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Predictors of mortality in propofol infusion syndrome

[black small square] Propofol is an anesthetic agent used as a sedative in the ICU for nearly 20 years. Although it's generally considered a safe agent when prescribed based on product labeling recommendations, a troublesome syndrome known as propofol infusion syndrome (PRIS) is reported with its use. Given the high mortality associated with this condition, researchers sought to identify predictors of mortality in patients receiving propofol who have PRIS-associated clinical manifestations, and propose a simple scoring system to identify patients with suspected PRIS who are at most risk of death.


After a comparison of demographic and clinical manifestations between survivors and nonsurvivors, a multivariate logistic regression model was built through a stepwise selection process and used to develop a simplified mortality scoring system. Of 1,139 patients with suspected PRIS, 342 (30%) were fatal. Death was more likely if patients were 18 years of age or younger, received a vasopressor, or had the following clinical manifestations: cardiac symptoms, metabolic acidosis, renal failure, hypotension, rhabdomyolysis, or dyslipidemia. The multivariable modeling process found that cardiac symptoms, rhabdomyolosis, hypotension, metabolic acidosis, renal failure, and age each affected survival, although significant interactions existed between some of these factors. Based on the combination of the presence or absence of the six factors in the multivariate model, a PRIS mortality risk score of 0 to 4 resulted in a pre dicted percentage and observed percentage mortality for each score of 0 (10%/10%), 1 (24%/24%), 2 (47%/44%), 3 (72%/81%), and 4 (89%/83%).


A number of characteristics are independently associated with higher mortality in patients with suspected PRIS, only some of which are currently reflected in the package insert. Further research should focus on prospectively evaluating the mortality scoring system in patients with suspected PRIS.


Source: Fong JJ, Sylvia L, Ruthazer R, et al. Predictors of mortality in patients with suspected propofol infusion syndrome. Crit Care Med. 2008;36(8):2281-2287.


Effect of clopidogrel reloading

[black small square] In the past, clopidogrel loading was mostly studied in clopidogrel-naive patients. Whether clopidogrel-treated patients readmitted for an acute coronary syndrome or percutaneous coronary intervention can benefit from a new load of clopidogrel and at what dose remains unknown. Researchers aimed to evaluate the impact of three different strategies of administration of a loading dose of 900 mg clopidogrel in patients already treated with a maintenance dose of 75 mg clopidogrel for at least 7 days on residual platelet aggregation.


Patients treated long term with clopidogrel 75 mg/day were assigned to receive a first loading dose of 300, 600, or 900 mg clopidogrel, and 4 hours later a second loading dose of 600, 300, or 0 mg, respectively, to achieve a total loading dose of 900 mg in all patients. Platelet aggregation was evaluated at baseline, at 4 hours after the initial load (and before the second load), and at 24 hours using light transmission aggregometry with 20 [mu]mol ADP and the point-of-care assay VerifyNow P2Y12. The primary objective of the study was to evaluate the inhibition of residual platelet aggregation (IRPA) between 600 and 900 mg first loading at 4 hours. IRPA at 24 hours was also evaluated as a secondary objective, as well as the rate of suboptimal response at 4 hours defined as an IRPA of less than 10%. Investigators included 166 consecutive patients with acute coronary syndromes (n = 80, 48%) or stable coronary artery disease (n = 86, 52%). Baseline characteristics were similar in the three dose groups. A significant stepwise increase was found in percentage IRPA assessed at 4 hours in patients initially assigned to 300 versus 600 versus 900 mg (30.7% versus 40.3% versus 64.0%, respectively). The difference in IRPA percentage at 4 hours was not significant between 300 and 600 mg, but was significant between 600 and 900 mg and between 300 and 900 mg. IRPA percentage assessed at 24 hours when all patients received 900 mg didn't differ between the three loading regimens. The rates of suboptimal response (IRPA < 10% at 4 hours) were 23.6%, 20.4%, and 5.3% with 300, 600, and 900 mg, respectively. In patients treated long term with 75 mg clopidogrel, a new loading dose of 900 mg improves IRPA and reduces poor or slow response to clopidogrel significantly more than that obtained with 300 or 600 mg.


Source: Collet JP, Silvain J, Landivier A, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose. Circulation. 2008;118 1225-1233.


Levosimendan superior to enoximone in refractory cardiogenic shock

[black small square] Cardiogenic shock is the leading cause of death in patients hospitalized for acute myocardial infarction. In a recent study, researchers investigated the effects of levosimendan, a novel inodilator, compared with the phosphodiesterase-III inhibitor enoximone in refractory cardiogenic shock complicating acute myocardial infarction in addition to current therapy.


