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Acute kidney injury (AKI) is a systemic inflammatory disease that contributes to remote organ failures. Multiple organ failure is the leading cause of death due to AKI, and lack of understanding of the mechanisms involved has precluded the development of novel therapies. Mitochondrial injury in AKI leads to mitochondrial fragmentation and release of damage-associated molecular patterns, which are known to active innate immune pathways and systemic inflammation. This review presents current evidence suggesting that extracellular mitochondrial damage-associated molecular patterns are mediators of remote organ failures during AKI that have the potential to be modifiable.

ObjectivesTo determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE).DesignA single-center prospective physiologic study.SettingAt a single university medical center.ParticipantsAdult patients with severe COVID-19 ARDS on VV ECMO.InterventionsParticipants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP=1 cmH2O), and (5) 2 hours after returning to LDPV.Main measurements and resultsTwenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p=0.481 and p=0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers.ConclusionsBiomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

Background Case-based Morning Report (MR) has long been the predominant educational conference in Internal Medicine (IM) residency programs. The last comprehensive survey of IM MR was in 1986. Much has changed in the healthcare landscape since 1986 that may impact MR. Objective We sought to determine the current state of MR across all US IM programs. Design In 2018, US IM program directors (PDs) were surveyed about the dynamics of MR at their institutions, perceived pressures, and realized changes. Key Results The response rate was 70.2% (275/392). MR remains highly prevalent (97.5% of programs), although held less frequently (mean 3.9 days/week, SD 1.2), for less time (mean 49.4 min, SD 12.3), and often later in the day compared to 1986. MR attendees have changed, with more diversity of learners but less presence of educational leaders. PD presence at MR is associated with increased resident attendance (high attendance: 78% vs 61%, p=0.0062) and punctuality (strongly agree/agree: 59% vs 43%, p=0.0161). The most cited goal for MR is utilizing cases to practice clinical reasoning. Nearly 40% of PDs feel pressure to move or cancel MR; of those, 61.2% have done so, most commonly changing the timing (48.5%), reducing the length (18.4%), and reducing the number of sessions per week (11.7%). Compared to community-based and to community-based, university-affiliated programs, university-based programs have 2.9 times greater odds (95% CI: 1.3, 6.9; p = 0.0081) and 2.5 times greater odds (95% CI 1.5, 4.4; p =0.0007), respectively, of holding MR after 9 AM, and 1.8 times greater odds (95% CI: 0.8, 4.2; p = 0.1367) and 2.0 times greater odds (95% CI: 1.2, 3.5; p = 0.0117), respectively, of reporting pressure to cancel or move MR compared to their counterparts. Conclusions While MR ubiquity reflects its continued perceived value, PDs have modified MR to accommodate changes in the healthcare environment. This includes reduced frequency, shorter length, and moving conferences later in the day. Additional studies are needed to understand how these changes impact learning. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07010-1.

Background Increased inflammation has been well defined in coronavirus disease 2019 (COVID-19), while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases, and acute respiratory distress syndrome, a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets. Methods Blood was obtained serially from critically ill COVID-19 patients for 11 days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis, and cytokine levels were assessed. Lung tissue was obtained immediately postmortem for immunostaining. PubMed searches for neutrophils, lung, and COVID-19 yielded 10 peer-reviewed research articles in English. Results Elevations in neutrophil-associated cytokines interleukin 8 (IL-8) and interleukin 6, and general inflammatory cytokines IFN-inducible protien-19, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 1β, interleukin 10, and tumor necrosis factor, were identified both at first measurement and across hospitalization (P Conclusions Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. Importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data show that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.

