Application of Cardiovascular Physiology to the Critically Ill Patient.

OBJECTIVES: To use the ventricular pressure-volume relationship and time-varying elastance model to provide a foundation for understanding cardiovascular physiology and pathophysiology, interpreting advanced hemodynamic monitoring, and for illustrating the physiologic basis and hemodynamic effects of therapeutic interventions. We will build on this foundation by using a cardiovascular simulator to illustrate the application of these principles in the care of patients with severe sepsis, cardiogenic shock, and acute mechanical circulatory support. DATA SOURCES: Publications relevant to the discussion of the time-varying elastance model, cardiogenic shock, and sepsis were retrieved from MEDLINE. Supporting evidence was also retrieved from MEDLINE when indicated. STUDY SELECTION, DATA EXTRACTION, AND SYNTHESIS: Data from relevant publications were reviewed and applied as indicated. CONCLUSIONS: The ventricular pressure-volume relationship and time-varying elastance model provide a foundation for understanding cardiovascular physiology and pathophysiology. We have built on this foundation by using a cardiovascular simulator to illustrate the application of these important principles and have demonstrated how complex pathophysiologic abnormalities alter clinical parameters used by the clinician at the bedside.

A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

Hemoadsorption: Consensus report of the 30th Acute Disease Quality Initiative workgroup.

Adsorption-based extracorporeal therapies have been subject to technical developments and clinical application for close to five decades. More recently, new technological developments in membrane and sorbent manipulation have made it possible to deliver more biocompatible extracorporeal adsorption therapies to patients with a variety of conditions. There are several key rationales based on physicochemical principles and clinical considerations that justify the application and investigation of such therapies as evidenced by multiple ex-vivo, experimental, and clinical observations. Accordingly, unspecific adsorptive extracorporeal therapies have now been applied to the treatment of a wide array of conditions from poisoning to drug overdoses, to inflammatory states and sepsis, and acute or chronic liver and kidney failure. In response to the rapidly expanding knowledge base and increased clinical evidence, we convened an Acute Disease Quality Initiative (ADQI) consensus conference dedicated to such treatment. The data show that hemoadsorption has clinically acceptable short-term biocompatibility and safety, technical feasibility, and experimental demonstration of specified target molecule removal. Pilot studies demonstrate potentially beneficial effects on physiology and larger studies of endotoxin-based hemoadsorption have identified possible target phenotypes for larger randomized controlled trials (RCTs). Moreover, in a variety of endogenous and exogenous intoxications, removal of target molecules has been confirmed in vivo. However, some studies have raised concerns about harm or failed to deliver benefits. Thus, despite many achievements, modern hemoadsorption remains a novel and experimental intervention with limited data, and a large research agenda.

Sepsis-associated acute kidney injury-treatment standard.

Sepsis is a host's deleterious response to infection, which could lead to life-threatening organ dysfunction. Sepsis-associated acute kidney injury (SA-AKI) is the most frequent organ dysfunction and is associated with increased morbidity and mortality. Sepsis contributes to ≈50% of all AKI in critically ill adult patients. A growing body of evidence has unveiled key aspects of the clinical risk factors, pathobiology, response to treatment and elements of renal recovery that have advanced our ability to detect, prevent and treat SA-AKI. Despite these advancements, SA-AKI remains a critical clinical condition and a major health burden, and further studies are needed to diminish the short and long-term consequences of SA-AKI. We review the current treatment standards and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of SA-AKI.

Implementation of Nephroprotective Measures to Prevent Acute Kidney Injury in Septic Patients: A Retrospective Cohort Study.

