Year in review 2011: Critical Care - cardiology
© BioMed Central Ltd. 2012
Published: 10 December 2012
We review key research papers in cardiology and intensive care published during 2011in Critical Care and quote related studies published in other journalswhenever appropriate. Papers are grouped into the following categories:cardiovascular therapies, mechanical therapies, biomarkers, prognostic markers,hemodynamic monitoring, cardiovascular diseases, microcirculation, hypertension incritically ill patients, and miscellaneous.
We review key research papers in intensive care cardiology published during 2011 inCritical Care. Related studies published in other journals are alsodiscussed, whenever appropriate.
Inotropic agents are used to increase oxygen delivery in the perioperative setting buttheir impact on mortality is not well defined. In a retrospective study including 1,326cardiac surgery patients, those exposed to inotropes had, as expected, a higherunadjusted mortality rate than those patients not exposed . After adjustment, inotrope exposure was still associated with increasedhospital mortality and renal dysfunction. A propensity score-matched analysis yieldedsimilar results. A limitation of this trial is that this type of analysis only takesinto account measured variables, but other factors may play a role. Postoperativeinotrope exposure may thus be associated with worse outcomes, but this should be testedin interventional trials.
Should nonadrenergic inotropic agents be preferred? A meta-analysis evaluated theeffects of levosimendan, versus control, in patients after percutaneous or surgicalcardiac revascularization . The meta-analysis included 729 patients from 17 studies. Levosimendanincreased the cardiac index. Compared with controls, levosimendan treatment wasassociated with a mortality reduction after coronary revascularization (odds ratio =0.40, 95% confidence interval (CI) = 0.21 to 0.76) and a reduction in the length of ICUstay. An important limitation of this analysis is that most of the studies included weresmall sized, and that there was an important heterogeneity in dosing and time ofadministration of levosimendan as well as in drugs used in the control arms. Thispotentially beneficial effect of levosimendan should be evaluated in a large-scalerandomized trial.
Another meta-analysis evaluated the renal effects of carperitide, an atrial natriureticpeptide, and nesiritide, a B-type natriuretic peptide (BNP) . The systematic review included 15 studies (11 with carperitide and four withnesiritide), of which nine were included in the meta-analysis. There was no dierence inmortality rates. Both drugs increased urine output, creatinine clearance and glomerularfiltration rate, and reduced the use of diuretics, renal replacement therapy and lengthof ICU and hospital stay. Unfortunately most trials were small sized and these resultsshould be confirmed in a larger randomized trial.
Anticoagulation during use of mechanical devices is a continuous challenge. Ranucci andcolleagues retrospectively compared a conventional heparin-based anticoagulationprotocol with a bivalirudin-based protocol in 21 patients submitted to extracorporealmembrane oxygenation (ECMO) after cardiac operations . Patients treated with bivalirudin achieved significantly better coagulationvariables. Thromboembolic complications did not differ between groups but bivalirudinpatients required less blood product transfusions. Accordingly, bivalirudin appears tobe an attractive alternative to conventional heparin, but this agent should be tested ina randomized trial.
Two papers report single-center experience of using mechanical interventions. One studylooked at the potential benefit of routine coronary angiography after out-of-hospitalcardiac arrest (OHCA). Cronier and colleagues evaluated a series of 111 consecutivehemodynamically stable patients resuscitated from OHCA due to ventricular fibrillationand treated with mild therapeutic hypothermia . Emergency coronary angiography was performed in most patients, regardless ofthe electrocardiogram pattern. Most patients (73%) had coronary heart disease, but thisincidence was lower in patients <45 years old than in other groups (41% vs. 81%;P = 0.01). Percutaneous coronary intervention was associated with survival.These results were extended later this year in a larger database of 1,040 OHCA patientsin Germany that reported similar benefits whatever the initial rhythm . The potential benefits of a combination of angiography and mild therapeutichypothermia were discussed in an accompanying editorial .
The other paper described the use of an intra-aortic balloon pump, ECMO andcontinuous-flow left ventricular assist devices in six patients with peripartumcardiomyopathy . Two patients showed partial recovery and could be weaned o the intra-aorticballoon pump while four patients were implanted with a left ventricular assist device,including the ECMO patient. Three left ventricular assist device patients weresuccessfully transplanted. Mechanical support should be considered in patients withperipartum cardiomyopathy not responding to medical therapy. The choice of the supportand optimal timing of implantation is still under debate.
