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Commentary

What'S New in Shock, August 2020?

Remick, Daniel G.

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doi: 10.1097/SHK.0000000000001614
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This month's issue of SHOCK will once again feature an outstanding array of papers ranging from basic science studies to clinical trials, so let's jump into the work.

Leonard et al. (1) describe the critical role of a member of the heat shock protein 70 family of chaperones, Mortalin/GRP75 in acute lung injury. Mortalin/GRP75 has been found to play a role in neurodegenerative diseases such as Parkinson's and Alzheimer's, where lower levels are found in the brains of patients suffering from this disease. The opposite effect is found in cancer where there is increased expression and a specific mortalin/GRP75 inhibitor, MKT-077, has had positive results in an early clinical trial for cancer patients. Using a murine model of acute lung injury induced with aerosolized lipopolysaccharide (LPS) this group examined whether MKT-077 would reduce lung injury. An important component of the study was providing the inhibitor either 1 h before, or 1 h after exposure to LPS, and sacrificing the mice at 16 h. Either protocol significantly reduced lung damage. Further in vitro studies with human endothelial cells showed that MKT-077 decreased inflammation and endothelial cell damage, results confirmed using siRNA knockdown of mortalin. The protective mechanism appears to be through decreasing the activation of Nuclear Factor-Kappa B (NF-κB). The amount of data presented in this paper was impressive.

An area of emerging importance is the development of sepsis-induced brain injury. Septic patients have both short-term (days to weeks) and long-term (months) declines in cognitive function. These declines have been attributed multiple abnormalities including increased free radicals and microvascular injury. Pang et al. (2) used the cecal ligation and puncture (CLP) model of sepsis to study changes at 1 and 4 days post-CLP. The investigators used a 7.0 Tesla MRI scanner to image the brains of septic mice, and compared the results with conventional techniques such as brain water. The type of MRI in this study is important, since higher resolution scanners for experimental animals are becoming available which provide better sensitivity. The traditional techniques did not show any significant increase in brain edema. In contrast, there was an increase in several MRI indices at day 4 post-CLP suggesting cytotoxic edema and cellular swelling. Changes were also observed indicating axonal swelling or injury. Immunohistochemistry stains of harvested brains documented the presence of microglial activation at day 1 post CLP in the cortex, hippocampus, and thalamus. These data provide the foundation of information to further examine the changes in the central nervous system in sepsis. Additional tests of cognitive function after sepsis will be able to correlate these with the MRI findings, since both may be done in a longitudinal fashion.

The brain was also studied in the paper by Kondo et al. (3). Their studies showed that adenosine monophosphate (AMP) injected into experimental animals induced a hypometabolic state with decreases in body temperature, respiratory rate, and heart rate. These changes were rapidly induced within 10 min and returned to baseline within 3 h. In vitro studies were performed next by adding AMP to a neuronal cell line where it reduced the metabolic rate. Next, a cell line or differentiated mouse neural stem cells were studied and AMP reduced mitochondrial membrane potential, which was associated with changes in mitochondrial calcium. Using the neuronal cell line, AMP inhibited the enzyme AMP-activated protein kinase. Since both AMP and ATP had similar effects, the authors investigated if adenosine rather than AMP mediated these mitochondrial changes and convincingly showed AMP was the responsible molecule. These data indicate that AMP will induce oxygen demand by neurons, which may protect the brain. To test this, mice were injected with AMP and then placed in a hypoxic environment (1% or 6% O2). Pretreatment with AMP only 2 min prior to hypoxia exposure significantly delayed mortality. Cooling has been recommended as a neuroprotective mechanism in patients, but external cooling may require substantial time, whereas AMP treatment may achieve similar results within minutes.

There has been recent interest in defining organ injury parameters since the publication of the Sepsis-3 criteria that state sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Abraham et al. (4) performed a comprehensive literature review to identify the metrics for organ dysfunction that may be observed in the CLP sepsis model. Table 1 in this article captures the important measures of organ dysfunction for the cardiac, pulmonary, hepatic, renal, gastrointestinal, neural, and skeletal muscle systems. They carefully tabulated whether changes were observed in patients or rodents subjected to CLP. Each of these abnormalities is carefully discussed along with recommendations for studies that should be done in experimental animals. The authors also present the limitations and caveats of their recommendations. Sepsis investigators should carefully read Table 1 when planning their experiments to select the appropriate organ dysfunction parameters that will be studied.

Sepsis disproportionately impacts the very young and the very old, so papers that study sepsis in these age groups deserve a careful read. Previous reports have shown that a loss of normal heart rate variability predicts mortality. Eftekhari et al. (5) performed sophisticated experiments to test whether a portion of the brain responsible for autonomic function, the nucleus of the solitary tract, fails to function properly in neonatal sepsis. Using the cecal slurry model in 14-day-old rats the study showed that sepsis increases the excitability of neurons in the NTS.

