Welcome to the August 2018 issue of Shock. One of the notable attributes of Shock is its combination of both clinical and basic papers addressing important responses in shock, sepsis, ischemia, and inflammation. This month offers a particularly strong interplay between clinical and basic studies, especially as related to cardiovascular system effects. The issues starts with an excellent review article by Geven et al. (1) addressing the effects of adrenomedullin on the vasculature. Adrenomedullin is a small peptide with vasodilator and endothelial-protective properties, but due to its dilator properties can exacerbate hypotension at too high a dose. This review summarizes the biology of adrenomedullin, but more importantly addresses a novel therapeutic strategy. Neutralizing antibodies have long been used to eliminate harmful proteins and peptides, but this group describes the use of a non-neutralizing antibody to stabilize plasma levels of adrenomedullin to enhance its biological effect without the risk of overdose. This information is not only of potential value related to adrenomedullin, but may be an effective strategy for enhancing the beneficial effect of other small peptides.
Excessive vasodilation can also be a problem following cardiopulmonary bypass. Lu et al. (2) provide a clinical report on the use of vasopressin as therapy for intractable vasodilation following cardiac surgery in pediatric patients to correct left or right heart anomalies. Seventy consecutive patients were infused with low dose vasopressin and hemodynamic parameters, lactate levels, and urine production monitored. Vasopressin infusion (0.0002 u/kg/min–0.002 u/kg/min) effectively increased blood pressure and total peripheral resistance. More importantly it decreased plasma lactate and increased urine production indicating improved tissue perfusion. The authors conclude that vasopressin at these doses is a safe and effective treatment for hypotension in this patient population.
Another clinical paper this month addresses cardiac function associated with heart failure and mechanical cardiac support. Lim and Howell (3) compared blood gas parameters in patients on mechanical cardiac support with acute myocardial infarction with those suffering from end-stage heart failure (ESHF). Their results showed that even with comparable degrees of heart failure, the ESHF patients had a distinct phenotype characterized by a different set of circulatory and metabolic changes. While it is uncertain whether the mechanism of the difference is related to the acute versus chronic nature of the failure, the authors point out that this information may help guide management based on underlying etiology of the heart failure.
Two basic science papers also address cardiac response. Ischemia/reperfusion (I/R) injury is common in cardiac surgery and coronary artery disease. Ischemic preconditioning is known to attenuate I/R injury but has practical limitations. More recently, pharmacologic approaches to pre and postconditioning have offered promise of effective and practical approaches. Chen et al. (4) previously showed effectiveness of remifentanil postconditioning and in this paper examine the possible role of histone deacetylase 3 (HDAC3) on the mechanisms. Using hypoxia/reoxygenation in cardiomyoblasts, they tested whether inhibition of HDAC3 phosphorylation of glycogen synthase-3β might contribute to suppression of apoptosis during reoxygenation. Their finding that this is the case suggests that manipulation of HDAC3 activity in I/R may be a promising therapeutic approach for the prevention of apoptotic injury. In the second basic paper, Ohno et al. (5) examined the potential role of cochaperone cytoplasmic constitutive active/androstane receptor retention protein (CCRP), a member of the HSP40 family of heat shock proteins on the damaging effect of endotoxin (LPS) in mice and a cardiac cells line. CCRP knock-out mice showed more severe contractile impairment following LPS treatment compared with wild type. In cultured cells, CCRP overexpression prevented nuclear factor κB p65 subunit from accumulating in the nucleus. These results suggest that CCRP may exert protective effects via inhibition of nuclear factor κB signaling.
Establishment of a valid experimental model is essential to investigate mechanisms and therapies for shock states. The cardiac theme continues with the paper by Ettl et al. (6). Cardiac arrest results in neurologic impairment that is dependent upon the duration of ischemia resulting from arrest. These investigators report a rat model in which cardiac arrest was induced by fibrillation followed by resuscitation after up to 8 min of arrest. They then provide a detailed characterization of blood metabolic parameters as well as cognitive function and brain histology. This well-characterized model should provide a baseline for future investigations into potential therapies for neurologic impairment after cardiac arrest. In this as well as other animal models of severe injury especially when “survival” studies are needed, the use of humane endpoints is essential. The development of profound hypothermia is commonly regarded as a valid indicator of impending death; however, accurate noninvasive measurement of relevant temperature is difficult. Laitano et al. (7) report the use of an inexpensive infrared surface temperature measurement of the xyphoid to monitor body temperature in a mouse model of sepsis induced by intraperitoneal injection of a fecal slurry. Their results showed excellent predictive value (within 4% of actual) of this surface temperature measurement. The low expense and ease of use will likely make this technique standard procedure for survival studies in sepsis and likely other pathologies.