Several studies evaluated in various settings the usefulness of biomarkers to understandpathophysiological processes, to guide therapy or to refine diagnosis.
Biomarkers as an inside to pathophysiology
Post-cardiac surgery vasoplegia frequently occurs, especially after prolongedcardiopulmonary bypass. A perioperative course of copeptin (a vasopressin precursor)and vasopressin plasma concentrations were studied in 64 consecutive patientssubmitted to elective cardiac surgery . Patients with vasoplegia had lower vasopressin concentrations 8 hoursafter surgery compared with controls. Interestingly, these patients had asignificantly higher copeptin plasma concentration, hyponatremia and a lower ejectionfraction before cardiopulmonary bypass compared with controls. They also experiencedmore complex surgery. A preoperative copeptin concentration >9.43 pmol/l predictedthe occurrence of postoperative vasoplegia. These results suggest that preoperativeactivation of the vasopressin system before surgery may induce vasopressin deficiencyafter surgery, through depletion of endogenous hypothalamo-pituitary stores.
Microvascular permeability in burn injury leads to central hypovolemia and tissueedema. In 38 consecutive patients with severe burn injury, BNP and proteinuria wereused to assess evolution of microvascular permeability . BNP increased from admission to day 3 and then reached a plateau.Patients with higher BNP had lower proteinuria and received less fluids than theother patients. This observation suggests that high BNP/low proteinuria can be usedas a marker of microvascular permeability. Even though low permeability is associatedwith a better outcome, it is not clear whether these biomarkers may help to guideresuscitation.
Biomarkers as a guide for therapy
BNP and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are often used toidentify patients with increased hydrostatic pressure. To evaluate whether changes inBNP and NT-proBNP may help to better characterize the response to therapy, these weremeasured at presentation, 24 hours, 48 hours and discharge in 171 consecutivepatients presenting to the emergency department with acute decompensated heartfailure . BNP and NT-proBNP levels were higher in nonsurvivors than in survivors atall time points (all P <0.001). Treatment reduced BNP and NT-proBNPlevels in survivors by more than 50% (P <0.001), while treatment innonsurvivors did not lower BNP and NT-proBNP levels. Evolution of these markers canbe used to early assess treatment efficacy.
C-type natriuretic peptide and N-terminal pro-C-type natriuretic peptide (NT-proCNP)may reflect vascular activation in sepsis. The ability of NT-proCNP (measured at ICUadmission, day 3 and day 7) to identify sepsis was evaluated in 273 critically illpatients . Patients with sepsis had higher NT-proCNP levels than nonsepsis patients.NT-proCNP was strongly associated with inflammatory parameters and severity ofdisease. Elevated NT-proCNP levels at admission and day 3 predicted death, whileNT-proCNP decline after the initial measurement was associated with reduced mortalitycompared with stable or increasing levels. Although interesting, this biomarker wasnot superior to conventional prognostic indicators.
Cell-free DNA is detected in blood in many diseases, including sepsis andpancreatitis, but also in healthy individuals. Cell-free DNA can originate fromnecrotic cells or apoptotic processes, but is also released by living cells. Levelsof plasma cell-free DNA and their prognostic value were evaluated in 580 patientsneeding mechanical ventilation in 25 Finnish ICUs . Blood samples were taken at study admission (day 0) and on day 2. Plasmacell-free DNA concentrations were similar at day 0 and day 2. Concentrations atadmission were significantly higher in 90-day nonsurvivors than survivors, andremained an independent predictor of 90-day mortality in a multivariate logisticregression analysis. However, its clinical benefit as a prognostic marker seems to belimited given the relatively low area under the curve (AUC) (0.624, 95% CI = 0.572 to0.676). This AUC is indeed lower than in patients after OHCA (0.796, 95% CI = 0.701to 0.890) , which was discussed in the accompanying editorial .
