Noninvasive cardiac output monitoring (NICOM): a clinical validation.

OBJECTIVE: To evaluate the clinical utility of a new device for continuous noninvasive cardiac output monitoring (NICOM) based on chest bio-reactance compared with cardiac output measured semi-continuously by thermodilution using a pulmonary artery catheter (PAC-CCO). DESIGN: Prospective, single-center study. SETTING: Intensive care unit. PATIENTS: Consecutive adult patients immediately after cardiac surgery. INTERVENTIONS: Cardiac output measurements obtained from NICOM and thermodilution were simultaneously recorded minute by minute and compared in 110 patients. We evaluated the accuracy, precision, responsiveness, and reliability of NICOM for detecting cardiac output changes. Tolerance for each of these parameters was specified prospectively. MEASUREMENTS AND RESULTS: A total of 65,888 pairs of cardiac output measurements were collected. Mean reference values for cardiac output ranged from 2.79 to 9.27 l/min. During periods of stable PAC-CCO (slope<+/-10%, 2SD/mean<20%), the correlation between NICOM and thermodilution was R=0.82; bias was +0.16+/-0.52 l/min (+4.0+/-11.3%), and relative error was 9.1%+/-7.8%. In 85% of patients the relative error was <20%. During periods of increasing output, slopes were similar with the two methods in 96% of patients and intra-class correlation was positive in 96%. Corresponding values during periods of decreasing output were 90% and 84%, respectively. Precision was always better with NICOM than with thermodilution. During hemodynamic challenges, changes were 3.1+/-3.8 min faster with NICOM (p<0.01) and amplitude of changes did not differ significantly. Finally, sensitivity of the NICOM for detecting significant directional changes was 93% and specificity was 93%. CONCLUSION: Cardiac output measured by NICOM had most often acceptable accuracy, precision, and responsiveness in a wide range of circulatory situations.

Tolerability to 1-year treatment with once-daily molsidomine in patients with stable angina.

Prolonged-release molsidomine 16 mg once daily) QD (has proved effective in the short-term treatment of patients with stable angina. The purpose of this multicenter study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly) in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2-4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drug-related AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni's comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 and P=.12,respectively), but their frequency was significantly (ie, approximately 50%) lower than during a preceding short-term treatment period (P<.0001 and P=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni's comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status )P=.10, P=.11, and P=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability: P=.44; angina: P=.39; nitroderivatives: P=.72; VAS for clinical status: P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.

Efficacy and safety of once- and twice-daily formulations of molsidomine in patients with stable angina pectoris: double-blind and open-label studies.

Molsidomine, a sydnonimine acting as a heterocyclic direct nitric oxide donor, has been used for many years in several European countries for the treatment of patients with stable angina pectoris. The efficacy and tolerability of a novel once-daily 16-mg formulation of molsidomine (M16) were compared with those of the currently used twice-daily 8-mg molsidomine tablet (M8) in 666 patients. Study 1, a multicenter, randomized, double-blind, placebo-controlled, twin crossover study, involved 533 patients given acute and 2-week treatment with each drug formulation. Study 2, a multicenter, open-label, sequential, add-on trial, compared M16 and M8 in 133 patients. Drug effects on exercise capacity (study 1 only), frequency of anginal attacks and consumption of short-acting itroderivatives, and incidence of adverse events (AEs) were evaluated. Compared with placebo, M16 increased exercise capacity by 15% (P<.001) at the start of study 1 and by 13% (P<.001) after 2 weeks' treatment, and was not inferior to M8. In terms of anginal attack frequency and nitroderivative consumption, M16 was not inferior to M8 in either study. Moreover, compared with M8, M16 produced a statistically and clinically significant reduction in the incidence of anginal attacks in elderly (>/=75 y) but not in younger patients (<75 y) (study 2), nor in patients from study 1. No significant difference from M8 was found in either study in short-acting nitroderivative consumption. No tolerance to M8 or M16 was observed after 2-week treatment. No statistically significant differences in incidences of all AEs and drug-related AEs were observed between M16 and M8 in either study. The same held true for proportions of patients experiencing AEs and drug-related AEs on M16 vs M8: in study 1-14.3% and 11.8% for all AEs (P=.218), 6.9% and 5.4% for drug-related AEs (P=.280); in study 2-1.3% and 1.3% for all AEs, 0% and 1.3% for drug-related AEs (P>.10) in young patients; and in the elderly, 3.6% and 0% for drug-related AEs (P>.10). Only the proportion of elderly patients with all AEs was significantly higher with M16 than with M8: 14.5% vs 1.8% (P=.039). M16 once daily was effective and well tolerated in investigated patients with stable angina pectoris, particularly the elderly, affording 24 hours of therapeutic activity. M16 was not inferior to M8 given twice daily in terms of efficacy, safety profile, and tolerability.

Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris.

BACKGROUND: The objective of this study was to compare the efficacy and tolerability of molsidomine prolonged-release 16 mg once-a-day (o.a.d.) with 8 mg twice-a-day (b.i.d.) and placebo in patients with stable angina pectoris. METHODS: After a run-in placebo period of 7 days, the two formulations were compared acutely and then chronically (2 weeks) using cycloergometric tests and a randomized, multicenter, double-blind, double-dummy, crossover design in 533 patients. The quality of life was assessed using the frequency of anginal crises and nitrate sublingual tablets consumption. RESULTS: Both formulations significantly improved exercise test parameters compared with placebo, being it after acute drug intake or after a 2-week treatment period and independently of spontaneous diurnal variation in exercise tolerance. Noninferiority of molsidomine 16 mg compared with 8 mg was demonstrated with a statistically significant superiority of the 16-mg formulation from 14 to 24 h postintake. Both treatments reduced incidence of anginal attacks and use of sublingual isosorbide dinitrate tablets. Tolerability of active drugs was satisfactory, the incidence of drug-related headache being not significantly different from placebo. Only hypotension was significantly more frequent with molsidomine 16 mg than with placebo, pretrial diastolic blood pressure being significantly lower in these patients than in those who did not develop hypotension during the study. CONCLUSIONS: Both molsidomine formulations were effective in controlling patients' angina, did not induce any habituation and were well tolerated. However, the once-daily 16-mg formulation tended to provide better 24-h protection against myocardial ischemia than the 8-mg b.i.d. formulation.

Are we accurately predicting bladder capacity in infants?

INTRODUCTION: Estimating bladder capacity is an important component in the evaluation of many urological disorders. For estimates to be of clinical value, precise reference ranges are needed. While accepted reference ranges have been established in adults and older children, none have been validated in infants. We endeavour to determine the normal bladder capacity of children less than 1 year of age. METHODS: We retrospectively reviewed the charts of children aged 0 to 12 months with cutaneous stigmata of spinal dysraphism who were referred to the urology clinic to rule out tethered cord between October 2004 and July 2011. Patients with normal urologic assessment, who did not have surgery during the time they were followed, were included in the study cohort. Urodynamic studies were performed using the Laborie Medical Technologies UDS-600. Bladder filling occurred via a catheter at a rate of 10% of the expected total bladder capacity/minute. Bladder capacity was defined as the volume of filling when the child voided around the catheter. We collected data, including age at urodynamics, bladder capacity, detrusor pressure at capacity, bladder compliance and length of follow-up. RESULT: In total, 46% (84/183) of patients had a normal urologic assessment and met the inclusion criteria. The median age was 9.0 months (interquartile range [IQR] 6.8-11.0). The average bladder capacity was 48.9 mL (standard deviation [SD] 32.8) and the mean detrusor pressure at capacity was 8.5 cmH2O (SD 10.0). Mean compliance was 14.1 mL/cmH2O (SD 13.6). The average length of follow-up was 40.7 months (SD 26.2) and during this interval no patients were found to have urologic or neurologic abnormalities and none underwent tethered cord release. CONCLUSION: Bladder capacity in infants with a median age of 9.0 months was found to be 48.9 mL. This is less than half of the volume predicted by a commonly employed formula. A novel method of estimating bladder capacity in infants is required.

