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Commentary

What's New in Shock, April 2020?

Cirino, Jennifer A.; Delano, Matthew J.; Napolitano, Lena M.

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doi: 10.1097/SHK.0000000000001508
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Sepsis and septic shock, cardiac arrest and cardiogenic shock, and hemorrhagic shock are leading causes of mortality in our intensive care units (ICU) daily. The ICU patient population has increased significantly over the last decade, and is projected to continue to increase with the aging of our national population. We are in great need of new and innovative treatment approaches given the high associated mortality rates of the aforementioned shock states.

This issue of SHOCK highlights elegant research studies in these very important topics in critical care medicine. The clinical (five studies), translational (two studies), and basic science (nine studies) investigations in this issue aim to provide greater understanding of the pathophysiology and underlying mechanisms of shock and develop future more effective treatment strategies to save the lives of our critically ill and injured patients.

We have provided an abbreviated review of the important findings of each of the studies and commented on the need for future basic/translational studies and clinical trials. For some of the topics in this issue, there are already important ongoing clinical studies underway to further elucidate whether changes in clinical practice are warranted.

SEPSIS

The first two reviews are in the area of sepsis.

In sepsis, a timely diagnosis is essential for accurate treatment to increase survival. Huang et al. (1) provide a systematic review and meta-analysis (30 studies; 6,906 patients) of soluble urokinase-type plasminogen activator receptor (suPAR, at or within 24 h of admission) as a biomarker for sepsis and confirmed elevated suPAR levels had moderate sensitivity/specificity in differentiating sepsis from systemic inflammatory response syndrome (SIRS) and for mortality prediction. Similar diagnostic accuracy was identified for suPAR and procalcitonin (PCT) based on separate PCT meta-analyses, and suPAR was better than CRP, LBP, and IL-6. suPAR had a higher specificity (82%) for distinguishing sepsis from SIRS of noninfectious origins than the other biomarkers. The authors recommend that suPAR should be considered as a biomarker in clinical practice for patients with sepsis. But additional studies are clearly warranted to compare the diagnostic and prognostic value of both biomarkers (suPAR and PCT) in individual patients, as suPAR is increased in non-sepsis patients with tumors, acute kidney injury and inflammatory bowel disease. Given this, it may be that the use of suPAR with other physiologic, comorbidity and organ dysfunction scoring systems may be optimal to better predict sepsis outcomes.

Wang et al. (2) report a provocative review of the omentum as an immunologic organ which provides important defense against infection, inflammation, and injury. Evidence from prior studies has documented that omentectomy may have a detrimental effect on mortality, indicating that it should not be removed with impunity. They review that the omentum is the main route for the infiltration of inflammatory cells into the peritoneum, and its role in peritonitis is not yet fully understood. The authors further propose that functional immunologic units of the omentum referred to as “milky spots” or “omentum-associated lymphoid tissue,” composed of mainly macrophages, B and T cells, should be classified as a secondary lymphoid organ (with some functions similar to lymph nodes and the spleen), since they serve a dual role of limiting spread of infection and mounting a humoral and cytotoxic immune response with both innate and acquired immunity. Milky spots act as a portal of entry for other immune cells, such as neutrophils, into the peritoneal cavity in response to infection, and increase in size/mass in response to infection and decrease with age. Further study is needed regarding its exact role in the immune response to abdominal infections and peritonitis.

The next two papers examine potential predictors of clinical sepsis outcomes.

Rodriguez-Ruiz et al. (3) report the first study that examined the kinetics of plasma and skin advanced glycation end products (AGEs) and soluble form of their cell surface receptor (sRAGE) measured on days 1, 3, and 5 during sepsis in 90 patients with severe sepsis or septic shock. They confirmed an association of decreased plasma/skin AGES with higher 28-day mortality. AGEs levels correlated with age, diabetes, and chronic kidney disease whereas sRAGE levels correlated with high levels of inflammatory markers such as TNF alpha, IL-6, and IL-8, high APACHE-II, and SOFA scores, as well as ARDS. There was a higher mortality rate found in those that had a greater decrease in plasma AGEs in the first 5 days, and greater decrease in skin AGEs on the fifth day. In addition, sRAGE levels correlated with decreased plasma autofluorescence and skin autofluorescence as surrogates of circulating and skin AGEs, and were associated with increased 28-day mortality. The underlying mechanisms responsible for these kinetic changes and adverse outcome are at present unknown and will require further detailed investigation.

