing NLRP3 inflammasome and NF-kB. Future studies will be required to determine if any of these pathways may be exploited to reduce inflammation and acute lung injury.
Altered mitochondrial respiration comprises another early feature of organ dysfunction in sepsis. Jang et al. (4) used plasma derived bone marrow cells to evaluate mitochondrial respiration in patients with sepsis, compared with normal controls of various ages. They found a reduction in mitochondrial ATP production in sepsis that may signify impaired oxygen delivery or utilization in end organs, which could be detected and trended using this serum marker. The ability to measure mitochondrial respiration with a blood test represents a growing area of research into minimally invasive means of assessing cellular function to predict sepsis severity and prognosis.
Key to cellular function is microcirculatory function, the loss of which is a harbinger of poor prognosis in sepsis. Côrtes et al. (5) assessed microvascular function in sepsis using the perfusion index after transient arterial occlusion. The authors anticipated a larger delta would correlate with higher microvascular reserve, indicating less dysfunction and a better prognosis. However, they found a larger delta correlated with greater reactive hyperemia, increased serum lactate levels, and worse mortality. Vallée et al. (6) also used the perfusion index to assess microvascular dysfunction for predicting sepsis severity. The authors tested cutaneous capnography and perfusion index coupled with intermittent dynamic heating of the ear lobe to assess cutaneous vasoreactivity. This method was able to diagnose septic shock apart from cardiogenic shock, hemorrhage shock, and nonshock states, and predict mortality with high sensitivity and specificity. This study adds to a growing a body of literature demonstrating a link between microvascular vasoreactivity and prognosis in septic shock.
Although we search for new ways to predict outcomes and improve survival, early implementation of resuscitative measures, including antibiotics, has long been established as fundamental for improving survival from sepsis. Yu et al. (7) postulated the Emergency Department (ED) may have greater resources to allow for appropriate implementation of these time-critical therapies. To validate the findings of a previously published study from the United States, Yu et al. conducted a retrospective analysis of patients in Taiwan admitted with sepsis. They confirmed lower in-hospital and 90-day mortality in those admitted through the ED to those directly admitted. Future studies are needed to determine if this finding is in fact related to the timing of diagnosis and treatment.
One time-sensitive intervention that is frequently required for resuscitation and management of patients in septic shock is placement of a central venous catheter. Point of care ultrasound is commonly used for central lines placed by Emergency Medicine physicians and Intensivists. Ablordeppey et al. (8) conducted a survey of these providers to determine how often point of care ultrasound is being used to confirm the position of central venous catheters and rule out pneumothorax. Although ultrasound has similar sensitivity and specificity to chest x-ray, only 1% of physicians surveyed use ultrasound in place of chest x ray for this purpose. Major barriers to greater adoption of ultrasound confirmation include hospital politics/policy, and unfamiliarity/lack of comfort with the ultrasound technique. Future studies will evaluate whether targeted interventions aimed at reducing these barriers will improve adoption of ultrasound over chest x-ray.
Patients requiring ventilator support for respiratory failure during sepsis are at risk of developing a secondary pneumonia. The Centers for Disease Control and Prevention recently released new definitions of ventilator associated events (VAEs) to better characterize patients with worsening respiratory status who may have pneumonia. Younan et al. (9) investigated the outcomes of trauma patients with VAEs. They found patients on ventilatory support for 2 weeks or more were at similar risks for bad outcomes regardless of the VAE type they experienced. Among those with worsening respiratory status there was significantly increased odds of increased ventilator days, longer length of stay, and higher mortality, regardless of the presence or absence of fever or leukocytosis.
Two groups this month studied critical care devices. Moller et al. (10) studied increasing ECMO flows by increasing venous return through vasoconstriction, as compared with volume expansion, in a centrally cannulated swine model. They found both treatments generated similarly increased maximum achievable ECMO flow by different mechanisms. Although vasoconstriction increased flow without worsening positive fluid balance, volume expansion decreased vascular resistance and pump afterload, suggesting it may be preferable to vasoconstriction in patients sensitive to these insults. Johnson et al. (11) developed an automated, variable, partially occluding, intra-aortic balloon to augment mean arterial pressure to proximal organs in a technique they termed Endovascular Perfusion Augmentation for Critical Care (EPACC). Compared with traditional critical care with fluids and vasopressors alone, EPACC animals had a higher average mean arterial pressure, remained within a goal blood pressure range for a greater period of time, and required less intravenous fluids to maintain goal blood pressures without increased histological damage to distal organs. This study suggests EPACC may be a viable alternative technique for resuscitating refractory shock in austere environments where conservation of fluids is paramount.
Another prominent theme in this month's issue is the basic science aspect of increased mortality after burn injury. Burn patients who consumed alcohol before injury were observed to have worse clinical outcomes including increased mortality. Curtis et al. (12) investigated the physiologic changes that occur following multiday ethanol intoxication in a mouse model of burn injury. They found alterations in macrophage phenotype, increased circulating cytokines, and increased pulmonary inflammation that may yield a potential mechanism underlying the increased mortality observed in intoxicated burn patients. Randolph et al. (13) investigated blood brain barrier dysfunction after smoke inhalation. Smoke inhalation with or without concomitant burn injury was associated with diffuse microvascular hemorrhage throughout the brain and diffuse blood brain barrier dysfunction even in the absence of hypoxia. This finding may explain symptoms reported by patients who experienced inhalational injury and offer insight to the clinicians who treat them.