It is becoming increasingly recognized that mitochondrial function occupies a central role in determining cellular survival and functional integrity in many disease states. Rontoyanni et al. (8) examined the changes in mitochondrial respiratory capacity in permeabilized myotubes taken from burned children and correlated these findings with glucose kinetics and cardiorespiratory fitness. Increasing burn size correlated with increasing ATP-coupled respiration while the presence of sepsis decreased coupled respiration. Overall, hepatic glucose release and VO2max correlated with mitochondrial respiration indicating the importance of mitochondrial function. Interestingly, male and female patients showed significantly different mitochondrial responses compared with each other. These results suggest that further investigation of the role of gender in the mechanisms for mitochondrial function changes is warranted. Related to this report is an animal model study by Park et al. (9), examining mechanisms of mitochondrial quality control in sepsis. Mitochondria are highly dynamic organelles constantly turning over via mitochondrial biogenesis and mitophagy. This group examined the potential effect of heme oxygenase-1 (HO-1) on these mitochondrial dynamics. They found that induction of HO-1 by hemin increases mitogenesis and mitophagy as well as increased toll like receptor 4 expression. Moreover, a toll like receptor 4 antagonist mimicked the effect of hemin. The results suggest that part of the protective effect of HO-1 may be mediated through improved mitochondrial quality control.
The liver serves as a central regulator of metabolism which is impaired in sepsis. Two key functions of the liver are lactate clearance and bile production. Miyamoto et al. (10) performed a multicenter clinical trial to evaluate the efficacy of the α2 adrenergic agonist dexmetomidine (DEX) on lactate clearance in sedated, mechanically ventilated septic patients. DEX administration decreased plasma lactate and increased lactate clearance at 6 h while 28-day survival was unchanged. This suggests that sedation with DEX may have the added benefit of improved lactate clearance without significant deleterious effects. Another common sequela of sepsis is cholestasis. Jenniskens et al. (11) used a mouse model of sepsis and nutrient restriction to explore molecular pathways leading to the appearance of elevated markers of cholestasis in the blood during sepsis. Sepsis resulted in persistent elevation of bile acids as well as impairments of transporters, cytochrome P450 synthesis systems, and nuclear receptors. Nutrient restriction partly mimicked the effect on circulating bile acid and transporters but had no effect on synthesis systems or nuclear receptors, indicating the effect of sepsis is not solely the result of nutrient restriction.
Both the adaptive and innate immune systems are critical for the response to sepsis. Klingensmith et al. (12) investigated the effect of Honokiol, an extract from the bark of the magnolia tree on CD4+ T cells and tumor necrosis factor α (TNFα) as representatives of the innate immune response and systemic inflammation. Honokiol increased CD4+ cells and decreased TNFα while not affecting function of major organs. In spite of the apparent beneficial effect on the immune system, there was no benefit to 7-day survival. Thus while honokiol may provide some benefit, alone it is not sufficient to affect survival. Macrophages also occupy a central role in modulating the response to sepsis. Lachmann et al. (13) performed a retrospective study of the incidence of adult hemophagocytic lymphohistocytosis (aHLH) from 244 intensive care unit (ICU) patients. aHLH is a rare syndrome caused by excessive activation of macrophages and CD8+ cells. They found nine patients in this cohort with aHLH of whom seven (77%) were undiagnosed and 44% died. Thus, aHLH appears to be a potentially serious, but usually undiagnosed syndrome in ICU patients. In an animal model study of macrophage contribution to injury, Xing et al. (14) studied the role of M2 macrophages in kidney injury in a rat cecal ligation and puncture model. M2 macrophages can exert anti-inflammatory effects and may limit injury. They found that M2 phenotype macrophages infiltrated into the kidney following induction of sepsis. In addition, deletion of M2 macrophages with clodronate in liposomes decreased IL-10 and increased TNFα expression and exacerbated kidney injury. These results indicate that M2 macrophages are important for limitation of kidney injury in sepsis by virtue of their anti-inflammatory effects. In keeping with the importance of acute kidney injury in critical illness, Custodio de Carvalho et al. (15) performed an external validation of a recently reported prognostic model for patients receiving renal replacement therapy in a broader selection of patients. Although the validity of the model was somewhat limited in patients with unknown serum creatinine at admission, they found that the model could be useful for prediction of mortality even with a broad and unselected cohort.