Biomarkers for diagnosis
High-sensitivity troponin has been reported to facilitate the early diagnosis ofacute myocardial infarction . The diagnostic performances of high-sensitivity troponin and conventionaltroponin for the diagnosis of acute myocardial infarction were compared in 317consecutive patients presenting to the emergency department with chest painsuggestive of acute myocardial infarction . The pretest probability of acute myocardial infarction was assessedwithout knowledge of troponin results. In the low to moderate pretest probabilitygroup, high-sensitivity troponin levels ≥0.014 μg/l identified acutemyocardial infarction with a higher sensitivity than cardiac troponin I. Asspecificity of high-sensitivity troponin was lower, the AUCs were similar forhigh-sensitivity troponin and cardiac troponin I. Interestingly, the positivepredictive value was lower for high-sensitivity troponin than for cardiac troponin I(47% vs. 78%, P <0.05) but the negative predictive value was notdifferent (99% vs. 95%) for the entire population, with similar trends in differentpretest probability subgroups. These results cast some doubts on the diagnosticaccuracy of high-sensitivity troponin compared with cardiac troponin I.
Prognostic factors in cardiovascular diseases
Pulmonary embolism remains associated with significant mortality. The prognostic valueof markers of right ventricular dysfunction in pulmonary embolism was evaluated in ameta-analysis that retrieved eight echo-cardiographic marker-based studies (n =1,249), three computed tomography marker-based studies (n = 503) and sevennatriuretic peptide-based (BNP) studies (n = 582) . The presence of right ventricular dysfunction determined by echocardiographyand biological markers but not by computed tomography was associated with short-termmortality in patients with pulmonary embolism without hemodynamic compromise onadmission. However, the current prognostic value in clinical practice remains verylimited due to insufficient pooled positive and negative likelihood ratios.
Acute heart failure is another acute life-threatening disease leading to ICU admission.A large database of 4,153 patients hospitalized with acute heart failure was used toevaluate factors associated with outcome . De novo heart failure was seen in 58.3% of the patients.Mortality varied from 62.7% in cardiogenic shock, to 16.7% in right heart failure, to7.1% in pulmonary edema, to 6.1% in high-output heart failure, to <2.5% inhypertensive or diastolic heart failure. Invasive ventilation and age >70 years werethe most important predictive factors for mortality, with or without cardiogenicshock.
Cardiac output measurements
Analysis of the arterial pressure trace is a common way to non-invasively determinecardiac output (CO). Calibration is often required. The number of injections requiredat each calibration point was evaluated in 91 hemodynamically stable patientsmonitored by a PiCCO2 device (Pulsion, Munich, Germany) . At least three injections should be performed, which allows precision todrop below 10%: 8% (6 to 12%) for CO, 8% (6 to 14%) for global end-diastolic volumeand 8% (7 to 14%) for extravascular lung water. These results are important, both forroutine and investigational use.
The impact of vasopressor use on accuracy of pulse contour measurements of CO wasevaluated in 330 data pairs of pulse contour and transpulmonary thermodilution COmeasurements from 73 noncardiac surgery critically ill patients . Pulse contour-derived CO was recorded immediately before calibration.Agreement between the two methods was analyzed according to nor-epinephrine dosageand a time interval between calibrations of up to 24 hours. Pulse contour CO had amean bias of 0.16 l/minute with a percentage error of 38%. Bias was not affected bythe norepinephrine dosage or the time elapsed between calibrations.
Some of the usually calibrated devices also have an uncalibrated version. Thesedevices are mostly dedicated to evaluating changes in CO. The noncalibrated pulsepower CO (LiDCO; LiDCO, London, UK) was compared with transpulmonary thermodilution(PiCCO; Pulsion) in 42 patients . Several points were obtained before and after cardiopulmonary bypass.Before bypass, the percentage error was very high (86%). Changes in CO were notadequately tracked. This study is unfortunately limited by the acquisition ofmultiple (and variable) numbers of observations per patient.
There is a continuous search to develop new devices that non-invasively measure CO.An innovative technique based on measurement of spatial patterns of voltage changesdistributed over the thoracic skin has been presented . When applying a weak electric current over the thorax, emptying andfilling of the ventricles during the cardiac cycle induce cyclic voltage changes onthe thoracic skin, generating specific two-dimensional spatial patterns. Analysis ofthese patterns may enable measurement of changes in ventricular volume. In a pigmodel, CO was measured with the new device and an ultrasonic flow probe positionedaround the ascending aorta. Correlation between the two methods was excellent (r = 0.978). Bias was minimal (0.114 l/minute) and limits of agreement weresatisfactory (0.55 l/minute). This device therefore appears promising but requiresfurther validation.