In patients that survive a major burn, muscle wasting subsequent to inflammation and immobility is common. Ma et al. (14) hypothesized that there is also a component of central nervous system injury that contributes to muscle wasting after a burn. They found burn injury induces atrophy of spinal cord ventral horn motor neurons as a result of microglial cytokines release. These changes were associated with significant muscle loss that was worsened by concomitant immobilization. Further studies are needed to delineate the connection between microglial activation and motor neuron loss and whether targeted interventions can prevent or reverse muscle wasting associated with these changes.
Therapeutic hypothermia has been shown to improve neurologic outcomes following return of spontaneous circulation after ventricular fibrillation arrest. In this feasibility study, Li et al. (15) investigated whether a neurotensin receptor agonist could achieve therapeutic hypothermia to 34°C for 2.5 h and improve neurologic outcomes in a rat model of cardiac arrest. They found the novel drug was effective at inducing targeted hypothermia and significantly improved post resuscitation myocardial function, neurologic deficit scores, and survival. This study suggests the neurotensin receptor agonist ABS 201 may be a viable alternative to current cooling methods to improve outcomes after cardiac arrest.
Continuing on an emerging line of research investigating potential harms of hyperoxia, Yokoyama et al. (16) sought to evaluate the impact of hyperoxia on neurologic outcomes following subarachnoid hemorrhage (SAH). They found arterial PaO2 >120 mmHg during the first 24 h of ICU admission lead to unfavorable neurologic outcomes in mild to moderate SAH. More research is needed to determine the optimal PaO2 range for SAH patients.
Over all this month's edition of Shock provides many intriguing insights that may lead to novel therapies and improvements in the diagnosis and management of shock, injury, inflammation, and sepsis.
1. Soroush F, Tang Y, Guglielmo K, Engelmann A, Liverani E, Patel A, Langston J, Sun S, Kunapuli S, Kiani MF, et al. Protein kinase C-delta (PKCδ) tyrosine phosphorylation is a critical regulator of neutrophil-endothelial cell interaction in inflammation. Shock
2. Jin H, Aziz M, Ode Y, Wang P. CIRP induces neutrophil reverse transendothelial migration in sepsis. Shock
3. Yu J, Ni L, Zhang X, Zhang J, Abdel-Razek O, Wang G. Surfactant protein D dampens lung injury by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis. Shock
4. Jang DH, Orloski CJ, Owiredu S, Shofer FS, Greenwood JC, Eckmann DM. Alterations in mitochondrial function in blood cells obtained from patients with sepsis presenting to an emergency department. Shock
5. Côrtes de Menezes IA, Leinig da Cunha C, Junior HC, Luy AM. Increase of perfusion index during vascular occlusion test is paradoxically associated with higher mortality in septic shock after fluid resuscitation: a prospective study. Shock
6. Vallée F, Nougué H, Mari A, Vodovar N, Dubreuil G, Damoisel C, Dépret F, Mateo J. Variations of cutaneous capnometry and perfusion index during a heating challenge is early impaired in septic shock and related to prognostic in non-septic shock. Shock
7. Yu C-W, Chang S-S, Lai C-C, Wu J-Y, Yen DW, Lee M-tG, Yeh C-C, Chung J-Y, Lin Y-J, Lee C-C. Epidemiology of emergency department sepsis: a national cohort study between 2001 and 2012. Shock
8. Ablordeppey EA, Drewry AM, Theodoro DL, Tian LL, Fuller BM, Griffey RT. Current practices in central venous catheter position confirmation by point of care ultrasound: a survey of early adopters. Shock
9. Younan D, Griffin R, Zaky A, Pittet J-F, Camins B. A comparison of outcomes of trauma patients with ventilator-associated events by diagnostic criteria set. Shock
10. Moller PW, Hana A, Heinisch PP, Liu S, Djafarzadeh S, Haenggi M, Bloch A, Takala J, Jakob SM, Berger D. The effects of vasoconstriction and volume expansion on veno-arterial ECMO flow. Shock
11. Johnson MA, Tibbits EM, Hoareau GL, Simon MA, Davidson AJ, DeSoucy ES, Faulconer ER, Grayson JK, Neff LP, Williams TK. Endovascular perfusion augmentation for critical care: partial aortic occlusion for treatment of severe ischemia–reperfusion shock. Shock
12. Curtis BJ, Boe DM, Shults JA, Ramirez L, Kovacs EJ. Effects of multiday ethanol intoxication on postburn inflammation, lung function, and alveolar macrophage phenotype. Shock
13. Randolph AC, Fukuda S, Ihara K, Enkhbaatar P, Micci M-A. Blood–brain barrier dysfunction after smoke inhalation injury, with and without skin burn. Shock
14. Ma L, Zhou Y, Khan MAS, Yasuhara S, Martyn JAJ. Burn-induced microglia activation is associated with motor neuron degeneration and muscle wasting in mice. Shock
15. Li H, Hua T, Wang W, Wu X, Miao C, Huang W, Xiao Y, Yang J, Bradley JL, Peberdy MA, et al. The effects of pharmacological hypothermia induced by neurotensin receptor agonist ABS 201 on outcomes of CPR. Shock
16. Yokoyama S, Hifumi T, Kawakita K, Tamiya T, Minamino T, Kuroda Y. Early hyperoxia in the intensive care unit is significantly associated with unfavorable neurological outcomes in patients with mild-to-moderate aneurysmal subarachnoid hemorrhage. Shock