As L.M. Montgomery puts it in her classic children's novel Anne of Green Gables – “I’m so glad I live in a world where there are Octobers.” And so should the readers of SHOCK be. The October issue of SHOCK brings exciting new insights into the pathophysiology of sepsis, trauma, resuscitation, and hemorrhagic shock. This issue covers basic, translational, and clinical research and in addition includes two important invited reviews on intensely debated topics.

As basic research goes, this issue is flourishing with thought-provoking manuscripts. First, Isabelle Sobbe and co-workers (1) approach the pathophysiology of hemolytic-uremic syndrome triggered by Shiga-toxin-(Stx)-producing Escherichia coli infection using a Stx-treated mice model and asking whether the immune response of the infected organism triggered by Stx can affect the kidneys and contributes to acute kidney injury. The authors looked at the kidneys’ protein and gene expression in mice challenged with Stx and detected an enhanced translocation of NF-kB1 and RelA, as well as NF-kB2 and RelB into the nucleus accompanied by an increased gene expression of the NF-kB1-target cytokines CCL20, CXCL2, CCL2, CXCL1, IL-6, TNF-a, CXCL10, and CCL5, indicating an activation of the classical and non-canonical NF-kB Pathways. These results provide reliable in vivo evidence for an involvement of both NF-kB signaling pathways in renal pathophysiology of hemolytic-uremic syndrome triggered by Stx-producing Escherichia coli infection.

Another provocative manuscript comes from Yini Sun and colleagues (2). These authors based their hypothesis on the now well-established concept that sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction and that genetic deletion of myosin light chain kinase (MLCK) reverses intestinal hyperpermeability and improves survival in murine models of sepsis. They, therefore, asked if this concept could be translated into a therapeutic strategy and investigated if pharmacologic inhibition of MLCK using the membrane permeant inhibitor of MLCK would improve gut barrier function and survival following sepsis. The authors treated mice subjected to cecal ligation and puncture with the MLCK inhibitor PIK, and observed that PIK administration was not associated with significant differences in bacterial burden, cytokines, or intestinal integrity. However, PIK administration was associated with increased mortality and increased intestinal permeability in the leak pathway, suggesting that caution is required in targeting the gut barrier as a potential therapy in sepsis.

Still in the sepsis topic, Jean-Baptiste Gibier and his colleagues (3) bring us a mechanism-driven manuscript where they investigate if MUC1, a membrane-bound mucin expressed in both epithelial tubular cells and renal macrophages that regulates TLR4 expression, could mitigate the renal inflammatory response induced by TLR4 activation in a murine model of endotoxin-induced acute kidney injury (AKI). To test this hypothesis, the authors intraperitoneally injected LPS in Muc1−/− mice and observed a more severe renal dysfunction, an increased activation of the tissular NF-kB pathway and increased secretion of pro-inflammatory cytokines compared to Muc1+/+ mice. They went on to show that MUC1 is only induced in M1 type macrophages and that macrophages derived from Muc1−/− mice secreted more pro-inflammatory cytokines. They also showed, using HEK293 cells and proximity ligation assay, that MUC1 cytosolic domain seems necessary for the negative regulation of TLR4. The conclusion of this interesting manuscript is that in the context of endotoxin-induced AKI, MUC1 plays a significant role in controlling disease severity by regulating negatively the TLR4-MD2 axis.

Moving on in the basic research articles, Tang et al. (4) investigate the consequences of long-term dobutamine used on sepsis-induced cardiomyopathy. Here again the classic cecal ligation and puncture sepsis model was used to induce sepsis in rats. The authors report that myocardial depression occurs earlier than hepatic and renal dysfunction in sepsis and serum cTnI, NT-proBNP, and H-FABP are not suitable as early biomarkers for sepsis-induced myocardial dysfunction. As for the effect of dobutamine administration for 2, 6 h after cecal ligation and puncture, the authors observed that dobutamine treatment in the presence of myocardial dysfunction improves survival in septic rats; however, it neither improves myocardial function and hemodynamics nor attenuates myocardial injury at the later stages of sepsis.

