This edition of Shock features a wide diversity of articles surely to be of interest to our readers, ranging from clinical to translational to basic science on topics ranging from coagulopathy, hemorrhage, sepsis, and burns to coronary artery disease, heatstroke, and hepatitis. Speaking of coagulopathy, our lead article by Moore et al. (1) is an invited pro-con debate of coagulopathy, based on the lively discussion by the authors at the 39th annual meeting of the Shock Society held in June 2016. The question posed was: “Is coagulopathy an appropriate therapeutic target during critical illness?” This is a very well-written and informative article that concisely reviews the good and the bad related to the treatment of coagulopathy. The authors aptly point out the heterogeneous nature of the disease which is complicated by a lack of a precise definition and diagnosis. This is a must read!
Continuing on this theme, Honickel et al. (2) inform us on the reversal of direct oral anticoagulants (DOACs) in animal models. As the use of DOACs such as direct thrombin and factor Xa inhibitors increase in use, reversal of these agents in patients with bleeding after injury or in need of emergency surgery represents a challenge to clinicians. Strategies for reversal are evolving and strong evidence in support of specific inhibitors is lacking. The authors nicely review available reversal agents for DOACs, both those in clinical and preclinical phases of use. They then review 26 preclinical animal studies and conclude with some worthy key points including: the need for standardized animal models and outcomes; the lower cost and higher output of small animal models but that larger animal modes more closely mimic human blood loss and hemodynamics; the need for awareness of species-specific differences in response to DOACs and their reversal; and the plea that blood loss and not laboratory values be the preferred primary endpoint in studies of reversal of DOACs.
Since we are discussing bleeding, let us move onto our next debate in this month's Shock related to the use of cryopreserved red blood cells. Cryopreserved cells are frozen within several days of donation and have the advantage of prolonged storage while frozen and after thawing. Chang et al. (3) previously reported that the post-thaw characteristics of cryopreserved units are not comparable to fresh red cells and that the development of the red cell storage lesion may actually be enhanced. In this month's Shock, Preston et al. (4) point out that a major mechanism of the red blood cell storage lesion is the accumulation of oxidative stress, one not assessed by Chang et al. (3). These authors measured the oxidation-reduction potential (ORP) in young and old units of traditionally stored blood and found that the older units accumulated more ORP during storage than younger units and suggested such a measurement be considered point of care testing. Chang and Pritts (5) agreed that ORP should be further explored to evaluate this measurement under various storage periods and conditions. I think it was a win-win!
Switching now from global disturbances to organ-specific injury, we learn from Zhu et al. (6) that an imbalance in plasma human neutrophil elastase (HNE) and the endogenous proteinase inhibitor, elafin (P13), can help prognosticate outcome in patients with acute respiratory distress syndrome (ARDS). These authors performed a prospective observational study of 167 patients with ARDS in China. HNE and P13 were measured over time and found to inversely correlate with survival; a higher HNE was found in non-survivors and higher P13 in survivors of ARDS. While the use of both biomarkers could predict 28-day mortality, combining these biomarkers with Berlin categories of ARDS and APACHE II further improved prognostic power. Going forward, these two biomarkers may help to predict the onset of ARDS. Hemorrhagic shock impairs perfusion of all organs, with the gastrointestinal track being particularly susceptible to low flow conditions. Bloch et al. (7) tested the ability of impedance spectroscopy to detect early changes in the gut in a pig model of hemorrhagic shock. Unfortunately, this technology was unable to do so, thus leaving clinicians with no reliable way to diagnose early gut hypoperfusion. Kudos to the authors for trying!
Talk about a challenge, Zhao et al. (8) compared the use of hypertonic saline dextran (HSD) to Lactated Ringer for fluid resuscitation in rats subjected to simulated altitude, as large volumes of crystalloid may induce pulmonary edema at altitude. Though pulmonary edema was not measured, the authors report that a bolus of HSD reduced blood loss and serum lactate with superior oxygen saturation, hemoglobin, and survival compared to Lactated Ringer. Grab some HSD before your next flight.
Going on to the “heart” of the matter, Ye et al. (9) investigated the effect of percutaneous coronary intervention (PCI) after acute myocardial infarction (MI) on microparticles and their potential role in post-PCI endothelial dysfunction and platelet activation. Microparticles from 38 patients suffering from an acute MI were isolated from blood pre- and post-PCI and compared to healthy controls. Interestingly, microparticle concentrations were increased after acute MI but were not significantly altered by subsequent PCI. However, ratios of endothelial-derived microparticles increased while platelet-derived microparticles decreased after PCI. Additionally, microparticles, particularly those post-PCI, impaired endothelium-dependent vasodilation via a number of eNOS-mediated pathways. Those malicious microparticles!