BACKGROUND: Sepsis remains the leading cause of mortality in critically ill patients, and mortality is increased when acute kidney injury (AKI) occurs. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends the implementation of supportive measures in patients at high risk for AKI. However, it remains unclear to what extent these nephroprotective measures are implemented in daily clinical practice in critically ill patients, especially those with high-risk exposures such as sepsis. METHODS: We analyzed the Medical Information Mart for Intensive Care IV (MIMIC-IV) database to identify septic patients with and without AKI. The primary outcome of interest was the adherence to the KDIGO bundle consisting of avoidance of nephrotoxic agents, implementation of a functional hemodynamic monitoring, optimization of perfusion pressure and volume status, close monitoring of renal function, avoidance of hyperglycemia, and avoidance of radiocontrast agents. Secondary outcomes included the development of AKI, progression of AKI, the use of renal replacement therapy (RRT), mortality, and a composite end point consisting of progression of AKI and mortality within 7 days. RESULTS: Our analysis included 34,679 patients with sepsis with 1.6% receiving the complete bundle (10% received 5, 42.3% 4, 35.4% 3, and 9.8% 2 bundle components). In 56.4%, nephrotoxic agents were avoided, and hemodynamic optimization was reached in 86.5%. Secondary end points were improved in patients with bundle adherence. Avoidance of nephrotoxic drugs and optimization of hemodynamics were significantly associated with lower rates of AKI and improved patient outcomes, including 30-day mortality. CONCLUSIONS: Implementation of the KDIGO bundle is poor in patients with sepsis but may be associated with improved outcomes.

Outcomes of systemic bivalirudin and sodium bicarbonate purge solution for Impella 5.5.

BACKGROUND: Impella 5.5 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation and sodium bicarbonate-dextrose purge solution (SBPS) in IMP5.5. METHODS: This single center, retrospective study included 34 patients supported on IMP5.5 with BIV based AC and SBPS between December 1st 2020 to December 1st 2021.The efficacy and safety end points were incidence of development of HIT, Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure as well as clinically significant bleeding. RESULTS: The median duration of IMP5.5 support was 9.8 days (IQR: 6-15). Most patients were bridged to HTX (58%) followed by recovery (27%) and LVAD implantation (15%). Patients were therapeutic on bivalirudin for 64% of their IMP5.5 support. One patient (2.9%) suffered from ischemic stroke and 26.5% (9) patients developed clinically significant bleeding. tPA was administered to 7(21%) patients. One patient in the entire cohort developed HIT. CONCLUSIONS: Our experience supports the use of systemic BIV and SBPS as a method to avoid heparin exposure in a patient population predisposed to the development of HIT.

Association of Metformin Use During Hospitalization and Mortality in Critically Ill Adults With Type 2 Diabetes Mellitus and Sepsis.

OBJECTIVES: Whether metformin exposure is associated with improved outcomes in patients with type 2 diabetes mellitus and sepsis. DESIGN: Retrospective cohort study. SETTING: Patients admitted to ICUs in 16 hospitals in Pennsylvania from October 2008 to December 2014. PATIENTS: Adult critical ill patients with type 2 diabetes mellitus and sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We conducted a retrospective cohort study to compare 90-day mortality in diabetic patients with sepsis with and without exposure to metformin during hospitalization. Data were obtained from the electronic health record of a large healthcare system in Pennsylvania from October 2008 to December 2014, on patients admitted to the ICU at any of the 16 hospitals within the system. The primary outcome was mortality at 90 days. The absolute and adjusted odds ratio (OR) with 95% CI were calculated in a propensity score-matched cohort. Among 14,847 patients with type 2 diabetes mellitus and sepsis, 682 patients (4.6%) were exposed to metformin during hospitalization and 14,165 (95.4%) were not. Within a total of 2,691 patients subjected to propensity score-matching at a 1:4 ratio, exposure to metformin (n = 599) was associated with decreased 90-day mortality (71/599, 11.9% vs 475/2,092, 22.7%; OR, 0.46; 95% CI, 0.35-0.60), reduced severe acute kidney injury (50% vs 57%; OR, 0.75; 95% CI, 0.62-0.90), less Major Adverse Kidney Events at 1 year (OR, 0.27; 95% CI, 0.22-0.68), and increased renal recovery (95% vs 86%; OR, 6.43; 95% CI, 3.42-12.1). CONCLUSIONS: Metformin exposure during hospitalization is associated with a decrease in 90-day mortality in patients with type 2 diabetes mellitus and sepsis.