Hsieh et al. (4) report that preadmission antihypertensive use was associated with increased hospital mortality (adjusted OR 1.8, 95% CI 1.74–1.87, P < 0.001) in a sepsis cohort (n = 33,231 sepsis antihypertensive drug use patients of total 223,560 sepsis patients over 15 years, 1999–2013) using the National Health Insurance Research Database in Taiwan with an equal number of matched patients as the control cohort. Conversely, in septic shock patients, preadmission antihypertensive use (ACEI, ARB, calcium channel-blockers, and beta-blockers) was associated with significantly decreased hospital mortality (adjusted OR 0.66, 95% CI 0.55–0.80, P < 0.001) by logistic regression analyses. Finally, ACEIs or ARB use was associated with decreased total hospital mortality in both sepsis and septic shock patients. The recent Angiotensin II for the Treatment of High-Output Shock trial led to the FDA approval of angiotensin II as a vasopressor to increase blood pressure in adults with septic shock or other distributive shock, and supports a role for angiotensin in the pathophysiology of vasodilatory shock (5). A significant limitation of this study, however, is that the Sepsis-2 definition based on SIRS was used, rather than the new Sepsis-3 definition. Additional limitations include use of administrative data, the matching method used only age, sex, and index year, and the logistic regression analyses adjusted only for age, sex, insurance premium, urbanization level, and comorbidities. There is also concern for “healthy use bias” since antihypertensive use patients were more likely to be followed by a doctor regularly and have other healthy habits than the control cohort, however, they did have a greater proportion of comorbidities. Despite these limitations, however, this is a very large population-based study which will warrant future prospective RCTs to validate these findings.

The next paper by Kim et al. (6) examined the impact of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy in a murine cecal ligation and puncture model, since it has been proposed that improved human survival with the Marik protocol is due to reduced oxidative stress. A very important innovation in the current study was stratification of mice into groups predicted to live or die based on sepsis physiology (heart rate, respiratory rate, pulse distension), parameters that also predict mortality in sepsis patients. HAT treatment administered 7 h after CLP was associated with significant increased survival and heart rate and reduced oxidative stress in mice predicted to die only, using a personalized sepsis treatment approach in this murine CLP model. A number of clinical trials [including the VICTAS (7) and VITAMINS (8) trials] are underway to assess the impact of HAT therapy on human sepsis outcomes. The recent CITRIS-ALI trial (9) is the first published report of a multicenter RCT (n = 167) comparing intravenous vitamin C (50 mg/kg q6 h × 4 d) to placebo, and reported no difference in the primary outcome measure of organ failure SOFA scores. Importantly, vitamin C was associated with a significant reduction in the secondary outcome of 28-day mortality (29.8% vs. 46.3%, P = 0.03) with increased Kaplan–Meier survival (P = 0.01). We will await the results of the ongoing clinical HAT therapy studies to determine definitive impact of HAT on sepsis outcomes.

A murine CLP model was also used in the study by Vu et al. (10) to assess whether blockade of the PD-1/PD-L pathway with anti-PD-1 drug was an effective treatment strategy for postabdominal sepsis aspergillosis. Mice were inoculated with Aspergillosis when immune exhaustion was demonstrated 5 days post-CLP by reduction in CD86 and MHC class II cells and increased PD-1 cells. Improved survival in mice who received Amphotericin B plus an anti-PD-1 drug was observed when compared with mice who received Amphotericin B only (40% vs 10% respectively). Use of anti-PD-1 drugs in these mice leads to reinvigoration of sepsis-induced immune suppression by upregulating CD86 expression, INF-γ production, and dampened IL-10 production. This represents a promising adjunct to treatment of post-sepsis secondary fungal infections. Although the first Phase 1 trial with anti-PD-1 therapy (anti-PD-1 antibody nivolumab) in human sepsis has been reported (11), it did not investigate post-sepsis fungal infection.