This review is being written during the COVID-19 pandemic where the issue of sufficient support for patients is being actively discussed. While many issues are related to the number of available respirators in the world, extracorporeal membrane oxygenation (ECMO) would also be appropriate therapy for some patients. Peetermans et al. (6) described the use of intravenous immunoglobulin (IVIG) in patients with severe lung injury caused by bacteria that produce toxins in ECMO patients. A total of 34 ECMO patients were studied, 15 of whom had toxin-producing bacterial infections. The overall mortality was 30%, less than the predicted mortality of 90%. This small study shows that the use of IVIG in ECMO patients was safe, and possibly decreased mortality.

That famous philosopher, Yogi Berra, once said it's tough to make predictions, especially about the future. Predicting mortality in septic patients presenting to the emergency department (ED) is complicated and several scoring systems have been proposed. Cleek et al. (7) compared the ability of the quick sequential organ failure score (qSOFA) to the predictions of ED physicians. These physicians predicted 28-day mortality and these predictions were compared to the qSOFA scores. Experienced clinicians will not be surprised to learn that the ED physicians more accurately predicted mortality than the qSOFA!

It has long been recognized that aging increases the incidence of several lethal diseases, such as atherosclerotic cardiovascular disease, cancer, and sepsis. Joseph and Scalea (8) reviewed the impact of aging on the response to injury. Numerous physiological changes are present in older adults, in addition to the accumulation of comorbid conditions such as diabetes, pulmonary disease, and other significant medical conditions. They discuss the concept of frailty, a multidimensional syndrome with depleted physiologic reserves and diminished capacity to respond to stress. Immunosenescence as an element of the decreased response to insults is presented along with the term inflammaging—the decline of inflammation with age. This is an excellent overview of the topic.

Endotoxin derived from gram-negative bacteria has been implicated as a driver of sepsis, although it is recognized that it is not the sole cause of sepsis. Regardless, the presence of substantial amounts of endotoxin in the blood probably does not provide any benefit to the host. Lipcsey et al. (9) studied the impact of an endotoxin removal device in patients with sepsis in a phase IIa clinical trial. Only 15 patients were enrolled and the study needed to be terminated due to low recruitment. The amount of endotoxin present was very low, and the endotoxin removal device did not significant reduce these low levels, or alter any markers of inflammation. The authors (and the journal Shock) are to be commended for publishing these negative data.

Previous studies have shown that there is an association between an individual's blood type and outcomes from traumatic injury. Specifically, the association was with patients who have type O blood. The potential association between blood type and outcome after traumatic injury was studied in a paper by Griffin et al. (10) in a study with nearly 4,000 trauma patients from the University of Alabama Birmingham. There was no difference between the different blood types and all-cause mortality. This was a well-done study, but since it conflicts with other papers the issue still warrants additional investigation.

Complement plays an important role in the innate immune response to injury and infection. Cheng et al. (11) studied whether low levels of C3 alpha predicted mortality in patients with septic shock. Many previous reports measured various components of complement using an ELISA, which may not distinguish between the different complement fragments. This group used the more laborious but specific Western blot technique to measure the alpha chain of C3. They demonstrated that patients with low levels of C3 alpha have significantly lower survival. These data suggest that in the non-survivor, there is either excess consumption of C3 or failure of replacement.

The role of complement in activating the coagulation system was also examined in the article by Abe et al. (12). This group measured different components of the complement system, specifically the soluble components of the membrane attack complex, C5b-C9 (SC5a9) as well as C3 levels. The major goal of this paper was to determine the relationship between complement activation and the development of disseminated intravascular coagulation (DIC). This paper did not specify the technique used to measure C3, but did use an Enzyme Immunoassay (EIA, another name for an ELISA) to measure the SC5b9 levels. Patients with DIC did have lower levels of C3 and higher levels of SC5b9, indicating that the complement system was activated. Both studies show that excessive activation of the complement system is associated with adverse outcomes.

Both of these papers set the stage for the review of burn-induced coagulopathies (BIC) by Ball et al. (13). This extensive review covers the interactions between coagulation, fibrinolysis, and inflammation, including complement activation. The review starts with a history of BIC including the tests used to document the presence of BIC. The article carefully dissects the coagulation pathways including identifying both the pro-coagulant and anticoagulant components.

Patients with traumatic injuries are at risk for developing hypovolemic shock. The potential use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) was evaluated in a clinical study of 74 patients in a study by McGreevy et al. (14). The report was an international multicenter study and included 25 institutions from 13 countries. During this time of the COVID-19 pandemic, it is very reassuring to see healthcare personnel working together. Insertion and inflation of the balloon raised systolic blood pressure to 90 mm Hg. Thirty-seven percent of the patients who had REBOA survived.