Inflammation and oxidative stress are not only involved in sepsis, but also have a major role in heat stroke, a condition with mortality rates that remains above 60% despite prompt diagnosis and interventions. Vascular endothelial glycocalyx shedding is a consequence of the inflammatory response and excessive oxidative stress and is implicated in heat stroke mortality. In this issue, Truong and co-workers (5) investigated if the inhalation of hydrogen, a gas with antioxidation and anti-inflammatory potency, would impact on the survival and thickness of the vascular endothelial glycocalyx of rats subjected to heat stroke. Mechanically ventilated rats were sedated and placed on a heat-controlled chamber to induce heat stroke. Hydrogen at 2% or 4% was administered during the stabilization period after heat stroke and maintained throughout the experiment. In their manuscript, the authors report that 2% (4% was less effective) hydrogen gas significantly improved survival and partially preserved the thickness of the endothelial glycocalyx. In addition, serum levels of endotoxin, syndecan-1, malondialdehyde, and TNF-α decreased, whereas superoxide dismutase levels increased, indicating that inhalation of 2% hydrogen attenuated the damage to the vascular endothelial glycocalyx through its antioxidative and anti-inflammatory effects.

Hemorrhagic shock is one of the main causes of death in patients with severe trauma and the decreased vascular reactivity to vasoactive agent plays a key role in severe hemorrhagic shock-induced refractory hypotension. In an interesting manuscript in this issue of SHOCK, Yue and colleagues (6) investigate if 17b-estradiol (E2) can restore vascular hyporeactivity induced by hemorrhagic shock, and whether E2 effects are associated with RhoA-Rho kinase (ROCK)-myosin light chain kinase phosphatase pathway. They established a hemorrhagic shock model in ovary intact sham operated, ovariectomized (OVX), and OVX plus E2 supplemented female mice and showed that hemorrhagic shock significantly reduced norepinephrine microvascular reactivity which was exacerbated by OVX and reversed by E2 supplement. While investigating the involvement of RhoA-ROCK pathway, these authors showed that U-46619 (RhoA agonist) increased microvascular reactivity and Y-27632 (ROCK inhibitor) inhibited sham mice microvascular reactivity. Yue and co-workers than conclude that estrogen improves microvascular reactivity during hemorrhagic shock, and that RhoA-ROCK signaling pathway seems to mediate E2 effects and go on suggesting that their findings may implicate a new strategy using estrogen for prevention and treatment of organ injury induced by severe hemorrhagic shock.

Resuscitation is the subject of yet another insightful manuscript by Jia and colleagues (7) in this issue of SHOCK. In this case, the authors draw their attention to resuscitation after cardiac arrest and the potential benefits of levosimendan, a non-adrenergic inotropic calcium sensitizer and a non-selective adenosine triphosphate-sensitive potassium channel agonist, for dynamic changes in intestine and systemic hemodynamics post-resuscitation. Using a rat model of ventricular fibrillation induced cardiac arrest and cardiopulmonary resuscitation, these authors showed that myocardial injury and global and intestinal perfusion/metabolism were significantly improved by levosimendan treatment. Moreover, the effect on intestinal microcirculation dysfunction was at least partly independent of its effects on systemic circulation. Although preliminary, this study brings important new information regarding levosimendan mechanism of action and potential effects in post-cardiac arrest syndrome.

In this issue of SHOCK, a spotlight is also casted on translational research and Lopez and collaborators (8) ask if low pressure (hypobaria) and hypoxia caused by aeromedical evacuation of traumatically injured patients could impact on the inflammatory response, organ injury, and mortality using a mouse model of polytrauma. The mice were subjected to bowel ischemia by superior mesenteric artery occlusion, hindlimb muscle crush, and tibia fracture and 2 h after injury they underwent 6 h of hypobaria or sea-level room air conditions. Interestingly, Hypobaric exposure after polytrauma led to decreased ejection fraction and increased plasma hyaluronic acid, thrombomodulin, and syndecan-1 levels indicating that hypobaria exposure worsens cardiac dysfunction and endothelial injury following polytrauma and thus may represent a physiological “second hit” following traumatic injury. This observation deserves to be confirmed in the clinical scenario and may lead to the development of new protocol for aeromedical evacuation of traumatically injured patients.