ECMO and Impella Support Strategies as a Bridge to Surgical Repair of Post-Infarction Ventricular Septal Rupture.

Background and Objectives: Post-infarct ventricular septal rupture (PIVSR) continues to have significant morbidity and mortality, despite decreased prevalence. Impella and venoarterial extracorporeal membranous oxygenation (VA-ECMO) have been proposed as strategies to correct hemodynamic derangements and bridge patients to delayed operative repair when success rates are higher. This review places VA-ECMO and Impella support strategies in the context of bridging patients to successful PIVSR repair, with an additional case report of successful bridging with the Impella device. Materials and Methods: We report a case of PIVSR repair utilizing 14 days of Impella support. We additionally conducted a systematic review of contemporary literature to describe the application of VA-ECMO and Impella devices in the pre-operative period prior to surgical PIVSR correction. Expert commentary on the advantages and disadvantages of each of these techniques is provided. Results: We identified 19 studies with 72 patients undergoing VA-ECMO as a bridge to PIVSR repair and 6 studies with 11 patients utilizing an Impella device as a bridge to PIVSR repair. Overall, outcomes in both groups were better than expected from patients who were historically managed with medicine and balloon pump therapy, however there was a significant heterogeneity between studies. Impella provided for excellent left ventricular unloading, but did result in some concerns for reversal of shunting. VA-ECMO resulted in improved end-organ perfusion, but carried increased risks of device-related complications and requirement for additional ventricular unloading. Conclusions: Patients presenting with PIVSR in cardiogenic shock requiring a MCS bridge to definitive surgical repair continue to pose a challenge to the multidisciplinary cardiovascular team as the diverse presentation and management issues require individualized care plans. Both VA-ECMO and the Impella family of devices play a role in the contemporary management of PIVSR and offer distinct advantages and disadvantages depending on the clinical scenario. The limited case numbers reported demonstrate feasibility, safety, and recommendations for optimal management.

Effects of 5% Albumin Plus Saline Versus Saline Alone on Outcomes From Large-Volume Resuscitation in Critically Ill Patients.

OBJECTIVES: To compare 5% albumin with 0.9% saline for large-volume resuscitation (> 60 mL/Kg within 24 hr), on mortality and development of acute kidney injury. DESIGN: Retrospective cohort study. SETTING: Patients admitted to ICUs in 13 hospitals across Western Pennsylvania. We analyzed two independent cohorts, the High-Density Intensive Care databases: High-Density Intensive Care-08 (July 2000 to October 2008, H08) and High-Density Intensive Care-15 (October 2008 to December 2014, H15). PATIENTS: Total of 18,629 critically ill patients requiring large-volume resuscitation. INTERVENTIONS: Five percent of albumin in addition to saline versus 0.9% saline. MEASUREMENTS AND MAIN RESULTS: After excluding patients with acute kidney injury prior to large-volume resuscitation, 673 of 2,428 patients (27.7%) and 1,814 of 16,201 patients (11.2%) received 5% albumin in H08 and H15, respectively. Use of 5% albumin was associated with decreased 30-day mortality by multivariate regression in H08 (odds ratio 0.65; 95% CI 0.49-0.85; p = 0.002) and in H15 (0.52; 95% CI 0.44-0.62; p < 0.0001) but was associated with increased acute kidney injury in H08 (odds ratio 1.98; 95% CI 1.56-2.51; p < 0.001) and in H15 (odds ratio 1.75; 95% CI 1.58-1.95; p < 0.001). However, 5% albumin was not associated with persistent acute kidney injury and resulted in decreased major adverse kidney event at 30, 90, and 365 days. Propensity matched analysis confirmed similar associations with mortality and acute kidney injury. CONCLUSIONS: During large-volume resuscitation, 5% albumin was associated with reduced mortality and major adverse kidney event at 30, 90, and 365 days. However, a higher rate of acute kidney injury of any stage was observed that did not translate into persistent renal dysfunction.