A new application for transpulmonary thermodilution was proposed. Severely burnedchildren often develop circulatory failure and increased permeability. This prospectivecohort study evaluated the feasibility of transpulmonary thermodilution (PiCCO) forhemodynamic measurements in 69 severely burned children . CO significantly increased from admission and was highest 3 weeks post burn.The intrathoracic blood volume index and the extravascular lung water index begin toincrease at days 8 to 9 post burn, and the extravascular lung water index wassignificantly higher in patients who did not survive burn injury. These data indicatethat the hyperdynamic state occurs 1 week post burn injury.
Several articles used echocardiography to assess hemodynamic function in criticallyill patients. Assessment of left ventricular function is an area of intense interest.Several echocardiographic indices for the assessment of left ventricular systolicfunction were compared in 50 patients with shock . Transthoracic echocardiographic evaluation was obtained daily for 7 days.All measured indices were easy to obtain. The eyeball ejection fraction was the mostreliable and easiest index to obtain for the evaluation of systolic function.
Transthoracic echocardiography can be used for the diagnosis of left ventricularthrombosis in the post-operative care unit . Five cases were observed in 160 patients. Thrombi were observed in threeof 35 patients with ischemic cardiomyopathy and in two of 21 patients with dilatedcardiomyopathy. Of note, these thrombi were absent in preoperative echocardiograms.These thrombi were probably facilitated by local low-flow conditions and thepostoperative procoagulant state. Clinicians should be aware of this potentialpostoperative complication.
Central venous oxygen saturation and lactate
Even though low central venous oxygen saturation values are associated with a pooroutcome in patients with septic shock, the prognostic value of high central venousoxygen saturation values is not well determined. The relation between maximal centralvenous oxygen saturation levels within the first 72 hours after the onset of shockand ICU survival was evaluated in a single-center retrospective study including 152patients in a 2-year period . The maximal level of central venous oxygen saturation was higher innonsurvivors compared with the survivors (85% (78 to 89%) vs. 79% (72 to 87%),respectively; P = 0.009). As the accompanying editorial commented , multiple causes may contribute to an increased central venous oxygensaturation, including microcirculatory alterations [29, 30], decreased oxygen handling by the cells due to mitochondrial dysfunction , and excessive inotropic/fluid therapy.
Evolution of lactate levels over the first 24 hours may reflect adequacy ofresuscitation. The prognostic value of time-weighted lactate levels was evaluated in5,041 consecutive critically ill patients from four Australian university hospitals . Both the time-weighted average lactate and the change in lactate over thefirst 24 hours were independently predictive of hospital mortality. The combinationof both computations significantly out-performed (P <0.0001) staticindices of lactate concentration, such as admission lactate, maximum lactate andminimum lactate. The same group recently reported in the same database thattime-weighted relative hyperlactatemia, defined as time-weighted lactate between 1and 2 mmol/l, is also associated with a significant increase in risk of death . Altogether these results show that dynamic indices of hyperlactatemia inthe first 24 hours following ICU admission are associated with outcome and aresuperior to static measurements of blood lactate levels.
Optimization of fluid therapy is a topic of intense research. Cardiac filling volumesand pressures are often used to guide fluid administration. The relative value ofcardiac filling volume and pressures for predicting fluid responsiveness wasevaluated in 32 patients after cardiovascular surgery . Regardless of the ejection fraction, baseline central venous pressure waslower in responding events. The pulmonary artery occlusion pressure was more usefulthan the global end-diastolic volume index for predicting fluid responsiveness whenthe ejection fraction was low, but when the ejection fraction is near normal thevolume index is more useful than the occlusion pressure. Could filling pressures bedetermined on chest X-ray imaging? The vascular pedicle width is determined on chestX-ray imaging and is a non-invasive measurement of intravascular volume status. Thevascular pedicle width and central venous pressure or pulmonary artery occlusionpressure were measured in 152 patients with acute lung injury . This retrospective cohort is a substudy of the Fluid and CatheterTreatment Trial . The vascular pedicle width correlated with the pulmonary artery occlusionpressure and central venous pressure. A vascular pedicle width ≥72 mmidentified a pulmonary artery occlusion pressure ≥18 mmHg with an AUC of 0.69(P = 0.001) but, admittedly, with modest sensitivity and specificity (61%for both).