Another translational approach is reported in this issue by Sadeghi and colleagues (9). Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been shown to be potentially lifesaving in exsanguinating torso hemorrhage, but ischemia distal to the occlusion and subsequent ischemia-reperfusion injury are serious complications. Partial REBOA, that is, a permissive distal flow, has been proposed to reduce the negative consequences of aortic occlusion and ischemia-reperfusion injury. In this manuscript, the authors try to estimate the ischemic consequences when using partial REBOA by investigating if end-tidal carbon dioxide (ETCO2) is correlated to degree of aortic occlusion, measured as distal aortic blood flow, and distal organ metabolism, estimated as systemic oxygen consumption (VO2), in a porcine model of normovolemia and hemorrhagic shock. They observed that ETCO2 was correlated to distal aortic blood flow and VO2 during incremental degrees of aortic occlusion thereby potentially reflecting the degree of aortic occlusion and the ischemic consequences of partial REBOA. Therefore, ETCO2 may be a useful marker of the degree of aortic occlusion and the ischemic consequences of partial REBOA.

REBOA has attracted a lot of attention in this issue of SHOCK and is the topic of one of our invited reviews this month. Ronaldi and collaborators (10) provide, in their review, a synopsis of the concept of targeted regional optimization (TRO), a partial REBOA strategy to augment proximal aortic and cerebral blood flow while targeting minimal threshold of distal perfusion beyond the zone of partial aortic occlusion. The authors included pre-clinical and translational experiences with TRO and early clinical outcomes in their careful review of the available literature. They concluded that the early results from TRO strategies are promising, but also cautioned that further studies are needed prior to large-scale use in clinical practice.

Systemic inflammation is an important basic feature of many critical conditions, and its early diagnosis and treatment can reduce the risk of organ failure and mortality. Heart rate variability (HRV) has potential for early identification of the onset of systemic inflammation. Koeneman and collaborators (11) conducted well-designed experiments to investigate the onset and kinetics of HRV changes as well as several inflammatory parameters and symptoms during experimental human endotoxemia, a model of systemic inflammation in humans. HRV was determined using a wireless wearable device, and parameters low to high frequency (LF:HF) ratio, root mean square of the successive differences, and standard deviation of normal-to-normal R–R intervals (SDNN) were calculated. Using this controlled human model of systemic inflammation, the authors were able to show that elevations in the LF:HF ratio followed very shortly after elevations in plasma cytokine levels and preceded onset of flu-like symptoms and alterations in vital signs. They propose that HRV may represent a rapid and easy to use diagnostic tool for early detection of developing inflammatory conditions.

The topics discussed in our basic research manuscript this month are pretty much matched by the clinical studies reported in this issue of SHOCK. We start discussing sepsis in a preplanned subanalysis of the sepsis cohort in a prospective, multicenter Focused Outcomes Research on Emergency Care for Acute respiratory distress syndrome, Sepsis, and Trauma study. In this study Fujishima and co-workers (12) of the JAAM Focused Outcomes Research on Emergency Care for Acute respiratory distress syndrome, Sepsis, and Trauma Group evaluated the incidence and risks of dysglycemia under current strategy of glycemic control in septic patients. A total of 1,140 patients with severe sepsis, including 259 patients with pre-existing diabetes, were analyzed. In non-diabetic patients, late hyperglycemia and early hypoglycemic episodes were positively associated with in-hospital mortality. Further subgroup analysis suggested that late hyperglycemia and early hypoglycemic episodes independently, and probably synergistically, affect the outcomes. However, these same correlations were not observed in diabetic patients, indicating that moderate glycemic control practice performed in standard ICUs resulted in a high incidence of dysglycemia that could affect outcomes, leaving room for improvements in this practice. Furthermore, the history of pre-existing diabetes seems to be an important indicator for clinicians to personalize glycemic control in sepsis minimizing the deleterious consequences of dysglycemia.

Sepsis is yet the topic of another two clinical research studies in this issue. First, Yoo and collaborators (13) asked if the plasma levels of the apoptosis regulator Fas ligand (FasL) are associated with the mortality of sepsis and necroptosis. They prospectively enrolled 188 critically ill adult patients that were diagnosed with sepsis (30.9%) and septic shock (44.7%). They measured plasma levels of FasL and receptor interacting protein kinase-3, an essential necroptosis mediator, to correlate with severity and mortality. The authors reported a significant difference in mortality between high and low FasL patients up to 90 days. Also, plasma level of FasL was associated with severity of sepsis and was predictive of mortality. However, it was not correlated with receptor interacting protein kinase-3 level. This study indicates that plasma level of FasL has potential as a biomarker for severity assessment and mortality prediction in critically ill patients with sepsis. FasL could become an interesting tool in predicting sepsis outcomes in the clinical scenario. Second, Lee and collaborators (14) questioned the beneficial effects on survival of Polymyxin B hemoperfusion (PMX-HP) in septic patients with continuous renal replacement therapy (CRRT). They studied 231 patients with sepsis undergoing CRRT alone or PMX-HP with CRRT and looked primarily to 28-day and 90-day all-cause mortality. The authors report that after propensity score matching the additional use of PMX-HP does not improve the clinical outcomes of patients with sepsis and acute kidney injury requiring CRRT. Future large-scale randomized controlled trials are warranted to investigate whether the very early simultaneous use of PMX-HP and CRRT is helpful to reduce the mortality rate in septic patients.