Comparison of Anticoagulation Strategies in Patients Requiring Venovenous Extracorporeal Membrane Oxygenation: Heparin Versus Bivalirudin.

OBJECTIVES: Extracorporeal membrane oxygenation is a life-sustaining therapy for severe respiratory failure. Extracorporeal membrane oxygenation circuits require systemic anticoagulation that creates a delicate balance between circuit-related thrombosis and bleeding-related complications. Although unfractionated heparin is most widely used anticoagulant, alternative agents such as bivalirudin have been used. We sought to compare extracorporeal membrane oxygenation circuit thrombosis and bleeding-related outcomes in respiratory failure patients receiving either unfractionated heparin or bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation support. DESIGN: Retrospective cohort study. SETTING: Single-center, cardiothoracic ICU. PATIENTS: Consecutive patients requiring venovenous extracorporeal membrane oxygenation who were maintained on anticoagulation between 2013 and 2020. INTERNVENTIONS: IV bivalirudin or IV unfractionated heparin. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were the presence of extracorporeal membrane oxygenation in-circuit-related thrombotic complications and volume of blood products administered during extracorporeal membrane oxygenation duration. One hundred sixty-two patients receiving unfractionated heparin were compared with 133 patients receiving bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation. In patients receiving bivalirudin, there was an overall decrease in the number of extracorporeal membrane oxygenation circuit thrombotic complications (p < 0.005) and a significant increase in time to circuit thrombosis (p = 0.007). Multivariable Cox regression found that heparin was associated with a significant increase in risk of clots (Exp[B] = 2.31, p = 0.001). Patients who received bivalirudin received significantly less volume of packed RBCs, fresh frozen plasma, and platelet transfusion (p < 0.001 for each). There was a significant decrease in the number major bleeding events in patients receiving bivalirudin, 40.7% versus 11.7%, p < 0.001. CONCLUSIONS: Patients receiving bivalirudin for systemic anticoagulation on venovenous extracorporeal membrane oxygenation experienced a decrease in the number of extracorporeal membrane oxygenation circuit-related thrombotic events as well as a significant decrease in volume of blood products administered.

Activation of AMP-activated protein kinase during sepsis/inflammation improves survival by preserving cellular metabolic fitness.

The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis-induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10- to 12-week-old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O2 consumption rates (OCR) and the membrane potential (Δψm ). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6-24 hours after CLP/IM. Pharmacologic activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK-driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects TEC, organs, and the host by preserving mitochondrial function and metabolic fitness likely through Sirt3 signaling.

Pannexin 1 mediates ferroptosis that contributes to renal ischemia/reperfusion injury.

Renal ischemia/reperfusion injury (IRI) is a significant challenge in perioperative medicine and is related to oxidative programmed cell death. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been evaluated widely. Pannexin 1 (PANX1), an ATP-releasing pathway family protein, has pro-apoptotic effects during kidney injury. Here, we demonstrate that PANX1 deletion protects against renal IRI by regulating ferroptotic cell death. Panx1 knockout mice subjected to renal IRI had decreased plasma creatinine, malondialdehyde (MDA) levels in kidney tissues, and tubular cell death (visible as decreased TUNEL-positive renal tubular cells) compared with WT mice. In cultured human kidney 2 (HK-2) cells, silenced Panx1 expression significantly attenuated ferroptotic lipid peroxidation and iron accumulation induced by the ferroptosis inducer erastin. Moreover, the Panx1 silencing significantly modulated ferroptosis-related protein expression. Furthermore, Panx1 deletion induced the expression of a cytoprotective chaperone, heme oxygenase-1 (HO-1), and inhibited ferroptinophagy via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. In summary, Panx1 deletion protects against renal IRI by attenuating MAPK/ERK activation in a ferroptotic pathway. Our findings provide critical insights into the role of PANX1 in ferroptotic cell death and highlight a potential therapeutic target for the management of acute kidney injury (AKI) during the perioperative period.

Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment.

Sepsis-associated acute kidney injury (S-AKI) is a frequent complication of the critically ill patient and is associated with unacceptable morbidity and mortality. Prevention of S-AKI is difficult because by the time patients seek medical attention, most have already developed acute kidney injury. Thus, early recognition is crucial to provide supportive treatment and limit further insults. Current diagnostic criteria for acute kidney injury has limited early detection; however, novel biomarkers of kidney stress and damage have been recently validated for risk prediction and early diagnosis of acute kidney injury in the setting of sepsis. Recent evidence shows that microvascular dysfunction, inflammation, and metabolic reprogramming are 3 fundamental mechanisms that may play a role in the development of S-AKI. However, more mechanistic studies are needed to better understand the convoluted pathophysiology of S-AKI and to translate these findings into potential treatment strategies and add to the promising pharmacologic approaches being developed and tested in clinical trials.

Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis.

Importance: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. Objective: To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs). Design, Settings, and Participants: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737). Exposures: All clinical and laboratory variables in the electronic health record. Main Outcomes and Measures: Derived phenotype (α, ß, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs. Results: The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the ß phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the ß phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm). Conclusions and Relevance: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.

Tailored Helicobacter pylori eradication based on prior intake of macrolide antibiotics allows the use of triple therapy with optimal results in an area with high clarithromycin resistance.

BACKGROUND: the previous intake of macrolide antibiotics is associated with a failure to eradicate Helicobacter pylori (H. pylori) with clarithromycin-containing regimens. However, the standard triple therapy achieves eradication rates of over 90% in patients without a previous use of macrolides in our health area. The aim of this study was to evaluate the efficacy of an H. pylori eradication strategy based on the intake of macrolides by the patient during the previous years. METHODS: one hundred and sixty-nine patients with H. pylori infection were prospectively included in the study. The electronic medical record of each patient was reviewed at the time of inclusion. Depending on their previous intake of macrolides, patients were assigned to one of two eradication regimens: group A) patients without a previous intake of macrolides received an optimized triple therapy for 14 days; and group B) patients with a previous intake of macrolides received bismuth quadruple therapy for ten days. RESULTS: ninety-one patients (53.84%) without a previous intake of macrolides received an optimized triple therapy (group A) and 78 patients (46.15%) with a previous intake of macrolides received bismuth quadruple therapy (group B). In group A, the H. pylori eradication rates were 90.11% in the intention-to-treat and 95.35% in the per-protocol analysis. In group B, the H. pylori eradication rates were 85.89% in the intention-to-treat and 98.5% in the per-protocol analysis. The overall eradication rates obtained using this strategy were 88.16% (95% CI: 82.32-92.02%) in the intention-to-treat and 96.75% (95% CI: 92.59-98.94%) in the per-protocol analysis. CONCLUSIONS: an H. pylori eradication strategy based on the intake of macrolides during the previous years achieves overall eradication rates close to 90% and allows the use of standard triple therapy in more than half of the patients from a health area with a high level of clarithromycin resistance.

Hepatitis B virus e antigen-negative chronic infection. Treatment based on glutamic pyruvic transaminase and hepatitis B virus deoxyribonucleic acid cut-off values. / Infección crónica por virus de la hepatitis B antígeno e negativo. Manejo en función de puntos de corte de glutámico-pirúvica transaminasa y ácido desoxirribonucleico del virus de la hepatitis B.