Acute respiratory distress syndrome (ARDS) is a common cause of mortality in patients with acute kidney injury (AKI). Inflammatory crosstalk from the kidney to the lung has been shown to contribute to lung injury after AKI, but anti-inflammatory therapies have not been proven beneficial in human studies. Recently, AKI was shown to alter mitochondria and related metabolic pathways in the heart, but the impact of AKI on lung metabolism has not been investigated to our knowledge. In this study, we evaluated the metabolomic profile of the lung following renal ischemia and reperfusion to identify novel pathways that may be modifiable. We randomized C57BL/6 mice to 20 minutes of bilateral renal arterial clamping or sham operation under ketamine/xylazine anesthesia. At 4 hours after reperfusion, we found a significant increase in markers of lung injury, as well as significant metabolomic changes across lung, kidney, plasma and bronchoalveolar lavage fluid (BALF) compared to shams. Comparative analyses revealed that the fatty acid oxidation pathway was the most significantly altered metabolic pathway, a finding which is consistent with mitochondrial dysfunction systemically and in the lung. These metabolomic changes correlated with the extracellular accumulation of the mitochondrial damage associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA) and transcription factor A, mitochondria (TFAM). Finally, we found that intraperitoneal injection of renal mtDAMPs caused metabolomic changes consistent with mitochondrial dysfunction in the lung in vivo. Mitochondrial function and mtDAMPs warrant further investigation as potential therapeutic targets in preventing lung injury because of AKI.

Objective: Although type 2 diabetes mellitus (T2DM) has been reported as a risk factor for coronavirus disease 2019 (COVID-19), the effect of pharmacologic agents used to treat T2DM, such as metformin, on COVID-19 outcomes remains unclear. Metformin increases the expression of angiotensin converting enzyme 2, a known receptor for severe acute respiratory syndrome coronavirus 2. Data from people with T2DM hospitalized for COVID-19 were used to test the hypothesis that metformin use is associated with improved survival in this population. Methods: Retrospective analyses were performed on de-identified clinical data from a major hospital in Wuhan, China, that included patients with T2DM hospitalized for COVID-19 during the recent epidemic. One hundred and thirty-one patients diagnosed with COVID-19 and T2DM were used in this study. The primary outcome was mortality. Demographic, clinical characteristics, laboratory data, diabetes medications, and respiratory therapy data were also included in the analysis. Results: Of these 131 patients, 37 used metformin with or without other antidiabetes medications. Among the 37 metformin-taking patients, 35 (94.6%) survived and 2 (5.4%) did not survive. The mortality rates in the metformin-taking group versus the non-metformin group were 5.4% (2/37) versus 22.3% (21/94). Using multivariate analysis, metformin was found to be an independent predictor of survival in this cohort (P = .02). Conclusion: This study reveals a significant association between metformin use and survival in people with T2DM diagnosed with COVID-19. These clinical data are consistent with potential benefits of the use of metformin for COVID-19 patients with T2DM.

Aims Type 2 diabetes mellitus (T2DM) is a strong risk factor for complications of coronavirus disease 2019 (COVID‐19). The effect of T2DM medications on COVID‐19 outcomes remains unclear. In a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID‐19 in Wuhan, we have previously found that metformin use prior to hospitalization is associated with reduced mortality. The current study aims to investigate the effects of inpatient use of T2DM medications, including metformin, acarbose, insulin and sulfonylureas, on the mortality of COVID‐19 patients with T2DM during hospitalization. Methods We continue to carry out a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID‐19 and treated with different combinations of diabetes medications. Results We found that patients using metformin (p = .02) and acarbose (p = .04), alone or both together (p = .03), after admission were significantly more likely to survive than those who did not use either metformin or acarbose. 37 patients continued to take metformin after admission and 35 (94.6%) survived. Among the 57 patients who used acarbose after admission, 52 survived (91.2%). A total of 20 patients used both metformin and acarbose, while 57 used neither. Of the 20 dual‐use patients, 19 (95.0%) survived. Conclusion Our analyses suggest that inpatient use of metformin and acarbose together or alone during hospitalization should be studied in randomized trials., We carried out a retrospective analysis of a cohort of 131 patients with T2DM hospitalized for COVID‐19 and treated with different combinations of diabetes medications. We found that patients using metformin and acarbose, alone or both together, after admission were significantly more likely to survive than those who did not use either metformin or acarbose.