Thirty-two patients with refractory cardiogenic shock for at least 2 hours requiring additional ther apy were studied at a medical and coronary ICU in a university hospital as part of a prospective, randomized, controlled, single-center clinical trial. Either an infusion of levosimendan (12 mcg/kg over 10 min, followed by 0.1 mcg/kg/min over 50 min, and of 0.2 mcg/kg/min for the next 23 hours) or enoximone (fractional loading dose of 0.5 mg/kg,followed by 2 to 10 mcg/kg/min continuously) was administered after initiation of current therapy, always including revascularization, intra-aortic balloon pump counterpulsation, and inotropes. The survival rate at 30 days was significantly higher in the levosimendan-treated group (69%, 11 of 16) compared with the enoximone group (37%, 6 of 16). Invasive hemodynamic parameters during the first 48 hours were comparable in both groups. Levosimendan induced a trend toward higher cardiac index, cardiac power index, left ventricular stroke work index, and mixed venous oxygen saturation. In addition, lower cumulative values for catecholamines at 72 hours and for clinical signs of inflammation were seen in the levosimendan-treated patients. Multiple organ failure leading to death occurred exclusively in the enoximone group (4 of 16 patients).


Results indicated that in severe and refractory cardiogenic shock complicating acute myocardial infarction, levosimendan, added to current therapy, may contribute to improved survival compared with enoximone.


Source: Fuhrmann JT, Schmeisser A, Schulze MR, et al. Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med. 2008;36(8):2257-2266.


Dronedarone to control ventricular rate in permanent atrial fibrillation

[black small square] Dronedarone is a new multichannel blocker for atrial fibrillation (AF) previously demonstrated to display both rhythm and rate control properties in paroxysmal and persistent AF. The Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) trial assessed the efficacy of dronedarone in the control of ventricular rate in patients with permanent AF when added to standard therapy.


In a randomized, double-blind, multinational trial, dronedarone, 400 mg twice a day (n = 85) or matching placebo (n = 89) was administered for 6 months to adult patients with permanent AF, in addition to standard therapy. The primary end point was the change in mean ventricular rate between baseline and day 14, as assessed by 24-hour Holter. The ventricular rate was also assessed during submaximal and maximal exercise.


Dronedarone significantly decreased mean 24-hour ventricular rate. Compared with placebo, the mean treatment effect at day 14 was a reduction of 11.7 beats/minute. Comparable reductions were sustained throughout the 6-month trial. During maximal exercise and compared to placebo, there was a mean reduction of 24.5 beats/minute, without any reduction in exercise tolerance as measured by maximal exercise duration. The effects of dronedarone were additive to those of other rate-control agents, including beta-blockers, calcium antagonists, and digoxin.


In addition to its reported rhythm-targeting and rate-targeting therapeutic actions in paroxysmal and persistent AF, dronedarone improves ventricular rate control in patients with permanent AF. Dronedarone was well tolerated with no evidence of organ toxicities or proarrhythmias in this short-term study.


Source: Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: The Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008;156(3):527e1-529el.


Trimetazidine's benefits in idiopathic dilated cardiomyopathy

[black small square] The anti-ischemic agent trimetazidine improves ejection fraction in heart failure that's hypothetically linked to inhibitory effects on cardiac free fatty acid (FFA) oxidation. However, FFA oxidation remains unmeasured in humans. Researchers investigated the effects of trimetazidine on cardiac perfusion, efficiency of work, and FFA oxidation in idiopathic dilated cardiomyopathy (IDCM).


Nineteen nondiabetic patients with IDCM on standard medication were randomized to single-blind trimetazidine (n = 12) or placebo (n = 7) for 3 months. Myocardial perfusion, FFA, and total oxidative metabolism were measured using positron emission tomography with [15O]H2O, [11C]acetate, and [11C]palmitate. Cardiac function was assessed echocardiographically; insulin sensitivity was assessed by the homeostasis model assessment index. Trimetazidine increased ejection fraction from 30.9 +/- 8.5% to 34.8 +/- 12% versus placebo. Myocardial FFA uptake was unchanged, and the beta-oxidation rate constant decreased only 10%. Myocardial perfusion, oxidative metabolism, and work efficiency remained unchanged. Trimetazidine decreased insulin resistance (glucose: 5.9 +/- 0.7 versus 5.5 +/- 0.6 mmol/L; insulin: 10 +/- 6.9 versus 7.6 +/- 3.6 mU/L; homeostasis model assessment index: 2.75 +/- 2.28 versus 1.89 +/- 1.06). The degree of beta-blockade and trimetazidine interacted positively on ejection fraction. Plasma high-density lipoprotein concentrations increased 11%.


In IDCM with heart failure, trimetazidine increased cardiac function and had both cardiac and extracardiac metabolic effects. Cardiac FFA oxidation modestly decreased and myocardial oxidative rate was unchanged, implying increased oxidation of glucose. Trimetazidine improved whole-body insulin sensitivity and glucose control in these insulin-resistant patients with IDCM, thus hypothetically countering the myocardial damage of insulin resistance. Additionally, the trimetazidine-induced increase in ejection fraction was associated with greater beta1-adrenoceptor occupancy, suggesting a synergistic mechanism.

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Source: Tuunanen H, Engblom E, Naum A, et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation. 2008;118(12):1250-1258.