Moving onto sepsis, a condition associated with significant morbidity and mortality. Sepsis-associated encephalopathy (SAE), which is a rapid decline in cognitive function, especially memory, is a major complication of sepsis and has no known treatment. Hoshino et al. (10) investigated the effects of minocycline, a potential neuroprotective agent for SAE, on hippocampal long-term potentiation, a measure of synaptic strength. Using a mouse model of cecal ligation and puncture (CLP), they found that CLP-associated sepsis attenuated the excitatory postsynaptic potentials. However, mice receiving minocycline demonstrated a near return to control-level excitatory postsynaptic potentials. As minocycline is also anti-inflammatory, IL-1β receptor inhibition was tested and found to restore the CLP group's excitatory postsynaptic potentials to control levels. The authors demonstrated for the first time that minocycline prevented impaired long-term potentiation related to SAE in the mouse hippocampus, and that mechanisms associated with IL-1 receptor activity may be involved. Moving down to the thymus, to better understand which thymic subpopulations were responsible for acute thymic involution after sepsis, Netzer et al. (11) used a rodent model of CLP. Fluorescence-activated cell sorting demonstrated that predominantly immature thymocytes were reduced and that single positives were the most diminished and had the highest rate of apoptosis, with a lesser reduction in double-positive thymocytes and lesser rate of apoptosis. Surprisingly, the expected emigration inhibition was not seen. Based on their PCR analysis of Notch expression on thymocytes, they suggest that this may be an additional mechanism to explain the decline in thymocytes following sepsis.
Finally, multi-organ failure and poor glucose control are well-known complications of sepsis. Hydrogen sulfide (H2S) may have an effect of glucose metabolism and has been studied as a potential therapeutic to slow metabolism. Nußbaum et al. (12) investigated GYY4137 (morpholin-4-ium-4-methoxyphenyl (morpholino) phosphinodithioate), a slow-releasing H2S donor that also has anti-inflammatory effects, in a porcine model of resuscitated septic shock with pre-existing atherosclerosis. Interestingly, impaired endogenous H2S production may also play a role in atherosclerosis. They found GYY4137 administration was associated with an increased exogenous glucose requirement, and a reduced pH and base excess 24 h after injury. CO2 production, as compared with controls, was similar; however, the fraction of CO2 production from glucose oxidation was significantly higher in the GYY4137 group. The GYY4137 group also demonstrated elevated troponin levels that may have been secondary to reduced eNOS expressed. The authors propose that their cautious dosing, timing of GYY4137, and interspecies differences most likely account for the absence of any anti-inflammatory or organ-protective effects of GYY4137 in their study.
Similar to sepsis, burns injuries are also associated with cytokine proliferation, a pro-inflammatory state, and depending upon the total body surface area and location affected, a high level of mortality. Khan et al. (13) hypothesized that the selective alpha 7 acetylcholine receptor (α7AChR) agonist, GTS-21, would induce IL-6 release in association with myonuclear accretion, enhance insulin signaling in muscle cells, and improve survival of burn-injured mice. They found that GTS-21 dose dependently increased IL-6 in myoblasts and myotubes in vitro and after using an α7AChR agonist and Stat-3 and -5 inhibitors, demonstrated the mechanism of action was through the α7AChR pathways. In vivo they found that GTS-21 enhanced insulin sensitivity in IL-6 KO mice. Most importantly, GTS-21-induced IL-6 led to an impressive reduction in survival in both WT and KO burn injured mice, suggesting that it may be a potential therapeutic after burns. Sehat's group investigated IL-6's role in mitochondrial fission-associated cell death also in a burn mouse model (14). Caspase-3, a cell death protease, was significantly elevated in mouse C2C12 myoblasts when subjected to burn serum stimulation. The C2C12 myoblast mitochondrial elongation index decreased and fusion protein, Mfn1, concentration increased further supporting mitochondrial fragmentation. When treated with recombinant IL-6, mitochondria demonstrated a reversal of the burn serum insult. This suggests IL-6 plays a role in cell death regulation through mitochondria manipulation. Stock up on your IL-6!
Anyone who has occasionally imbibed a few too many times might want to carefully read the article by Souza-Smith et al. (15). These authors have shown that repeated binge-like alcohol intoxication (RBAI) induces mesenteric lymphatic hyperpermeability and perilymphatic adipose tissue inflammation. In a rat model, they now demonstrate that RBAI promotes mesenteric fat adaptive immune cell infiltration and inflammation and decreases adiponectin and visfatin levels, resulting in impaired mesenteric fat insulin signaling. These effects were not seen in subcutaneous fat, likely due to the lack of contact with gut lymphatics. They propose “lymphatic-mesenteric perilymphatic adipose tissue crosstalk” as an explanation to link visceral adipose tissue inflammation and the increased risk for metabolic disorders stemming from RBAI. Still targeting the end-result of excess alcohol intake, Utaipan et al. designed ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a bile-acid phospholipid conjugate, used to prevent endotoxin-associated hepatitis. This group now assessed UDCA-LPE's ability to protect against CD95/FAS-induced fulminant hepatitis (16). Jo-2, a CD95/FAS agonist monoclonal antibody known to cause hepatocyte apoptosis and induce severe fulminant hepatitis, was given to mice in the presence or absence of UDCA-LPE pretreatment. UDCA-LPE administration attenuated Jo-2-associated hepatic apoptosis, hepatitis, and inflammation. A win!