Dynamic indices better predict fluid responsiveness than static indices. Aclosed-loop fluid-management algorithm using a patient simulator including a pulsepressure variation output was tested in three phases . In different hemorrhage scenarios, the algorithm better maintainedhemodynamics compared with no management. In the second phase, compared with 20practicing anesthesiologists for the management of a simulated hemorrhage scenario,the algorithm intervened earlier, gave more fluids and better preserved CO. Thealgorithm was relatively insensitive to noise and artifacts.
Dynamic indices may be limited by several factors. Respiratory variation inplethysmography, as a consequence of stroke volume variations, can non-invasivelypredict volume responsiveness . Vasoconstriction altered this signal in 67 patients . Plethysmography variability was related to pulse pressure variation inpatients not receiving norepinephrine, while this relation-ship was lost in patientstreated with norepinephrine. In the latter, plethysmography variations were unable topredict the response to fluids. The tidal volume may also affect pulse pressurevariations . Lakhal and colleagues observed in 65 patients with acute respiratorydistress syndrome that variations in pulse pressure fail to predict fluidresponsiveness . The importance of the driving pressure was illustrated well : pulse pressure variation adequately predicted fluid responsiveness in thesubgroup of patients experiencing a respiratory variation in pulmonary arteryoccluded pressure >4 mmHg, reflecting large changes in pleural pressure. Whenthese indices are ineffective, one may consider using the passive leg raising test.Interestingly, this test can be applied even in the most severe patients such aspatients treated with venovenous ECMO . In 17 patients, an increase in stroke volume >10% during passive legraising predicted the response to fluids.
The increase in arterial pressure during fluid administration depends not only on theincrease in CO but also on arterial tone. However, predicting whether a given patientwould present increased arterial pressure before performing fluid administrationremains challenging. Monge García and colleagues present an elegant method toevaluate vascular tone . These authors computed dynamic arterial elastance as the slope of pulsepressure variations divided by stroke volume variations over the same respiratorycycle. In 25 preload responsive patients, dynamic arterial elastance >0.89predicted an increase in arterial pressure in response to volume loading inpreload-dependent patients with a sensitivity of 93.75% (95% CI = 69.8 to 99.8%) anda specificity of 100% (95% CI = 66.4 to 100%).
Perioperative management of high-risk surgical patients
Perioperative hemodynamic optimization is recommended in high-risk surgical patients . Cecconi and colleagues extend this concept somewhat . They randomized 40 patients submitted to elective total hip arthroplastyunder regional anesthesia to receive either conventional hemodynamic therapy orgoal-directed hemodynamic therapy (GDT). Patients randomized to the GDT group received agreater volume of intravenous fluids, more red blood cell transfusions, and moredobutamine during the intraoperative period, although control group patients receivedgreater volumes of blood replacement postoperatively. There was an increased number ofcomplications in the control group compared with GDT patients (100 vs. 80%; P =0.05), predominantly due to a difference in minor complications. This trial isnevertheless in line with another trial in the field, using the same monitoring tool . In a meta-analysis including 26 randomized trials, perioperativegoal-directed therapy was also found to decrease infections, including surgical siteinfections (pooled odds ratio = 0.58, 95% CI = 0.46 to 0.74; P <0.0001),pneumonia (pooled odds ratio = 0.71, 95% CI = 0.55 to 0.92; P = 0.009), andurinary tract infections (pooled odds ratio = 0.44, 95% CI = 0.22 to 0.84; P =0.02) .
Fluids are an important part of GDT. Cuthbertson and colleagues conducted a multicenterrandomized controlled trial of fluid loading in 111 high-risk surgical patientsundergoing major elective abdominal surgery (the FOCCUS study) . The patients underwent preoperative fluid loading with 25 ml/kg Ringer'ssolution in the 6 hours before surgery and the control group had no preoperative fluidloading. Patients in the intervention group spent fewer days in hospital after surgery(mean 12.2 (standard deviation 11.5) days compared with 17.4 (20.0) days) and presentedan adjusted mean difference of 5.5 days (median 2.2 days; 95% CI = -0.44 to 11.44; P = 0.07). There was a reduction in adverse events in the intervention group (P = 0.048).
