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Purpose: We have recently shown that PCSK9 reduces the clearance of endotoxin and is therefore a critical regulator of the innate immune response during infection. However, plasma PCSK9 levels during human sepsis and their relationship to outcomes are not known. Our objective was to determine the relationship between plasma PCSK9 levels and the rate of endotoxin clearance, and then correlate PCSK9 levels with the development of acute organ failures in a cohort of patients with sepsis. Methods: Using human hepatocyte cells, we determined the threshold at which PCSK9 is able to reduce Escherichia coli endotoxin uptake by cultured human hepatocytes. In a single-centre observational cohort at St. Paul's Hospital in Vancouver, Canada, we recruited 200 patients who activated our Emergency Department's sepsis protocol and measured plasma PCSK9 and lipid levels at triage and throughout the admission. Outcomes were the development of sepsis-induced cardiovascular or respiratory failure. Results: We reviewed the literature and determined that the normal human range of PCSK9 found in plasma is 170-220 ng/ml, while levels of 250 ng/ml and above reduced E. coli endotoxin clearance in cultured human hepatocytes. In septic patients, the median levels associated with new-onset respiratory and cardiovascular failure were 370 (250-500) and 380 (270-530) ng/ml, respectively, versus 270 (220-380) ng/ml in patients who did not go on to develop any organ failure (p = 0.003 and 0.005, respectively). Conclusions: Plasma PCSK9 levels are greatly increased in sepsis. At normal levels, PCSK9 has no influence upon hepatocyte bacterial endotoxin clearance, but as levels rise, there is a progressive inhibition of clearance. During sepsis, PCSK9 levels are highly correlated with the development of subsequent multiple organ failure. Inhibition of PCSK9 activity is an attractive target for treating the spectrum of sepsis and septic shock.

Limited echocardiography-guided management following early resuscitation is associated with improved survival, less fluid, and increased inotropic prescription. A prospective randomized control trial is required to verify these results.

BackgroundIn critically ill patients at risk for organ failure, the administration of intravenous fluids has equal chances of resulting in benefit or harm. While the intent of intravenous fluid is to increase cardiac output and oxygen delivery, unwelcome results in those patients who do not increase their cardiac output are tissue edema, hypoxemia, and excess mortality. Here we briefly review bedside methods to assess fluid responsiveness, focusing upon the strengths and pitfalls of echocardiography in spontaneously breathing mechanically ventilated patients as a means to guide fluid management. We also provide new data to help clinicians anticipate bedside echocardiography findings in vasopressor-dependent, volume-resuscitated patients.ObjectiveTo review bedside ultrasound as a method to judge whether additional intravenous fluid will increase cardiac output. Special emphasis is placed on the respiratory effort of the patient.ConclusionsPoint-of-care echocardiography has the unique ability to screen for unexpected structural findings while providing a quantifiable probability of a patient’s cardiovascular response to fluids. Measuring changes in stroke volume in response to either passive leg raising or changes in thoracic pressure during controlled mechanical ventilation offer good performance characteristics but may be limited by operator skill, arrhythmia, and open lung ventilation strategies. Measuring changes in vena caval diameter induced by controlled mechanical ventilation demands less training of the operator and performs well during arrythmia. In modern delivery of critical care, however, most patients are nursed awake, even during mechanical ventilation. In patients making respiratory efforts we suggest that ventilator settings must be standardized before assessing this promising technology as a guide for fluid management.

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Urgent cardiac ultrasound examination in the critical care setting is clinically useful. Application of goal-directed echocardiography in this setting is quite distinct from typical exploratory diagnostic comprehensive echocardiography, because the urgent critical care setting mandates a goal-directed approach. Goal-directed echocardiography most frequently aims to rapidly identify and differentiate the cause(s) of hemodynamic instability and/or the cause(s) of acute respiratory failure. Accordingly, this paper highlights 1) indications, 2) an easily memorized differential diagnostic framework for goal-directed echocardiography, 3) clinical questions that must be asked and answered, 4) practical issues to allow optimal image capture, 5) primary echocardiographic views, 6) key issues addressed in each view, and 7) interpretation of findings within the differential diagnostic framework. The most frequent indications for goal-directed echocardiography include 1) the spectrum of hemodynamic instability, shock, and pulseless electrical activity arrest and 2) acute respiratory failure. The differential diagnostic categories for hemodynamic instability can be remembered using the mnemonic ‘SHOCK’ (for Septic, Hypovolemic, Obstructive, Cardiogenic, and (K) combinations/other kinds of shock). RESP-F (for exacerbation of chronic Respiratory disease, pulmonary Embolism, ST changes associated with cardiac or pericardial disease, Pneumonia, and heart Failure) can be used for acute respiratory failure. The goals of goal-directed echocardiography in the unstable patient are: assessing global ventricular systolic function, identifying marked right ventricular and left ventricular enlargement, assessing intravascular volume, and the presence of a pericardial effusion. In an urgent or emergent setting, it is recommended to go directly to the best view, which is frequently the subcostal or apical view. The five views are the subcostal four-chamber view, subcostal inferior vena cava view, parasternal long axis view, parasternal short axis view, and the apical four chamber view. Always interpret goal-directed echocardiographic findings in the context of clinically available hemodynamic information. When goal-directed echocardiography is insufficient or when additional abnormalities are appreciated, order a comprehensive echocardiogram. Goal-directed echocardiography and comprehensive echocardiography are not to be used in conflict with each other.

Preoperative and intraoperative variables can be used on admission to a cardiac surgical ICU to estimate 30-day mortality. The score could be used for risk stratification after cardiac surgery and evaluation of performance of cardiac surgical ICUs.