The contribution of transcription factors (TFs) and gene regulatory programs in the immune response to COVID-19 and their relationship to disease outcome is not fully understood. Analysis of genome-wide changes in transcription at both promoter-proximal and distal cis-regulatory DNA elements, collectively termed the ’active cistrome,’ offers an unbiased assessment of TF activity identifying key pathways regulated in homeostasis or disease. Here, we profiled the active cistrome from peripheral leukocytes of critically ill COVID-19 patients to identify major regulatory programs and their dynamics during SARS-CoV-2 associated acute respiratory distress syndrome (ARDS). We identified TF motifs that track the severity of COVID- 19 lung injury, disease resolution, and outcome. We used unbiased clustering to reveal distinct cistrome subsets delineating the regulation of pathways, cell types, and the combinatorial activity of TFs. We found critical roles for regulatory networks driven by stimulus and lineage determining TFs, showing that STAT and E2F/MYB regulatory programs targeting myeloid cells are activated in patients with poor disease outcomes and associated with single nucleotide genetic variants implicated in COVID-19 susceptibility. Integration with single-cell RNA-seq found that STAT and E2F/MYB activation converged in specific neutrophils subset found in patients with severe disease. Collectively we demonstrate that cistrome analysis facilitates insight into disease mechanisms and provides an unbiased approach to evaluate global changes in transcription factor activity and stratify patient disease severity.

Acute kidney injury (AKI) significantly contributes to morbidity and mortality in critically ill patients. AKI is also an independent risk factor for the development and progression of chronic kidney disease. Effective therapeutic strategies for AKI are limited, but emerging evidence indicates a prominent role of mitochondrial dysfunction and altered tubular metabolism in the pathogenesis of AKI. Therefore, a comprehensive, mechanistic understanding of mitochondrial function and renal metabolism in AKI may lead to the development of novel therapies in AKI. In this review, we provide an overview of current state of research on the role of mitochondria and tubular metabolism in AKI from both pre-clinical and clinical studies. We also highlight current therapeutic strategies which target mitochondrial function and metabolic pathways for the treatment of AKI.

Rationale: The ideal ventilator settings in patients with severe acute respiratory distress syndrome (ARDS) while on Extracorporeal Membrane Oxygenation (ECMO) are unknown. ELSO recommends modest driving pressures and PEEP (i.e., “lung rest”) during ECMO to minimize ventilator induced lung injury (VILI) and improve mortality. However, even lower driving pressures (DP) may improve inflammatory and lung injury biomarker profiles, and possibly improve mortality. The focus of this study was to evaluate the feasibility and impact of very-low DP in patients with ARDS on ECMO. Methods: Patients on ECMO due to ARDS from coronavirus disease 2019 had their DP decreased from 10 to 1-5 cmH2O for two hours, as tolerated. The other ventilator settings were unchanged and were consistent with ELSO guidelines;positive end-expiratory pressure (10-15 cmH2O) and a respiratory rate 10 breaths per minute. During the low DP protocol, the transpulmonary pressure was monitored with esophageal manometry. Plasma (for IL6 and sRAGE) and urine were collected before and after the protocol. Results: Thirty patients were enrolled and ultimately 21 patients underwent the low DP protocol. Seventeen were male, aged 51 ± 9 years, median BMI of 31.7 kg/m2 (IQR 27.4-35.2), with a median SOFA score of 10 (IQR 8-12) at ICU admission. There were no complications during the low DP protocol (1-5 cm H2O). The protocol was performed a median of 16 (IQR 13.5-20) hours after ECMO initiation. Average ECMO days were 21 (IQR 12.5-41) with a survival to hospital discharge of 43% (9/21). Baseline average tidal volume (TV) was 3.4±2.6 ml/kg of predicted body weight (PBW), during the low DP protocol the TV decreased to 2.7±3.2 ml/kg of PDW. Two groups were noted-those who had spontaneous breaths vs. those who did not (see Figure 1). Ten patients during the low DP protocol continued to have unchanged TV, 5.2±2.8 to 5.4±2.7 ml/kg of PBW due to spontaneous breathing found on esophageal manometry. Eleven patients had no spontaneous breaths and TV decreased from 1.76±0.57 to 0.2±0.38 ml/kg of PBW during the low DP protocol. The spontaneous vs. nonspontaneous breathing groups has a statistically different TV before, during, and after the low DP protocol (p