The concept of impaired cerebral autoregulation of cardiovascular responses in trauma patients was explored in the paper by Caldas et al. (15). This study included 25 patients with shock and 28 healthy matched controls and an autoregulatory index (ARI) was calculated for each subject. A reduced ARI was considered evidence of impaired cerebral autoregulation. Compared to the healthy controls, the shock patients had a lower ARI. Additionally, the decreased ARI correlated with greater evidence of organ injury.

Animal models have been used to study human disease, although it must be acknowledged that the results from these studies have not always translated into effective human therapies. An interesting commentary by Dobson et al. (16) raises concerns about using pathogen-free animals. The gut microbiome plays an important role in developing the immune response to several challenges. Specific pathogen-free animals probably do not have a gut microbiome that replicates the heterogeneity of humans, creating difficulties when attempting to translate rodent studies to humans.

REFERENCES

1. Leonard A, Su PY, Yule DI, Rahman A, Fazal F. Critical role of mortalin/GRP75 in endothelial cell dysfunction associated with acute lung injury. Shock 54:245–255, 2020.
2. Pang D, Wu YL, Alcamo AM, Cummings J, Di Caro V, Walko T III, Hsue V, Clark RSB, Panigrahy A, Kochanek PM, et al. Early axonal injury and delayed cytotoxic cerebral edema are associated with microglial activation in a mouse model of sepsis. Shock 54:256–264, 2020.
3. Kondo Y, Sueyoshi K, Zhang J, Bao Y, Li X, Fakhari M, Slubowski CJ, Bahrami S, Ledderose C, Junger WG. Adenosine 5’-monophosphate protects from hypoxia by lowering mitochondrial metabolism and oxygen demand. Shock 54:237–244, 2020.
4. Abraham MN, Kelly AP, Brandwein AB, Fernandes TD, Leisman DE, Taylor MD, Brewer MR, Capone CA, Deutschman CS. Use of organ dysfunction as a primary outcome variable following cecal ligation and puncture: recommendations for future studies. Shock 54:168–182, 2020.
5. Eftekhari G, Shojaei A, Raoufy MR, Azizi H, Semnanian S, Mani AR. Neonatal sepsis alters the excitability of regular spiking cells in the nucleus of the solitary tract in rats. Shock 54:265–271, 2020.
6. Peetermans M, Wan RYY, Camporota L, Barrett NA, Retter A. Use of intravenous immunoglobulins in patients with suspected toxin-mediated shock requiring extracorporeal membrane oxygenation. Shock 54:209–212, 2020.
7. Cleek WR, Johnson NJ, Watsjold BK, Hall MK, Henning DJ. Comparing mortality prediction by quick sequential organ failure assessment with emergency physician judgment. Shock 54:213–217, 2020.
8. Joseph B, Scalea T. The consequences of aging on the response to injury and critical illness. Shock 54:144–153, 2020.
9. Lipcsey M, Tenhunen J, Pischke SE, Kuitunen A, Flaatten H, De Geer L, Sjölin J, Frithiof R, Chew MS, Bendel S, et al. Endotoxin removal in septic shock with the ALTECO LPS adsorber was safe but showed no benefit compared to placebo in the double-blind randomized controlled trial—the asset study. Shock 54:224–231, 2020.
10. Griffin RL, Jansen JO, Bosarge PL, Marques MB, Kerby JD. The association between ABO blood type and mortality among severely injured trauma patients. Shock 54:205–208, 2020.
11. Cheng TH, Puskarich M, Li X, Fang Z, Xu F, Chen Y, Jiang X-C, Worah S, Jones AE, Zhang M. Circulating complement C3-alpha chain levels predict survival of septic shock patients. Shock 54:190–197, 2020.
12. Abe T, Kubo K, Izumoto S, Shimazu S, Goan A, Tanaka T, Koroki T, Saito K, Kawana R, Ochiai H. Complement activation in human sepsis is related to sepsis-induced disseminated intravascular coagulation. Shock 54:198–204, 2020.
13. Ball RL, Keyloun JW, Brummel-Ziedins K, Orfeo T, Palmieri TL, Johnson LS, Moffatt LT, Pusateri AE, Shupp JW. Burn-induced coagulopathies: a comprehensive review. Shock 54:154–167, 2020.
14. McGreevy DT, Abu-Zidan FM, Sadeghi M, Pirouzram A, Toivola A, Skoog P, Idoguchi K, Kon Y, Ishida T, Matsumura Y, et al. Feasibility and clinical outcome of REBOA in patients with impending traumatic cardiac arrest. Shock 54:218–223, 2020.
15. Caldas JR, Passos RH, Ramos JGR, Ramalho C, Sancho LS, Salinet AM, Farias S, Gobatto A, Bombonato G, Benigno P, et al. Dynamic autoregulation is impaired in circulatory shock. Shock 54:183–189, 2020.
16. Dobson GP, Morris JL, Biros E, Letson HL. Specific pathogen-free animals for civilian and military trauma: a cautionary note in the translation of new drug therapies. Shock 54:232–236, 2020.
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