However, giving fluids as a fixed amount may not be optimal. The effects of arestrictive versus conventional strategy of crystalloid administration duringgoal-directed therapy were tested in 88 high-risk surgical patients . Patients were randomized to receive 4 ml/kg/hour (restrictive) or 12ml/kg/hour (conventional) Ringer's lactate solution as fluid maintenance during surgery.In both groups, dobutamine and fluid challenges were administered as necessary tooptimize oxygen delivery. The conventional treatment group received a significantlygreater amount of fluids than the restrictive group but oxygen delivery was similar inthe two groups. The restrictive group had a 52% lower rate of major postoperativecomplications than the conventional group (P = 0.046). This further illustratesthat fluids should be given as needed but not using fixed amounts.
Finally, how frequently is GDT applied? Current hemodynamic management practices inpatients undergoing high-risk surgery in Europe and in the United States were evaluatedin a survey among members of the American Society of Anesthesiologists and the EuropeanSociety of Anaesthesiology . CO is monitored by only 34% of American Society of Anesthesiologists andEuropean Society of Anaesthesiology respondents (P = 0.49), while centralvenous pressure is monitored by 73% of American Society of Anesthesiologists respondentsand by 84% of European Society of Anaesthesiology respondents (P <0.01). Thepulmonary artery catheter is being used more frequently in the United States than inEurope in the setup of high-risk surgery (85.1% vs. 55.3%, P <0.001). Theseresults indicate a considerable gap between clinical practices in Europe and the UnitedStates. Of note, technologies required for perioperative hemodynamic optimization wereused only by one-third of responders.
This year, several trials also focused on the microcirculation. The microcirculatoryeffects of fluids were investigated using near-infrared spectroscopy during a vascularocclusion test during 42 fluid challenges in patients undergoing major abdominal surgery .
Before fluids, the tissue oxygen saturation recovery slope was lower in positive fluidchallenges than in negative fluid challenges (P = 0.02) while baseline tissueoxygen saturation did not differ. Volume expansion increased the tissue oxygensaturation recovery slope both in positive fluid challenges (62 ± 49%, P <0.001) and in negative fluid challenges (26 ± 34%, P = 0.04).Hence, fluid loading significantly improved the tissue oxygen saturation recovery slope,even when associated with ineffective changes in systemic hemodynamics.
The effects of vasopressin agonists on sublingual microcirculation were evaluated in 60patients with septic shock . These patients were randomized to receive continuous infusions of eitherterlipressin (1 μg/kg/hour), vasopressin (0.04 U/minute) or placebo (isotonicsaline). Terlipressin and vasopressin decreased norepinephrine requirements at the endof the 6-hour study period. There were no differences in sublingual microcirculatoryvariables and systemic hemodynamics among the three study groups during the entireobservation period.
Hypertension in critically ill patients
Euro-STAT is an observational study performed in 11 hospitals in seven Europeancountries including 791 consecutive adult patients treated with intravenousantihypertensive therapy in the emergency department, perioperative unit or ICU . Nitroglycerine was the most commonly used antihypertensive treatment (40% ofpatients), followed by urapidil (21%), clonidine (16%) and furosemide (8%). Hypotensionoccurred in 10% of patients.
What is the best therapy for acute hypertension? In a multicentric trial in 226patients, nicardipine-treated patients more often reached target pressure within 30minutes than labetalol-treated ones (91.7% vs. 82.5%, P = 0.039) . Use of rescue medications did not dier between nicardipine and labetaloltreatment (15.5% vs. 22.4%, P = 0.183). Nicardipine may thus more rapidlycontrol hypertension.
Is it useful to drain pleural effusions in mechanically ventilated patients? Ameta-analysis including 19 observational studies and 1,124 patients showed that effusiondrainage improved the PaO2:FiO2 ratio by 18% . Complication rates were low for pneumothorax (3.4%) and hemothorax (1.6%).Ultrasound guidance was not associated with a reduction in the risk of pneumothorax.
area under the curve
B-type natriuretic peptide
extracorporeal membrane oxygenation
N-terminal pro-B-type natriuretic peptide
N-terminal pro-C-type natriuretic peptide
out-of-hospital cardiac arrest
FiO2, ratio of partial pressure of arterial oxygen to thefraction of inspired oxygen.
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