Coronavirus disease 2019 (COVID-19) includes the cardiovascular complications in addition to respiratory disease. SARS-CoV-2 infection impairs endothelial function and induces vascular inflammation, leading to endotheliitis. SARS-CoV-2 infection relies on the binding of Spike glycoprotein (S protein) to angiotensin converting enzyme 2 (ACE2) in the host cells. We show here that S protein alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein downregulation of AMPK and upregulation of MDM2, causing ACE2 destabilization. Thus, the S protein-exerted vascular endothelial damage via ACE2 downregulation overrides the decreased virus infectivity.

Summary COVID-19 is becoming a leading cause of mortality throughout the world, and few effective therapies are currently available. Angiotensin converting enzyme 2 (ACE2) is essential to COVID-19 pathogenesis, as the binding of SARS-CoV-2 spike protein (S protein) is required for viral entry and development of COVID-19. ACE2 regulates the protective arm of the renin-angiotensin-aldosterone system (RAAS) that endows anti-hypertensive and anti-inflammatory effects in the cardiovascular and pulmonary systems. Preclinical data suggest ACE2 might be downregulated after SARS-CoV-2 binding, and treatments that increase ACE2 may prevent cardiopulmonary injury. Development, testing, and mass production of novel ACE2 therapies may take years, whereas more effective treatments for COVID-19 are needed urgently. Metformin is a widely available anti-diabetic agent that has an excellent safety profile, and clinical and preclinical data suggest metformin may offer cardiopulmonary protection in COVID-19 via enhanced ACE2 expression., Virology; Endocrinology

Acute respiratory distress syndrome (ARDS) is defined by acute onset of bilateral lung infiltrates with impaired gas exchange that is not entirely due to congestive heart failure (1). Strategies to manage ARDS are primarily supportive, with the bulk of the evidence suggesting that improvement in mortality is achieved with optimal setting of mechanical ventilation (2). The mortality rate due to ARDS remains unacceptably high at 30–40%, and a number of recent studies have examined the impact of prone positioning (PP) in ARDS as a life-saving intervention (3,4). The concept of proning patients on mechanical ventilation was proposed in the 1970s and has been used for several decades, although definitive mortality outcome data were only available more recently with the publication of the PROSEVA trial in 2013 and subsequent meta-analyses (3,4). In the APRONET study by Guerin et al., the authors conducted the first prospective multicenter International prevalence study investigating the use of PP in ARDS patients (5). The authors predicted that PP use would be increasing in patients with ARDS given recent publications demonstrating safety and efficacy (3,4). Overall, 6,723 patients from 141 intensive care units (ICUs) in 20 different countries were screened by the APRONET investigators. The authors observed that PP was generally under-utilized, as only 101 of the 735 patients found to have ARDS received at least one proning session [5.9% of mild ARDS patients, 10.3% of moderate ARDS patients and 32.9% of severe ARDS patients, (P=0.0001)]. These rates are gradually increasing over time compared to prior epidemiological studies, but the numbers remain surprisingly low, especially in severe ARDS where PP has been shown to improve survival. The authors also performed a secondary analysis investigating the reasons for not utilizing PP, and found that the perception that hypoxemia was not severe enough to justify proning and concerns regarding hemodynamic instability were the 2 most common reasons. We applaud the efforts of Guerin et al. to identify barriers to implementation of prone ventilation given that it is a safe and inexpensive approach. Their findings suggest that clinicians may have some misconceptions regarding proning, or are unaware of the potential mortality benefits of PP in patients with severe ARDS. In this review, we discuss a few of these issues in more detail with a focus on the mechanical ventilation benefits of PP beyond gas exchange, hemodynamic effects of PP, and alternatives to PP.