Wedn et al. (12) used a rat endotoxemia (6-h period of LPS exposure) model to investigate the impact of nicotine on hemodynamic and renal alterations, and to assess the role of α7-nAchR/HO-1 signaling in the nicotine-LPS interaction. Nicotine administration abrogated the LPS lethal, hemodynamic, and renal effects in this clinically relevant endotoxemia model. The administration of antagonists of α7-nAchR and HO-1 negated the protective effects of nicotine, thus validating the role of α7-nAchR/HO-1 signaling as an underlying mechanism of nicotinic protection against endotoxemia. This area of investigation is exciting and the authors provide important information on future potential treatment strategies other than nicotine via the same pathway. At present, current data are limited due to the use of experimental endotoxemia models, rather than more clinically relevant preclinical sepsis models.

The last paper in this sepsis section by Qin et al. (13) examined PMN and monocyte activation under baseline (nonstimulated) and ex vivo cell stimulation (LPS and phorbo ester) conditions with comparisons by sex alone, and/or IRAK1 genotype. They found that grouping by sex alone did not have significant differences. However, stratification by the IRAK1 genotype revealed augmented cell activation in variant-IRAK1 subjects, which was accompanied by decreased intrasubject cell response variabilities. Variant IRAK1 also suppressed injury-induced de novo ChrX skewing in trauma patients during the clinical course. These differences in cellular phenotypes between WT and variant IRAK1 subjects may be contributing factors affecting the course of sepsis and may also impact sex-based outcome differences due to the X-linked inheritance pattern and high prevalence of the IRAK1 haplotype.

CARDIAC CLINICAL STUDIES

Pepe et al. (14) provide an excellent comprehensive review of the epidemiology, pathophysiology, and treatment strategies for cardiogenic shock, and the current European Society of Cardiology (ESC) recommendations. Given that short-term mortality in cardiogenic shock after acute myocardial infarction ranges from 40 to 60%, this is an important review of available treatment options. The ESC guidelines recommend early revascularization for both NSTEMI and STEMI (emergency PCI of the culprit lesion and emergency CABG if not amenable to PCI), optimal medical therapy and mechanical circulatory support [MCS, including intra-aortic balloon pump, Impella, TandemHeart, veno-arterial extracorporeal membrane oxygenation (VA-ECMO)]. Very little randomized trial data are available regarding the benefit of MCS, and despite significant technical progress, the use of MCS remains controversial and had a IIb-C recommendation in the latest ESC Guidelines. The Expert Consensus Statement on MCS from the American College of Cardiology provides consensus-based summary statements, including “early placement of an appropriate MCS may be considered in those who fail to stabilize after initial interventions (revascularization and pharmacologic therapy),” and recommends that randomized trials in different clinical scenarios are critically needed (15).

A retrospective single-center study of 101 patients requiring mechanical circulatory support (VA-ECMO) for cardiogenic shock over 4 years (2013–2016) by Besnier et al. (16) examined the impact of positive fluid balance on patient outcomes. Overall 28-day mortality was high at 47.5%, secondary to multiple organ dysfunction (63%) and brain death (23%) in most. These findings are comparable to the July 2019 International Extracorporeal Life Support Organization outcome data for adult cardiac support, with 22,193 total runs and extracorporeal life support (ECLS) survival rate of 59%, reduced to 43% survival rate to discharge or transfer (17). Importantly, they confirmed that increasing positive fluid balance was associated with increasing mortality, with day-1 positive fluid balance confirmed as an independent predictor of mortality (OR 14.34, P = 0.02) after adjusting for confounding variables (age, sex, VA-ECMO for cardiac arrest, SAPS-2 score at admission, and hear of VA-ECMO implementation). It is unclear whether all the important covariates that impact outcome have been included in this multivariable logistic regression analysis. The challenging question is whether this positive fluid balance is due to the patient's severity of illness and shock state, or related to inappropriate ICU fluid management. Until we have data from randomized controlled trials comparing optimal fluid strategies in VA-ECMO for cardiogenic shock, it is imperative to monitor and attempt to optimize fluid management in an effort to improve patient outcomes.