The final paper in this month's issue addresses the potential role of caveolin-1 in lung injury in sepsis (16). Caveolin-1 is a major component of caveolae which are plasma membrane invaginations implicated in cell transport in many cells as well as in regulation of endothelial nitric oxide synthase activity in vascular endothelial cells. Their results showed a downregulation of caveolin-1 which in the lung may help serve to limit the entry of pathogens into cells during sepsis. The overall roles of caveolin-1 in inflammation remain complex and warrant further investigation.
1. Geven C, Bergmann A, Kox M, Pickkers P. Vascular effects of adrenomedullin and the anti-adrenomedullin antibody adrecizumab in sepsis. Shock
50: 132–140, 2018.
2. Lu Z, Wang X, Yang J, Li S, Yan J. Vasopressin in vasodilatory shock for both left and right heart anomalous pediatric patients after cardiac surgery. Shock
50: 173–177, 2018.
3. Lim HS, Howell N. Cardiogenic shock due to end-stage heart failure and acute myocardial infarction: characteristics and outcome of temporary mechanical circulatory support. Shock
50: 167–172, 2018.
4. Chen M, Liu Q, Chen L, Zhang L, Cheng X, Gu E. HDAC3 mediates cardioprotection of Remifentanil postconditioning by targeting GSK-3β in H9c2 cardiomyocytes in hypoxia/reoxygenation injury. Shock
50: 240–247, 2018.
5. Ohno M, Moore R, Myers P, Negishi M. Co-chaperone-mediated suppression of LPS-induced cardiac toxicity through NF-κB signaling. Shock
50: 248–254, 2018.
6. Ettl F, Magnet IAM, Weihs W, Warenits A-M, Grassmann D, Wagner M, Teubenbacher U, Högler S, Sterz F, Janata A. Establishing a rodent model of ventricular fibrillation cardiac arrest with graded histologic and neurologic damage with different cardiac arrest durations. Shock
50: 219–225, 2018.
7. Laitano O, Van Steenbergen D, Mattingly AJ, Garcia CK, Robinson GP, Murray KO, Clanton TL, Nunamaker EA. Xiphoid surface temperature predicts mortality in a murine model of septic shock. Shock
50: 226–232, 2018.
8. Rontoyanni VG, Malagaris I, Herndon DN, Rivas E, Capek KD, Delgadillo AD, Bhattarai N, Elizondo A, Voigt CD, Finnerty CC, et al. Skeletal muscle mitochondrial function is determined by burn severity, sex, and sepsis, and is associated with glucose metabolism and functional capacity in burned children. Shock
50: 141–148, 2018.
9. Park J-S, Choi H-S, Yim S-Y, Lee S-M. Heme oxygenase-1 protects the liver from septic injury by modulating TLR4-mediated mitochondrial quality control in mice. Shock
50: 209–218, 2018.
10. Miyamoto K, Nakashima T, Shima N, Kato S, Ueda K, Kawazoe Y, Ohta Y, Morimoto T, Yamamura H. on behalf of DESIRE Trial Investigators. Effect of dexmedetomidine on lactate clearance in patients with septic shock: a subanalysis of a multicenter randomized controlled trial. Shock
50: 162–166, 2018.
11. Jenniskens M, Güiza F, Oorts M, Perre SV, Derde S, Dufour T, Thiessen S, Annaert P, Van den Berghe G, Langouche L. On the role of illness duration and nutrient restriction in cholestatic alterations that occur during critical illness. Shock
50: 187–198, 2018.
12. Klingensmith NJ, Chen C-W, Liang Z, Burd EM, Farris AB, Arbiser JL, Ford ML, Coopersmith CM. Honokiol increases CD4+
T cell activation and decreases TNF but fails to improve survival following sepsis. Shock
50: 178–186, 2018.
13. Lachmann G, Spies C, Schenk T, Brunkhorst FM, Balzer F, La Rosée P. Hemophagocytic lymphohistiocytosis: potentially underdiagnosed in intensive care units. Shock
50: 149–155, 2018.
14. Li X, Mu G, Song C, Zhou L, He L, Jin Q, Lu Z. Role of M2 macrophages in sepsis-induced acute kidney injury. Shock
50: 233–239, 2018.
15. Custodio de Carvalho GM, Leite TT, Libório AB. Prediction of 60-day case fatality in critically ill patients receiving renal replacement therapy: External validation of a prediction model. Shock
50: 156–161, 2018.
16. Kataki A, Karagiannidis I, Memos N, Koniaris E, Antonakis P, Papalois A, Zografos GC, Konstadoulakis MM. Host's endogenous caveolin-1 expression is downregulated in the lung during sepsis to promote cytoprotection. Shock
50: 199–208, 2018.