Author(s): Hepokoski, Mark L; Bellinghausen, Amy L; Bojanowski, Christine M; Malhotra, Atul

Acute kidney injury (AKI) continues to be a major therapeutic challenge. Despite significant advances made in cellular and molecular pathophysiology of AKI, major gaps in knowledge exist regarding the changes in renal hemodynamics and oxygenation in the early stages and through the continuum of AKI. Particular features of renal hemodynamics and oxygenation increase the susceptibility of the kidney to sustain injury due to oxygen demand-supply mismatch and also play an important role in the recovery and repair from AKI as well as the transition of AKI to chronic kidney disease. However, lack of well-established physiological biomarkers and noninvasive imaging techniques limit our understanding of the interactions between renal macro and microcirculation and tissue oxygenation in AKI. Advances in our ability to assess these parameters in preclinical and clinical AKI will enable the development of targeted therapeutics to improve clinical outcomes.

Research by the U.S. National Institute for Occupational Safety and Health (NIOSH) has shown that heat/humidity buildup is a major concern within coal mine refuge alternatives. High temperature and humidity levels inside a refuge alternative may expose occupants to heat stress. Due to the safety risks associated with testing using human subjects, NIOSH partnered with ThermoAnalytics Inc. to create detailed thermal simulation models of refuge alternatives with human occupants. The objective of this effort was to predict a miner's core temperature response and moisture loss in environments that may be encountered in a coal mine refuge alternative. These parameters were studied across a range of temperatures and relative humidity values to determine if the current 35 °C (95 °F) apparent temperature limit for refuge alternatives is reasonable. The results indicate that the apparent temperature limit is protective, provided that miners are supplied with sufficient water. The results also indicate that the body core temperature does not reach dangerous levels even at an apparent temperature of 54 °C (130 °F). However, the results show that moisture loss increases with apparent temperature. Therefore, if the apparent temperature limit were raised, the water provided in a refuge alternative would have to be increased to offset moisture loss.

The most common cause of acute lung injury is ischemia-reperfusion injury (IRI), during which mitochondrial damage occurs. We have previously demonstrated that mitochondrial transplantation is an efficacious therapy to replace or augment mitochondria damaged by IRI, allowing for enhanced muscle viability and function in cardiac tissue. Here, we investigate the efficacy of mitochondrial transplantation in a murine lung IRI model using male C57BL/6J mice. Transient ischemia was induced by applying a microvascular clamp on the left hilum for 2 h. Upon reperfusion mice received either vehicle or vehicle-containing mitochondria either by vascular delivery (Mito V) through the pulmonary artery or by aerosol delivery (Mito Neb) via the trachea (nebulization). Sham control mice underwent thoracotomy without hilar clamping and were ventilated for 2 h before returning to the cage. After 24 h recovery, lung mechanics were assessed and lungs were collected for analysis. Our results demonstrated that at 24 h of reperfusion, dynamic compliance and inspiratory capacity were significantly increased and resistance, tissue damping, elastance, and peak inspiratory pressure (Mito V only) were significantly decreased (P < 0.05) in Mito groups as compared with their respective vehicle groups. Neutrophil infiltration, interstitial edema, and apoptosis were significantly decreased (P < 0.05) in Mito groups as compared with vehicles. No significant differences in cytokines and chemokines between groups were shown. All lung mechanics results in Mito groups except peak inspiratory pressure in Mito Neb showed no significant differences (P > 0.05) as compared with Sham. These results conclude that mitochondrial transplantation by vascular delivery or nebulization improves lung mechanics and decreases lung tissue injury.

Sepsis-associated acute kidney injury (AKI) is frequently observed and has poor prognosis with no effective treatments. The lack of complete understanding of its pathogenesis is a significant barri...