An observational multicenter study using the Korean Cardiac Arrest Research Consortium (KoCARC) registry (18) examined lactate/albumin ratio (LAR) obtained in the emergency department as a prognostic tool for outcome prediction in patients with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA, n = 524). Increased initial LAR was associated with significantly decreased favorable neurologic outcomes (OR 0.787, P = 0.035) and decreased survival to discharge (OR 0.744, P < 0.001) in patients with ROSC after OHCA, and was superior to lactate alone. Nomograms were developed using independent predictors of outcome from the multivariate logistic model (age, arrest to ROSC time, hemoglobin, witnessed arrest, revascularization and LAR) showed close approximation between the observed and predicted outcomes based on the nomograms. Since these nomogram parameters are readily available early after ROSC in OHCA patients, validation of these important findings can easily be accomplished in the future.

The last Cardiac paper by Jentzer et al. (19) from the Mayo Clinic is a retrospective single-center cohort study (n = 10,004; 2007–2015) that assessed the impact of vasopressor and inotropic use in the cardiac ICU on patient outcomes. Interestingly, 24.7% of patients received vasoactive drugs during the ICU stay, with 62.4% who received only vasopressors, and 22.3% who received both inotropes and vasopressors. Overall Dopamine use was more common (49%) than Norepinephrine (NE, 29%), but NE use significantly increased over the study period (19.7% in 2007 to 56.2% in 2015), with concomitant decreased Dopamine use (65.7% 2007 to 27.6% in 2015). Among patients receiving vasoactive drugs, NE was associated with a lower risk of hospital mortality (OR 0.66, 95% CI, 0.49–0.90, P = 0.008) after adjustment for illness severity and peak Vasoactive-Inotropic Score (VIS) calculated using peak vasoactive drug doses during the ICU stay. This is clearly an exploratory study with significant limitations, including potential unmeasured confounders, the use of multiple vasoactive drugs in many patients making it difficult to determine the impact of a single drug, and most importantly unknown factors regarding how specific vasoactive agents were chosen for specific ICU patients. Additional studies will be required to determine the optimal vasopressor and inotrope medications in acute cardiac disease to optimize cardiac ICU patient outcomes.

TRAUMA/HEMORRHAGE

Hemorrhagic shock is the leading cause of preventable death after severe trauma in both military and civilian settings. Three interesting studies in this issue provide greater understanding of the pathogenesis of coagulopathy and mortality following hemorrhagic shock. Furthermore, the investigations provide much needed information to identify critical targets and treatment strategies to reduce mortality in traumatic hemorrhagic shock.

Using a rat polytrauma and hemorrhage model, Darlington et al. (20) characterized platelet dysfunction and its contribution to trauma-induced coagulopathy. In this model, they confirmed an acute increase in platelet-granulocyte aggregates with concomitant fall in platelet count by 4 h, and significantly reduced platelet aggregation at 2 to 4 h. Intracellular cAMP in platelets significantly increased (doubled), but cGMP, ATP, and GTP decreased over the 4 h. Additional in vitro studies using platelet-rich plasma from normal humans confirmed that platelet aggregation was inhibited more than 50% with prostaglandin I2 treatment which resulted in doubling of cAMP. These studies suggest that post-trauma decreased platelet function may be due to increased adenylate cyclase activity and cAMP, which is known to inhibit platelet function. It is uncertain whether post-trauma/hemorrhage human platelet response is similar to the findings in this rat trauma/hemorrhage model. In a similar rabbit model (bilateral femur fractures, laparotomy, and class IV hemorrhagic shock), early thrombocytopenia and decreased impedance aggregometry were identified, but significantly increased fibrinogen binding of ADP-activated platelets (platelet hyperreactivity, possibly due to newly released platelets from the storage pool) by flow cytometry was also noted (21). We must be cautious in interpretation of post-trauma platelet function as measured by different methodologies (22). It is also unclear whether impaired platelet function is similar after tissue injury/hemorrhagic shock versus either tissue injury or hemorrhagic shock alone, as one human study reported rising platelet counts postinjury, but persistent post-trauma platelet dysfunction (23). This is a very important line of investigation in the field of trauma-induced coagulopathy and supports the need for additional studies, particularly in humans, to further discern post-trauma platelet function phenotypes and impact on outcome.