As summer is upon us, read up on the protective effect of dexmedetomidine (DEX) against multi-organ dysfunction secondary to heat stroke by Xia et al. (17). Dexmedetomidine is a selective α2 adrenoceptor agonist commonly employed in the intensive care unit as a sedative. In a rodent model of heat stroke, the authors demonstrated that DEX-reduced heat stroke elevated organ biomarkers (ALT, AST, ALP, BU, and Cr) and inflammatory cytokines (TNF-α, IL-6 and IL-1β, and NF-κB). Heat stroke-induced gut permeability was also decreased by DEX as evidenced by preservation of tight junction proteins, partial restoration of occludin and ZO-1 concentrations, and decreased of pro-apoptotic protein, Bax, and increased anti-apoptotic protein, Bcl-2. These results suggest that DEX may protect against inflammation and multi-organ injury induced by heatstroke via a reduction in enterocyte apoptosis and sustaining intestinal integrity.
It was an honor and privilege to have the opportunity to comment on all of the outstanding contributions to this month's Shock. Congratulations to all of the authors!
1. Moore HB, Winfield RD, Aibiki M, Neal MD. Is coagulopathy an appropriate therapeutic target during critical illness such as trauma or sepsis? Shock
2. Honickel M, Akman N, Grottke O. The reversal of direct oral anticoagulants in animal models. Shock
3. Chang AL, Hoehn RS, Jernigan P, Cox D, Schreiber M, Pritts TA. Previous cryopreservation alters the natural history of the red blood cell storage lesion. Shock
4. Preston K, Harm S, Dreyfus N, Villalba N, Freeman K. Packed red blood cells accumulate oxidative stress with increased storage duration. Shock
5. Chang AL, Pritts TA. Reply to “Packed red blood cells accumulate oxidative stress with increased storage duration”. Shock
6. Wang T, Zhu Z, Liu Z, Yi L, Yang Z, Bian W, Chen W, Wang S, Li G, Li A, et al. Plasma neutrophil elastase and elafin as prognostic biomarker for acute respiratory distress syndrome: a multicenter survival and longitudinal prospective observation study. Shock
7. Bloch A, Kohler A, Posthaus H, Berger D, Santos L, Jakob S, Takala J, Haenggi M. Gastrointestinal impedance spectroscopy to detect hypoperfusion during hemorrhage. Shock
8. Zhao J, You G, Wang B, Sun Z, Wang Z, Xia S, Zhao L, Zhou H. Hypotensive resuscitation with hypertonic saline dextran improves survival in a rat model of hemorrhagic shock at high altitude. Shock
9. Ye S, Shan X-F, Han W-Q, Zhang Q-R, Gao J, Jin A-P, Wang Y, Sun C-F, Zhang S-L. Microparticles from patients undergoing percutaneous coronary intervention impair vasodilatation by uncoupling endothelial nitric oxide synthase. Shock
10. Hoshino K, Hayakawa M, Morimoto Y. Minocycline prevents the impairment of hippocampal long-term potentiation in the septic mouse. Shock
11. Netzer C, Knape T, Kuchler L, Weigert A, Zacharowski K, Pfeilschifter W, Sempowski G, Parnham MJ, Brüne B, von Knethen A. Apoptotic diminution of immature single and double positive thymocyte subpopulations contributes to thymus involution during murine polymicrobial sepsis. Shock
12. Nußbaum BL, Vogt J, Wachter U, McCook O, Wepler M, Matallo J, Calzia E, Gröger M, Georgieff M, Wood ME, et al. Metabolic, cardiac, and renal effects of the slow hydrogen sulfide-releasing molecule GYY4137 during resuscitated septic shock in swine with pre-existing coronary artery disease. Shock
13. Khan MAS, Khan MF, Kashiwagi S, Kem WR, Yasuhara S, Kaneki M, Tompkins RG, Martyn JAJ. An alpha7 nicotinic acetylcholine receptor agonist (GTS-21) promotes C2
myonuclear accretion in association with release of interleukin-6 (IL-6) and improves survival in burned mice. Shock
14. Sehat A, Huebinger RM, Carlson DL, Zang QS, Wolf SE, Song J. Burn serum stimulates myoblast cell death associated with IL-6-induced mitochondrial fragmentation. Shock
15. Souza-Smith FM, Ford SM Jr, Simon L, Molina PE. Repeated binge-like alcohol intoxication: depot-specific adipose tissue immuno-metabolic dysregulation. Shock
16. Utaipan T, Otto A-C, Gan-Schreier H, Chunglok W, Pathil A, Stremmel W, Chamulitrat W. Ursodeoxycholyl lysophosphatidylethanolamide protects against CD95/Fas-induced fulminant hepatitis. Shock
17. Xia Z-N, Zong Y, Zhang Z-T, Chen J-K, Ma X-J, Liu Y-G, Zhao L-J, Lu G-C. Dexmedetomidine protects against multi-organ dysfunction induced by heatstroke via sustaining the intestinal integrity. Shock