Acute respiratory distress syndrome (ARDS) was first defined by Ashbaugh et al . in 1967 (1). They described 12 patients who developed the acute onset of hypoxemic respiratory failure, diffuse bilateral alveolar infiltrates, and low respiratory system compliance brought on by a variety of different insults. Decades of dedicated research have followed this initial description, yet ARDS remains a common critical illness with an exceptionally high mortality rate of 35–46% (2). At the 2016 American Thoracic Society (ATS) International Meeting, Dr. Brian Kavanagh, a Professor of Anesthesia from the University of Toronto, delivered a highly popular keynote speech addressing the role professional societies play in promoting universal management guidelines. He made several important points about the challenges and possible downsides to this strategy. This article reviews the potential for a more patient-specific approach to ARDS care based on presentations at the ATS meeting and the recent literature.

Electronic (e)-cigarettes theoretically may be safer than conventional tobacco. However, our prior studies demonstrated direct adverse effects of e-cigarette vapor (EV) on airway cells, including decreased viability and function. We hypothesize that repetitive, chronic inhalation of EV will diminish airway barrier function, leading to inflammatory protein release into circulation, creating a systemic inflammatory state, ultimately leading to distant organ injury and dysfunction. C57BL/6 and CD-1 mice underwent nose only EV exposure daily for 3–6 mo, followed by cardiorenal physiological testing. Primary human bronchial epithelial cells were grown at an air-liquid interface and exposed to EV for 15 min daily for 3–5 days before functional testing. Daily inhalation of EV increased circulating proinflammatory and profibrotic proteins in both C57BL/6 and CD-1 mice: the greatest increases observed were in angiopoietin-1 (31-fold) and EGF (25-fold). Proinflammatory responses were recapitulated by daily EV exposures in vitro of human airway epithelium, with EV epithelium secreting higher IL-8 in response to infection (227 vs. 37 pg/ml, respectively; P < 0.05). Chronic EV inhalation in vivo reduced renal filtration by 20% ( P = 0.017). Fibrosis, assessed by Masson’s trichrome and Picrosirius red staining, was increased in EV kidneys (1.86-fold, C57BL/6; 3.2-fold, CD-1; P < 0.05), heart (2.75-fold, C57BL/6 mice; P < 0.05), and liver (1.77-fold in CD-1; P < 0.0001). Gene expression changes demonstrated profibrotic pathway activation. EV inhalation altered cardiovascular function, with decreased heart rate ( P < 0.01), and elevated blood pressure ( P = 0.016). These data demonstrate that chronic inhalation of EV may lead to increased inflammation, organ damage, and cardiorenal and hepatic disease.

BACKGROUND: Mechanical ventilation is associated with significant increases in the risk of acute kidney injury (AKI). The rate of AKI due to mechanical ventilation and the associated mortality remain unacceptably high. Preventative and therapeutic strategies are clearly lacking. SUMMARY: Ventilator induced kidney injury (VIKI) is believed to occur due to changes in hemodynamics that impair renal perfusion, neurohumoral mediated alterations in intra-renal blood flow, and systemic inflammatory mediators generated by ventilator induced lung injury (VILI). The risk of injury to the kidney by these mechanisms may be modified by open lung protective ventilation with low tidal volumes and high positive end expiratory pressure (PEEP). However, these strategies may also increase risk of injury in some settings, and clinicians have limited means to identify the optimal ventilator strategy for each specific patient. Novel urinary biomarkers have demonstrated the ability to predict AKI prior to classic clinical signs such as decreased urine output and increased creatinine. These biomarkers may serve as an early indication to intensivists of an injurious ventilator strategy and failure of traditional management. KEY MESSAGES: VIKI remains a common and serious problem in critically ill patients. Open lung protective ventilation is the only proven strategy to improve renal outcomes in mechanically ventilated patients, and novel strategies are urgently needed. Interventional trials focused on using early biomarkers of renal injury to guide ventilator management may offer important insights and improve outcomes.