Trauma is a major cause of death and disability throughout the world and could not be left aside on our clinical research manuscripts this month. Based on encouraging results from pre-clinical studies Lal Gupta and co-workers (15) hypothesized that early administration of estrogen in male trauma hemorrhagic shock patients may reduce the inflammatory storm, prevent sepsis-associated problems, and subsequently reduce mortality. In this pilot study with 40 patients, the authors studied the safety of early administration of estrogen as a therapeutic adjunct in the emergency department and its effects on the inflammatory storm, prevention of sepsis, and mortality during the intensive care unit stay. Their results showed that patients did not develop any major or minor adverse events and showed favorable clinical outcomes in the estrogen group. Also, these estrogen-treated patients showed levels of T regulatory cells, monocytes, and systemic cytokines significantly reduced and showed a balanced inflammatory response. The exciting conclusion of this pilot study was that intravenous estrogen therapy is safe and reduced the inflammatory insult due to trauma hemorrhagic shock.

The use of vasopressors is always a matter of interest and debate in intensive care medicine. In their manuscript in this issue of SHOCK, Burstein and colleagues (16) describe the association between norepinephrine and mortality in cardiac ICU patients with severe shock. Burstein and his colleagues retrospectively evaluated Mayo Clinic cardiac ICU patients treated with vasopressors from 2007 to 2015 and included 2,090 patients in their analysis. Hospital mortality was higher among patients receiving high-dose vasopressors (HDV). On multivariable analysis in HDV patients, hospital mortality increased with rising peak norepinephrine equivalent dose (used to compare vasopressor doses) and the use of norepinephrine was associated with lower hospital mortality. After adjustment for illness severity, peak norepinephrine equivalent dose and norepinephrine use were not associated with mortality among patients who did not require HDV. These results allowed the authors to conclude that the mortality is high among cardiac ICU patients requiring HDV, and rises with increasing vasopressor requirements, but the use of NE was associated with lower mortality among patients requiring HDV implying that patients with more severe shock may benefit from preferential use of NE.

Trauma and resuscitation are also topics of the manuscript by Chow and co-workers (17). In this case, the authors were interested in predicting the need for massive transfusion and aimed at developing a pre-hospital and admission Algorithm to Examine the Risk of massive Transfusion (ALERT) scores that could accurately predict massive transfusion using available pre-hospital and admission data. The ALERT scores were constructed with logistic regression of pre-hospital and admission vitals, and focused assessment with sonography for trauma examination results. The authors included 2,592 patients in their cohort. Systolic blood pressure (SBP), diastolic blood pressure, heart rate, respiratory rate, SpO2, motor Glasgow Coma Scale score, and penetrating mechanism were the variables included in the pre-hospital ALERT score. Eight variables from 2,307 patients were included in the admission ALERT score: admission SBP, heart rate, respiratory rate, Glasgow Coma Scale score, temperature, focused assessment with sonography for trauma examination result, and pre-hospital SBP and diastolic blood pressure. The pre-hospital ALERT score had equivalent diagnostic accuracy to the Assessment of Blood Consumption score, a score already validated at multiple trauma centers, and the admission ALERT score outperformed both the Assessment of Blood Consumption and the pre-hospital ALERT scores. The authors conclude that the pre-hospital and admission ALERT scores can accurately predict massive transfusion in trauma patients without the use of time-consuming laboratory studies. However, the authors cautioned that due to the retrospective design of their present study, prospective studies are needed to validate these findings.