Using a porcine 35% hemorrhagic shock model without tissue injury, Shaylor et al. (24) determined early predictors of mortality including low cardiac output, diastolic blood pressure, stroke volume, oxygen delivery, mixed venous saturation, and high lactate. Animals developed these maladaptive hemodynamic and cardiac responses immediately after hemorrhage with resultant early arrhythmias and death within 1 to 32 min after the onset of arrhythmia. These findings are very important and relevant, as it supports the need for personalized trauma resuscitation, rather than damage control hypotensive resuscitation in all patients. Hypotensive resuscitation may actually be harmful in trauma victims with marked vasodilation. The etiology of these changes is unknown, but vasopressin deficiency has been documented in severely injured trauma patients requiring blood transfusions (25, 26). A potential treatment strategy for low diastolic and mean arterial pressure is vasopressin repletion, and the recent AVERT Shock Trial examined the additional of low-dose vasopressin as an adjunct to early resuscitation of patients with trauma and hemorrhagic shock, and reported significantly decreased total volume of blood products transfused at 48 h and no mortality difference (27).

Using a rat model of hemorrhagic shock without tissue injury, Nugent et al. (28) compared resuscitation with a novel bovine PEGylated carboxyhemoglobin-based oxygen carrier (PEG-COHb, Sanguinate, which is currently undergoing multiple phase 2 clinical trials) versus 6% hetastarch (Hextend). PEG-COHb was associated with higher mean arterial pressure, improved microcirculatory measurements of interstitial oxygenation, decreased lactate post-resuscitation, and increased survival time. Hemoglobin-based oxygen carriers (HBOC) have the advantage of no need for crossmatch, stability at room temperature, and seem ideal for prehospital use.

Planning is underway for a multicenter clinical trial (Multi-Center, Prospective, Randomized Clinical Study of Bioplasma Freeze Dried Plasma and Hemopure for use in Treatment of Trauma Patients with Significant Haemorrhage) across South African hospitals and ambulance bases for prehospital use of a bovine HBOC (Hemopure, HbO2 Therapeutics) with freeze-dried plasma (BioPlasma FDP, National Biologics Institute), expected to enroll 1,400 patients over 3 years in a study supported by the US Department of Defense and the University of Stellenbosch (Cape Town, South Africa) (29, 30). Prehospital plasma use was associated with a survival benefit (lower 30-day mortality) in the Prehospital Air Medical Plasma (PAMPer) multicenter trial (31), and with decreased 24-h and 28-day mortality reported in blunt injured patients in a secondary analysis of data from the single-center Control of Major Bleeding After Trauma (COMBAT) randomized trial in addition to the PAMPer trial (32). Interestingly, no survival benefit was noted with prehospital plasma in the subgroup of trauma patients (n = 104) requiring massive transfusion (defined as receiving >/= 10 units of red cells in 24 h) in the PAMPer trial (33). The findings of the trauma trial linking prehospital HBOC and plasma treatments will be of great interest.

In the final paper in this issue, Abdullahi et al. (34) examine how catecholamines induce endoplasmic reticulum (ER) stress in both hepatocytes and adipocytes (but not fibroblasts) in vitro, and that these effects can be reversed by adrenergic receptor antagonists. Data from these elegant studies confirm that catecholamines play a key role in induction of ER stress, which may in part be the mechanism responsible for the hypermetabolic syndrome with muscle catabolism and lipolysis that is evident in major burn patients. The alpha-1 blocker prazosin and the beta-blocker propranolol blocked ER stress induction by norepinephrine in these studies, and these findings warrant further confirmation with in vivo studies.

In summary, the 16 research studies in this issue of SHOCK have provided significantly greater understanding of these disease states that affect our critically ill and injured patients. Studies like these are imperative to further expand our knowledge of these disease states and guide our future treatment approaches. The authors of these studies are to be congratulated for their continuing efforts to further delineate pathobiology and investigate novel interventions to ultimately improve patient outcomes during critical illness.

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