In critical illness, such as sepsis or the acute respiratory distress syndrome, acute kidney injury (AKI) is common and associated with increased morbidity and mortality. Mechanical ventilation in critical illnesses is also a risk factor for AKI, but it is potentially modifiable. Injurious ventilation strategies may lead to the systemic release of inflammatory mediators from the lung due to ventilator induced lung injury (VILI). The systemic consequences of VILI are difficult to differentiate clinically from other systemic inflammatory syndromes, such as sepsis. The purpose of this study was to identify unique changes in the expression of inflammatory mediators in kidney tissue in response to VILI compared with systemic sepsis to gain insight into direct effects of VILI on the kidney. Four groups of mice were compared—mice with sepsis from cecal ligation and puncture (CLP), mice subjected to injurious mechanical ventilation with high tidal volumes (VILI), mice exposed to CLP followed by VILI (CLP+VILI), and sham controls. Protein expression of common inflammatory mediators in kidneys was analyzed using a proteome array and confirmed by Western blot analysis or ELISA. VEGF and VCAM-1 were found to be significantly elevated in kidneys from VILI mice compared with sham and CLP. Angiopoietin-2 was significantly increased in CLP+VILI compared with CLP alone and was also correlated with higher levels of AKI biomarker, neutrophil gelatinase-associated lipocalin. These results suggest that VILI alters the renal expression of VEGF, VCAM-1, and angiopoietin-2, and these proteins warrant further investigation as potential biomarkers and therapeutic targets.

Keywords: disease progression; kidney disease; oxidative stress; renin–angiotensin system; sleep apnoea

U PDATE Update in Critical Care Medicine: Evidence Published in 2016 Mark Hepokoski, MD, and Atul Malhotra, MD W e summarize key articles in critical care medicine published in 2016. We used an informal survey of academic and community intensivists to identify novel articles from high-impact journals that had important effects on clinical practice. In addition, we searched the most accessed journals from the American College of Physicians' JournalWise database to find articles that were particularly relevant to internal medicine clinicians. We included 2 studies on acute respiratory distress syndrome (ARDS) that solidified the need to better un- derstand the epidemiology of this disorder by demon- strating high rates of underrecognition and disparities in care. A novel noninvasive ventilation (NIV) device that may benefit patients with early ARDS was also identified, and lower oxygen targets may be appropri- ate. Studies of patients with severe sepsis showed no benefit of adjunctive steroid therapy; however, contin- uous infusion of antibiotics may significantly reduce mortality. Intensive blood pressure control does not seem to improve neurologic outcome in patients with acute intracerebral hemorrhage (ICH), and length of hospital stay may predict poor neurologic outcome and mortality in patients with in-hospital cardiac arrest. Progress was made in our understanding of the man- agement of critically ill patients with acute kidney injury (AKI), as a randomized trial suggested that earlier initi- ation of renal replacement therapy (RRT) decreases mortality. Finally, depressive symptoms were shown to be highly prevalent in caregivers of critically ill patients, and strategies that provide social support to these per- sons should be identified. ARDS and Acute Respiratory Failure ARDS Often Goes Unrecognized or Underappreciated, Even in ICUs Bellani G, Laffey JG, Pham T, et al; LUNG SAFE Investigators. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315:788-800. [PMID: 26903337] doi:10.1001/jama.2016.0291 Background: Acute respiratory distress syndrome is de- fined by acute onset of bilateral alveolar or interstitial infiltrates, with impaired gas exchange in the absence of congestive heart failure (1). In patients with known ARDS, lung protective ventilation has proven benefit (2, 3), but evidence suggests that many patients for which this therapy would be appropriate are not receiv- Ann Intern Med. 2017;166:W20-W26. doi:10.7326/M17-0138 For author affiliations, see end of text. This article was published at Annals.org on 30 March 2017. ing it (4, 5). Whether a diagnosis of ARDS affects what therapies the patient receives is also unclear, emphasiz- ing the need for further epidemiologic data on this condition. Findings: This multinational cohort included more than 29 000 patients admitted to participating intensive care units (ICUs). Of these patients, 10.4% fulfilled the crite- ria for ARDS, and most episodes occurred within 48 hours. Clinical recognition of ARDS varied from 51.3% in mild ARDS to 78.5% in severe ARDS. However, fewer than two thirds of patients with ARDS received a tidal volume of 8 mL per kg of ideal body weight or less, and plateau pressure was recorded in only 40.1%. Hospital mortality was 34.9% among patients with mild ARDS, 40.3% among those with moderate ARDS, and 46.1% among those with severe ARDS. The use of some ad- junctive therapies that are recommended by some ex- perts, such as neuromuscular blockade and prone po- sitioning, increased with clinical recognition. Cautions: The observational nature of this study pre- cludes conclusions regarding the appropriateness of the interventions that patients received. In addition, an emerging literature suggests that individualized ther- apy for mechanical ventilation in ARDS may be reason- able (3, 6). Thus, analyses of large cohorts using a one-size-fits-all approach may result in inappropriate assumptions, because the therapeutic decisions that treating clinicians make on the basis of bedside obser- vations and individual patient characteristics may be justifiable and reasonable. Implications: Acute respiratory distress syndrome re- mains common and underrecognized, with substantial associated mortality. Treating clinicians should be aware of the epidemiology of ARDS so that proven therapies (lung protective ventilation) may be instituted promptly with early disease recognition and other ther- apies considered. Future ARDS trials will also depend on accurate and timely diagnosis. ARDS-Related Mortality Is Decreasing, on the Basis of National Death Certificate Data Cochi SE, Kempker JA, Annangi S, et al. Mortality trends of acute respiratory distress syndrome in the United States from 1999 to 2013. Ann Am Thorac Soc. 2016;13:1742-51. [PMID: Background: Substantial advances have been made in the treatment and understanding of ARDS over the past 2 decades (7–9). However, recent assessments of mor- bidity and mortality trends have been mostly limited to single-center studies in specific geographic regions (10, 11). Temporal and demographic trends in ARDS are also underinvestigated. Annals of Internal Medicine W20 © 2017 American College of Physicians Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/936156/ by a University of California San Diego User on 06/20/2017