Many past studies have shown nonlinear relationships between systolic blood pressure, and outcomes, but the relationships between cumulative times at different SBP levels and outcomes in critically ill patients remain unclear. In this issue of SHOCK, Hu and colleagues (18) hypothesized that an appropriate SBP level is associated with a decrease in adverse outcomes after ICU admission. They performed a retrospective analysis of data from the Medical Information Mart for Intensive Care (MIMIC) III database, which includes more than 1,000,000 SBP records from 12,820 patients and correlate SBP levels to in-hospital, 1-, 3-, and 12-months mortality. Their robust analysis showed that SBP at 120 mm Hg to 140 mm Hg was associated with decreased adverse outcomes. It is concluded that all amounts of time at an SBP level between 120 mm Hg and 140 mm Hg in patients after early ICU admission were associated with decreased mortality. What we need to know next is whether interventions to maintain an SBP level of 120 mm Hg to 140 mm Hg decrease the risk of mortality in critically ill patients.

A major concern in ICUs everywhere in the world, sepsis-associated acute kidney injury (SA-AKI) is a common problem in critically ill patients and is associated with high morbidity and mortality. We desperately need a reliable prediction model for early prediction of mortality in hospitalized patients with SA-AKI. Hu and co-workers (19) approach this problem with a retrospective cohort analysis based on a training cohort of 2,066 patients enrolled from the Multiparameter Intelligent Monitoring in Intensive Care Database III (MIMIC III) and a validation cohort of 102 patients treated at Nanfang Hospital of Southern Medical University. Age, admission type, liver disease, metastatic cancer, lactate, BUN/SCr, admission creatinine, positive culture, and AKI stage were independently associated with survival and therefore combined in the SAKI model. The AUC in the training cohort was 0.77, 0.72, and 0.70 for the 7-day, 14-day, and 28-day probability of in-hospital survival, respectively. In the external validation cohort the AUC was 0.83, 0.73, and 0.67. They conclude that their proposed new SAKI model has predictive value for in hospital mortality in critically ill patients that outperforms generic scores. Validation of this model in different cohorts is now expected.

We finish up the October issue of SHOCK with a detailed review about fluid resuscitation and vasoactive therapy in sepsis and septic shock. Barlow and Bissell (20) team up to provide an evaluation of evidence and pharmacology of vasoactive therapy and fluid administration in sepsis and septic shock, with specific insight into the physiologic interplay of these agents. A total of 1,022 citations were reviewed with only relevant clinical data extracted. After their analysis of the literature, the authors conclude that while physiologic rationale provides a hypothetical foundation for interaction between fluid and vasopressor administration, current guidelines are not in alignment with the data available, which suggests a potential benefit from low-dose fluid administration and early vasopressor exposure. Randomized, controlled trials are needed to test this observation that go against current guidelines recommendations.

We congratulate the authors in the October issue of SHOCK for their excellent work and contribution to our Journal. We wish everyone happy and informative reading.