OBJECTIVES: To identify glutamic pyruvic transaminase (GPT) and hepatitis B virus DNA (HBV-DNA) cut-off values at diagnosis in patients with hepatitis B virus e antigen-negative chronic infection (HBeAg(-)), which may be predictors of clinical course, prognosis and/or the need for antiviral therapy. METHODS: A retrospective and observational cohort study of patients diagnosed with HBeAg(-) chronic infection (2005-2012). A normal GPT cut-off value at diagnosis that predicts abnormal GPT values in the clinical course of the infection, a baseline HBV-DNA cut-off value that predicts an increase in HBV-DNA above 2,000IU/ml, and GPT and HBV-DNA as predictors of the need for treatment were investigated using ROC curves. RESULTS: 126 patients were enrolled (follow-up: 42.1±21.5months), 93 of which had normal GPT levels at diagnosis. In the ROC curve analysis, 900IU/ml was found to be the HBV-DNA cut-off value that best predicted this value's increase above 2,000IU/ml (sensitivity: 90%; specificity: 88%; PPV: 79%; NPV: 100%; diagnostic precision: 89%), while 25mU/ml was the normal GPT cut-off value at diagnosis that best predicted subsequently elevated GPT levels (sensitivity: 95.4%; specificity: 81.6%; PPV: 67%; NPV: 96%; diagnostic precision: 80.6%). Patients with GPT 26-40mU/ml at diagnosis presented with more complications or required more treatment than subjects with GPT≤25mU/ml (P<.05). The combined GPT and HBV-DNA values that elicited the highest treatment need were 38mU/ml of GPT and 6,000IU/ml of HBV-DNA (sensitivity: 75%; specificity: 93.4%; PPV: 60%; NPV: 96.6%). CONCLUSION: HBeAg(-) patients with GPT<25mU/ml and HBV-DNA<900IU/ml at diagnosis have positive outcomes and may not require such stringent follow-up in the first years after diagnosis.

Insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2: differential expression and secretion in human kidney tubule cells.

We have characterized the expression and secretion of the acute kidney injury (AKI) biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in human kidney epithelial cells in primary cell culture and tissue. We established cell culture model systems of primary kidney cells of proximal and distal tubule origin and observed that both proteins are indeed expressed and secreted in both tubule cell types in vitro. However, TIMP-2 is both expressed and secreted preferentially by cells of distal tubule origin, while IGFBP7 is equally expressed across tubule cell types yet preferentially secreted by cells of proximal tubule origin. In human kidney tissue, strong staining of IGFBP7 was seen in the luminal brush-border region of a subset of proximal tubule cells, and TIMP-2 stained intracellularly in distal tubules. Additionally, while some tubular colocalization of both biomarkers was identified with the injury markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, both biomarkers could also be seen alone, suggesting the possibility for differential mechanistic and/or temporal profiles of regulation of these early AKI biomarkers from known markers of injury. Last, an in vitro model of ischemia-reperfusion demonstrated enhancement of secretion of both markers early after reperfusion. This work provides a rationale for further investigation of these markers for their potential role in the pathogenesis of acute kidney injury.

The crashing patient: hemodynamic collapse.

PURPOSE OF REVIEW: Rapid restoration of tissue perfusion and oxygenation are the main goals in the resuscitation of a patient with circulatory collapse. This review will focus on providing an evidence based framework of the technological and conceptual advances in the evaluation and management of the patient with cardiovascular collapse. RECENT FINDINGS: The initial approach to the patient in cardiovascular collapse continues to be based on the Ventilate-Infuse-Pump rule. Point of care ultrasound is the preferred modality for the initial evaluation of undifferentiated shock, providing information to narrow the differential diagnosis, to assess fluid responsiveness and to evaluate the response to therapy. After the initial phase of resuscitative fluid administration, which focuses on re-establishing a mean arterial pressure to 65 mmHg, the use of dynamic parameters to assess preload responsiveness such as the passive leg raise test, stroke volume variation, pulse pressure variation and collapsibility of the inferior vena cava in mechanically ventilated patients is recommended. SUMMARY: The crashing patient remains a clinical challenge. Using an integrated approach with bedside ultrasound, dynamic parameters for the evaluation of fluid responsiveness and surrogates of evaluation of tissue perfusion have made the assessment of the patient in shock faster, safer and more physiologic.