In principle, infrared (IR) imagery of exposed skin and clothing can provide a valuable source of data for thermo-physiological studies. In practice, and despite the fall in the cost of IR cameras, infrared imagery is not universally collected during human subject testing. One reason for this may be the relatively poor accuracy of IR cameras (typically ±2 °C). The repeatability of the measurements taken with a particular IR camera (both spatially and temporally) is much better than its accuracy, i.e., close to the camera's sensitivity. An IR camera's sensitivity (and repeatability) is typically on the order of hundredths of a degree Celsius. Consequently, a reference with known temperature and emissivity placed in the camera's field-of-view when taking measurements can provide two potential benefits: First, measurement error can be reduced by using a calibration procedure. Second, IR imagery taken by different IR cameras during different test episodes can be directly compared.

Thermophysiological models are used to predict thermal sensation, thermal comfort and human effectiveness for a wide range of environmental conditions. Typically, such models are based on the anatomy and physiological responses of an adult male. The objective of this study was to develop an adult female model and test it against experimental results from the literature.

Recent advances in computation technologies have facilitated computer simulation of human physiological regulation mechanisms at high spatial and temporal resolution. Improvements in manufacturing techniques and control strategies have resulted in the development of advanced thermal manikins. However, the broader acceptance of human thermophysiological simulation via modelling and measurement tools is limited by the scarce public domain resources and availability of validation data supporting such tools [1]. In this study a systematic approach to the development and validation of thermophysiology models and adaptive manikins was developed. This approach is based on both the evaluation of manikin responsiveness - to be able to follow the course of human physiological responses, and the adequate validation of an adaptive manikin against human experiments representing groups with increasing complexity of exposure.