1. Sobbe IV, Krieg N, Dennhardt S, Coldewey SM. Involvement of NF-κB1 and the non-canonical NF-κB signaling pathway in the pathogenesis of acute kidney injury in Shiga-toxin-2-induced hemolytic-uremic syndrome in mice. Shock 56:573–581, 2021. 2. Sun Y, Oami T, Liang Z, Miniet AA, Burd EM, Ford ML, Coopersmith CM. Membrane permeant inhibitor of myosin light chain kinase worsens survival in murine polymicrobial sepsis. Shock 56:621–628, 2021. 3. Gibier J-B, Swierczewski T, Csanyi M, Hemon B, Glowacki F, Maboudou P, Van Seuningen I, Cauffiez C, Pottier N, Aubert S, et al. MUC1 mitigates renal injury and inflammation in endotoxin-induced acute kidney injury by inhibiting the TLR4-MD2 axis and reducing pro-inflammatory macrophages infiltration. Shock 56:629–638, 2021. 4. Tang X, Xu Y, Dai X, Xing Y, Yang D, Huang Q, Li H, Lv X, Wang Y, Lu D, et al. The long-term effect of dobutamine on intrinsic myocardial function and myocardial injury in septic rats with myocardial dysfunction. Shock 56:582–592, 2021. 5. Truong SK, Katoh T, Mimuro S, Sato T, Kobayashi K, Nakajima Y. Inhalation of 2% hydrogen improves survival rate and attenuates shedding of vascular endothelial glycocalyx in rats with heat stroke. Shock 56:593–600, 2021. 6. Yue Y-X, Zhai J-Y, Du H-B, Jiang L-N, Zhang L-M, Wang C, Zhao Z-A, Zhang C-H, Zhao Z-G. Estrogen enhances the microvascular reactivity through RhoA-ROCK pathway in female mice during hemorrhagic shock. Shock 56:611–620, 2021. 7. Jia T, Wang S, Luo C, Wang Z, Liu G, Shang Z, Lu X, Yang Q, Zhu C. Levosimendan ameliorates post-resuscitation acute intestinal microcirculation dysfunction partly independent of its effects on systemic circulation: a pilot study on cardiac arrest in a rat model. Shock 56:639–646, 2021. 8. Lopez K, Suen A, Yang Y, Wang S, Williams B, Zhu J, Hu J, Fiskum G, Cross A, Kozar R, et al. Hypobaria exposure worsens cardiac function and endothelial injury in an animal model of polytrauma: implications for aeromedical evacuation. Shock 56:601–610, 2021. 9. Sadeghi M, Hurtsén AS, Tegenfalk J, Skoog P, Jansson K, Hörer TM, Nilsson KF. End-tidal carbon dioxide as an indicator of partial REBOA and distal organ metabolism in normovolemia and hemorrhagic shock in anesthetized pigs. Shock 56:647–654, 2021. 10. Ronaldi AE, Madurska MJ, Bozzay JD, Polcz JE, Baer DG, Burmeister DM, White PW, Rasmussen TE, White JM. Targeted regional optimization: increasing the therapeutic window for endovascular aortic occlusion in traumatic hemorrhage. Shock 56:493–506, 2021. 11. Koeneman M, Koch R, van Goor H, Pickkers P, Kox M, Bredie S. Wearable patch heart rate variability is an early marker of systemic inflammation during experimental human endotoxemia. Shock 56:537–543, 2021. 12. Fujishima S, Gando S, Saitoh D, Kushimoto S, Ogura H, Abe T, Shiraishi A, Mayumi T, Sasaki J, Kotani J, et al. Incidence and impact of dysglycemia in patients with sepsis under moderate glycemic control. Shock 56:507–513, 2021. 13. Yoo H, Lee JY, Park J, Suh GY, Jeon K. Association of plasma levels of fas ligand with severity and outcome of sepsis. Shock 56:544–550, 2021. 14. Lee JM, Baek SD, Kim TH, Jeon HR, Han JH, Chang JW. Uncertain clinical effect of polymyxin B hemoperfusion in patients with septic acute kidney injury requiring continuous renal replacement therapy. Shock 56:551–556, 2021. 15. Lal Gupta D, Tiwari S, Sinha TP, Dev Soni K, Galwankar S, Kumar S, Rao DN, Bhoi S. Estrogen as a safe therapeutic adjunct in reducing the inflammatory storm in trauma hemorrhagic shock patients. Shock 56:514–521, 2021. 16. Burstein B, Vallabhajosyula S, Ternus B, Murphree D, Barsness GW, Kashani K, Jentzer JC. Outcomes associated with norepinephrine use among cardiac intensive care unit patients with severe shock. Shock 56:522–528, 2021. 17. Chow JH, Richards JE, Galvagno SM, Coleman PJ, Lankford AS, Hendrix C, Dunitz J, Ibrahim I, Ghneim M, Tanaka KA, et al. The Algorithm Examining the Risk of Massive Transfusion (ALERT) score accurately predicts massive transfusion at the scene of injury and on arrival to the trauma bay: a retrospective analysis. Shock 56:529–536, 2021. 18. Hu A-M, Hai C, Wang H-B, Zhang H, Sun L-B, Zhang Z-J, Li H-P. Associations between elevated systolic blood pressure and outcomes in critically ill patients: a retrospective cohort study and propensity analysis. Shock 56:557–563, 2021. 19. Hu H, Li L, Zhang Y, Sha T, Huang Q, Guo X, An S, Chen Z, Zeng Z. A Prediction model for assessing prognosis in critically ill patients with sepsis-associated acute kidney injury. Shock 56:564–572, 2021. 20. Barlow B, Bissell BD. Evaluation of evidence, pharmacology, and interplay of fluid resuscitation and vasoactive therapy in sepsis and septic shock. Shock 56:484–492, 2021.