Oligonucleotide-based Preconditioning of DCD Cardiac Donors and Its Impact on Cardiac Viability.

BACKGROUND: While clinical donation after circulatory death (DCD) cardiac transplantation is being implemented with increasing frequency to address the supply/demand mismatch of donor grafts, no research to date has examined a strategy of donor preconditioning to optimize the viability of DCD hearts for transplantation. In our rat model of the DCD protocol, we investigate the impact of pretreating donors with phosphorothioate-linked cytosine and guanine rich oligodeoxynucleotides (CpG ODN) and their effects on cardiac function, injury, and a novel left ventricular (LV) mRNA biomarker panel. METHODS: DCD rats were subjected to a withdrawal protocol, followed by 20 minutes of warm acirculatory standoff, representing a group of severely injured hearts as previously demonstrated. Beating heart controls and DCD rats were pretreated with vehicle or stimulatory CpG ODN (beating heart control and DCD stimulated with CpG ODN, BST and DST). Hearts were harvested for ex situ heart perfusion (ESHP), where LV function, histochemical injury, and differences in gene expression were characterized between groups. RESULTS: Donor pretreatment with CpG ODN doubled the number of functional DCD hearts at ESHP. Pretreatment was associated with improved systolic and diastolic LV function, a reduction in histological injury, and markedly reduced elaboration of cardiac troponin-I in coronary effluent during ESHP. Pretreatment was also associated with a reduction in mRNA biomarkers associated with myocardial injury. CONCLUSIONS: A single dose of CpG ODN was associated with reduced biomarkers of cardiac injury and a 100% increase in cardiac viability in this rodent model of marginal DCD cardiac donation.

A score to estimate 30-day mortality after intensive care admission after cardiac surgery.

OBJECTIVE: Several risk-scoring systems have been developed to predict surgical mortality and complications in cardiac surgical patients, but none of the current systems include factors related to the intraoperative period. The purpose of this study was to develop a score that incorporates both preoperative and intraoperative factors so that it could be used for patients admitted to a cardiac surgical intensive care unit (ICU) immediately after surgery. METHOD: Preoperative and intraoperative data from 30,350 patients in four hospitals were used to build a multiple logistic regression model estimating 30-day mortality after cardiac surgery. Sixty percent of the patients were used as a derivation group and forty percent as a validation group. RESULTS: Mortality occurred in 2.6% of patients (n = 790). Preoperative factors identified in the model were age, female sex, emergency status, pulmonary hypertension, peripheral vascular disease, renal dysfunction, diabetes, peptic ulcer disease, history of alcohol abuse, and refusal of blood products. Intraoperative risk factors included the need for an intra-aortic balloon pump, ventricular assist device or extracorporeal membrane oxygenation leaving the operating room, presence of any intraoperative complication reported by the surgeon, the use of inotropes, high-dose vasopressors, red blood cell transfusion, and cardiopulmonary bypass time. When used after surgery at ICU admission, the model had C-statistics of 0.86 in both derivation and validation sets to estimate the 30-day mortality. CONCLUSIONS: 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.

Will This Hemodynamically Unstable Patient Respond to a Bolus of Intravenous Fluids?

IMPORTANCE: Fluid overload occurring as a consequence of overly aggressive fluid resuscitation may adversely affect outcome in hemodynamically unstable critically ill patients. Therefore, following the initial fluid resuscitation, it is important to identify which patients will benefit from further fluid administration. OBJECTIVE: To identify predictors of fluid responsiveness in hemodynamically unstable patients with signs of inadequate organ perfusion. DATA SOURCES AND STUDY SELECTION: Search of MEDLINE and EMBASE (1966 to June 2016) and reference lists from retrieved articles, previous reviews, and physical examination textbooks for studies that evaluated the diagnostic accuracy of tests to predict fluid responsiveness in hemodynamically unstable adult patients who were defined as having refractory hypotension, signs of organ hypoperfusion, or both. Fluid responsiveness was defined as an increase in cardiac output following intravenous fluid administration. DATA EXTRACTION: Two authors independently abstracted data (sensitivity, specificity, and likelihood ratios [LRs]) and assessed methodological quality. A bivariate mixed-effects binary regression model was used to pool the sensitivities, specificities, and LRs across studies. RESULTS: A total of 50 studies (N = 2260 patients) were analyzed. In all studies, indices were measured before assessment of fluid responsiveness. The mean prevalence of fluid responsiveness was 50% (95% CI, 42%-56%). Findings on physical examination were not predictive of fluid responsiveness with LRs and 95% CIs for each finding crossing 1.0. A low central venous pressure (CVP) (mean threshold <8 mm Hg) was associated with fluid responsiveness (positive LR, 2.6 [95% CI, 1.4-4.6]; pooled specificity, 76%), but a CVP greater than the threshold made fluid responsiveness less likely (negative LR, 0.50 [95% CI, 0.39-0.65]; pooled sensitivity, 62%). Respiratory variation in vena cava diameter measured by ultrasound (distensibility index >15%) predicted fluid responsiveness in a subgroup of patients without spontaneous respiratory efforts (positive LR, 5.3 [95% CI, 1.1-27]; pooled specificity, 85%). Patients with less vena cava distensibility were not as likely to be fluid responsive (negative LR, 0.27 [95% CI, 0.08-0.87]; pooled sensitivity, 77%). Augmentation of cardiac output or related parameters following passive leg raising predicted fluid responsiveness (positive LR, 11 [95% CI, 7.6-17]; pooled specificity, 92%). Conversely, the lack of an increase in cardiac output with passive leg raising identified patients unlikely to be fluid responsive (negative LR, 0.13 [95% CI, 0.07-0.22]; pooled sensitivity, 88%). CONCLUSIONS AND RELEVANCE: Passive leg raising followed by measurement of cardiac output or related parameters may be the most useful test for predicting fluid responsiveness in hemodynamically unstable adults. The usefulness of respiratory variation in the vena cava requires confirmatory studies.

Echocardiography as a guide for fluid management.

BACKGROUND: In 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. OBJECTIVE: To 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. CONCLUSIONS: Point-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.

Assessment of adequacy of volume resuscitation.

PURPOSE OF REVIEW: It has recently become evident that administration of intravenous fluids following initial resuscitation has a greater probability of producing tissue edema and hypoxemia than of increasing oxygen delivery. Therefore, it is essential to have a rational approach to assess the adequacy of volume resuscitation. Here we review passive leg raising (PLR) and respiratory variation in hemodynamics to assess fluid responsiveness. RECENT FINDINGS: The use of ultrasound enhances the clinician's ability to detect and predict fluid responsiveness, whereas enthusiasm for this modality must be tempered by recent evidence that it is only reliable in apneic patients. SUMMARY: The best predictor of fluid response for hypotensive patients not on vasopressors is a properly conducted passive leg raise maneuver. For more severely ill patients who are apneic, mechanically ventilated and on vasopressors, point of care echocardiography is the best choice. Increases in vena caval diameter induced by controlled positive pressure breaths are insensitive to arrhythmias and can be performed with relatively brief training. Most challenging are patients who are awake and on vasopressors; we suggest that the best method to discriminate fluid responders is PLR measuring changes in cardiac output.

Early veno-venous extracorporeal membrane oxygenation is associated with lower mortality in patients who have severe hypoxemic respiratory failure: A retrospective multicenter cohort study.

PURPOSE: The purpose of the study is to compare outcomes in patients who had severe hypoxemic respiratory failure (Pao2/fraction of inspired oxygen <100) who received early veno-venous extracorporeal membrane oxygenation (ECMO) as an adjunct to mechanical ventilation, to those in patients who received conventional mechanical ventilation alone. MATERIALS AND METHODS: This is a multicenter, retrospective unmatched and matched cohort study of patients admitted between April 2006 and December 2013. Generalized logistic mixed-effects models and Cox proportional hazards models were used to determine the association between treatment with ECMO that was started within 3 days of intensive care unit (ICU) admission and ICU and hospital mortality and length of stay, respectively. RESULTS: A total of 2440 patients who had severe hypoxemic respiratory failure due to various etiologies were included, 46 who received early veno-venous ECMO and 2394 unmatched and 398 matched controls who received conventional ventilation alone. Compared to matched controls, ECMO was associated with a lower odds of ICU (odds ratio [95% confidence interval], 0.30 [0.13-0.67]) and inhospital death (odds ratio 0.30 [0.14-0.67]). In addition, ECMO was associated with longer times to discharge from ICU and hospital (hazard ratio, 0.42 [0.37-0.47] and 0.53 [0.38-0.73], respectively). CONCLUSIONS: In this observational study, use of early ECMO compared to conventional mechanical ventilation alone in patients who had severe hypoxemic respiratory failure was associated with a lower risk of mortality and a longer length of stay.

Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis.

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.

Impact of work schedules on sleep duration of critical care nurses.

BACKGROUND: Sleep deprivation leads to reduced vigilance and potentially impairs work performance. Nurses may work long shifts that may contribute to sleep deprivation. OBJECTIVE: To assess how nurses' sleep patterns are affected by work schedules and other factors. METHODS: Between October 2009 and June 2010, a total of 20 critical care nurses completed daily sleep and activity logs and a demographic survey and wore an actigraph to objectively measure sleep time for 14 days. RESULTS: In a multivariate model with controls for repeated measures, mean sleep time between consecutive work shifts was short: 6.79 hours between 2 day shifts and 5.68 hours between 2 night shifts (P = .01). Sleep time was much greater between days when no shifts were worked (8.53 hours), consistent with catch-up sleep during these times. Every minute of 1-way commuting time was associated with a reduction of sleep time by 0.84 minutes. CONCLUSION: Critical care nurses obtain reduced amounts of sleep between consecutive work shifts, particularly between consecutive night shifts. Whether this degree of sleep deprivation adversely affects patients' safety needs further study.

Limited echocardiography-guided therapy in subacute shock is associated with change in management and improved outcomes.

PURPOSE: The purpose of the study was to compare the effect of limited echocardiography (LE)-guided therapy to standard management on 28-day mortality, intravenous fluid prescription, and inotropic dosing following early resuscitation for shock. MATERIALS AND METHODS: Two hundred twenty critically ill patients with undifferentiated shock from a quaternary intensive care unit were included in the study. The LE group consisted of 110 consecutive patients prospectively studied over a 12-month period receiving LE-guided management. The standard management group consisted of 110 consecutive patients retrospectively studied with shock immediately prior to the LE intervention. RESULTS: In the LE group, fluid restriction was recommended in 71 (65%) patients and initiation of dobutamine in 27 (25%). Fluid prescription during the first 24 hours was significantly lower in LE patients (49 [33-74] vs 66 [42-100] mL/kg, P = .01), whereas 55% more LE patients received dobutamine (22% vs 12%, P = .01). The LE patients had improved 28-day survival (66% vs 56%, P = .04), a reduction in stage 3 acute kidney injury (20% vs 39%), and more days alive and free of renal support (28 [9.7-28] vs 25 [5-28], P = .04). CONCLUSIONS: 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.

A practical approach to goal-directed echocardiography in the critical care setting.

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.

A survey of standardized management protocols after coronary artery bypass grafting surgery in Canadian intensive care units.

BACKGROUND: Patients undergoing surgical coronary revascularization typically recover in an intensive care unit where many aspects of patient care are protocolized despite absence of widespread evidence-based guidelines on perioperative management. It was hypothesized that the postoperative management strategies varied significantly among units. METHODS: We surveyed 31 Canadian cardiac surgical intensive care units to obtain their postoperative standing orders. Management strategies after coronary bypass surgery were compared to identify areas of variability in the care of frequent clinical scenarios. RESULTS: In all, 28 units (90%) responded, and 26 sites (84%) reported using at least 1 formal postoperative protocol. All but 1 of the responding units (96%) have specific orders for coronary artery bypass graft patients. Orders for allogeneic red blood cell transfusion threshold, postoperative extubation pathway, analgesia, and atrial fibrillation management were present in 40%, 74%, 60%, and 57% of the responding units, respectively. A protocolized trigger to notify the surgeon was specified for bleeding and hypotension in 75% and 35% of the centres, respectively. A standing order for aspirin administration was used in 91% of the centres, and statin administration was mentioned in 41%. Despite the frequent use of protocols in postoperative care, the content of the protocol varied significantly from centre to centre. CONCLUSION: The majority of Canadian centres use at least 1 formal protocol for the care of the postoperative coronary revascularization patient. There is, however, significant variability in these management protocols. Future studies should examine whether implementation of standardized protocols improves outcomes and what treatment strategies are optimal in postoperative cardiac surgical patients.