Comparative effects of once-daily molsidomine in coronary patients from two distinct European ethnicities.

INTRODUCTION: Molsidomine, a direct nitric oxide donor, is frequently used in several European countries for the treatment of stable angina. The aim of this study was to compare the effects of a new once-daily 16-mg dose formulation, Coruno (Therabel Pharmaceuticals, Loughrea, Ireland), in patients with stable angina belonging to two distinct European ethnicities. METHODS: A total of 261 Hungarian and 267 Polish patients took part in this multicenter, randomized, double-blind, placebo-controlled clinical trial. Exercise testing was performed after the first administration of molsidomine and repeated after a 2-week treatment. Frequency of anginal attacks, short-acting nitroderivative tablet consumption, and incidence of adverse events were also evaluated. RESULTS: Demographic and clinical characteristics were significantly different in Hungarian compared with Polish patients. Hungarian patients had a lower proportion of males, were shorter in stature, had less previous smoking experience, consumed more alcohol, had less severe coronary disease (electrocardiographic evidence, rate of anginal crises, and nitroderivative consumption), and higher exercise capacity. However, molsidomine-related improvement in exercise capacity at start of the study was similar in both cohorts. After a 2-week treatment, improvement was fully maintained in Polish and only minimally reduced in Hungarian patients. Furthermore, molsidomine reduced significantly more anginal episodes and nitroderivative consumption in the more severely affected Polish cohort. Proportions of patients reporting drug-related adverse events were similar on placebo and molsidomine in both cohorts. Most of the adverse events were not severe and resolved spontaneously. Less myocardial ischemia and gender (including height, a confounding covariate) acted positively and negatively, respectively, on the higher exercise capacity of Hungarian versus Polish patients. CONCLUSION: The once-daily 16-mg molsidomine formulation is effective and has good tolerability in both patient cohorts. Molsidomine does not induce any meaningful tolerance issues in Hungarian or Polish patients with stable angina, despite significant demographic and clinical disparities.

Sevoflurane-remifentanil versus propofol-remifentanil anesthesia at a similar bispectral level for off-pump coronary artery surgery: no evidence of reduced myocardial ischemia.

OBJECTIVE: Sevoflurane could decrease myocardial ischemic injury in patients undergoing off-pump coronary artery bypass surgery. This study was designed to compare postoperative troponin I (cTnI) concentrations after sevoflurane-remifentanil versus propofol-remifentanil anesthesia. DESIGN: Prospective, randomized single-blind clinical study. SETTING: University hospital. PARTICIPANTS: Eighteen patients. INTERVENTIONS: General anesthesia was conducted with sevoflurane-remifentanil (n = 9) or propofol-remifentanil (n = 9). Administration of sevoflurane and propofol was adjusted to maintain the bispectral index (BIS) between 40 and 60. MEASUREMENTS AND MAIN RESULTS: Groups were comparable regarding the patients' characteristics. The objective of BIS was maintained in both groups except during the period of coronary artery grafts (p < 0.001) when the BIS number in the propofol group fell below 40 and was significantly lower than in the sevoflurane group. Intraoperative hemodynamic variables were similar between groups. No patient required cardiopulmonary bypass. Need for inotropic and vasoactive support during the first graft was not necessary in the propofol group and occurred in 4 patients in the sevoflurane group (not significant). During the second graft, 2 patients in the propofol group and 3 in the sevoflurane group needed hemodynamic support. Postoperative hemodynamic variables were comparable between groups. Areas under the curve of postoperative increases in cTnI were 27.0 +/- 38.6 and 17.4 +/- 14.6 ng/mL/hour in the sevoflurane and propofol groups, respectively (not significant). CONCLUSION: This study does not support cardioprotective effects of sevoflurane. The particularly short total cumulative duration of ischemia and the relatively low administered end-tidal sevoflurane concentrations may explain this result.

A pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering from stable angina pectoris: correlation between efficacy and over time plasma concentrations.

OBJECTIVES: A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to demonstrate its clinical efficacy and safety versus placebo and to investigate correlations between pharmacokinetics and pharmacodynamics. METHODS: Forty-two patients were recruited in a double-blind, crossover, randomized placebo-controlled trial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specific time points (3, 6, 10, 14, 18, 22 and 24 h) after the administration of a single dose of molsidomine 16 mg o.a.d. in all patients distributed into seven groups. Twenty-eight of these 42 patients showed a positive baseline cycloergometric exercise test response during the run-in placebo period and were used to compare the efficacy of molsidomine to placebo. Relationships between plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28 patients with a positive exercise test at baseline. Indeed, the censored variable ischemia-limited tolerance to exercise could not be evaluated in those patients who did not show exercise-induced ischemia anymore under molsidomine 16 mg o.a.d. Pharmacokinetic-pharmacodynamic relationships were evaluated using regression models and correlation coefficients. RESULTS: The highest average concentration in molsidomine and SIN-1 occurred after 6 h, then a plateau of 15-20 ng/ml molsidomine and 0.8-3.0 ng/ml SIN-1 was maintained for at least 8 h and the mean residual molsidomine concentration 24 h post-drug intake was around 8 ng/ml, still in the effective range of 5-10 ng/ml. A significant increase in total workload (+52 W min, P=0.009), total exercise time (+32 s, P=0.003) and time to angina (+25 s, P=0.016) was measured with molsidomine 16 mg o.a.d. relative to placebo. Using linear regression, significant correlation coefficients were determined between molsidomine plasma concentrations (but not SIN-1) and exercise test improvements (r=0.827, P<0.001 for the total workload; r=0.772, P<0.001 for the total exercise time; and r=0.566, P=0.028 for the time to 1 mm ST-segment depression). CONCLUSION: The pharmacokinetics of molsidomine 16 mg in patients with stable angina pectoris is compatible with a o.a.d. dosage regimen. This o.a.d. formulation is effective and well-tolerated, providing a 24-h therapeutic control of myocardial ischemia. A positive and significant linear relationship between molsidomine plasma concentration and the increase in exercise tolerance was observed.

Use of non-invasive cardiac investigations to predict clinical endpoints after coronary bypass graft surgery in coronary artery disease patients: results from the prognosis and evaluation of risk in the coronary operated patient (PERISCOP) study.

AIMS: Little is known about which patients who have undergone coronary bypass surgery are at risk of future clinical cardiovascular events and may benefit from further medical treatment. We sought to determine if routine non-invasive cardiac investigations performed early after surgery were able to stratify the risk of cardiovascular events in this population. METHODS: Two thousand and sixty-five consecutive patients were enrolled in a prospective multicenter study (PERISCOP). Exercise testing, echocardiography, and 24-h ambulatory ECG monitoring were performed at day 20+/-10 after coronary bypass surgery. Follow-up was performed 1 year after coronary bypass surgery. Causes of all hospitalisation and death occurring within 1 year were documented and classified by an End-point Committee. The principal endpoint was the combination of all-cause deaths and cardiovascular events requiring hospitalisation (myocardial infarction, unstable or severe angina, stroke, congestive heart failure). RESULTS: The 1-year frequency of first events was 155 (8%). In multivariate analysis, exercise duration <420s (RR=1.68; 95% CI: 1.13-2.49), exercise induced ST segment depression >1mm (RR=1.90; 95% CI: 1.18-3.05), and left ventricular (LV) dysfunction (wall motion index <1.15) (RR=1.97; 95% CI: 1.10-3.51) were independent predictors of cardiovascular events and deaths. Ambulatory ECG monitoring had no predictive value. CONCLUSIONS: Exercise testing and echocardiography performed early after coronary bypass surgery are able to identify high-risk patients who may benefit from intensive secondary prevention.

Factors influencing return to work at one year after coronary bypass graft surgery: results of the PERISCOP study.

PURPOSE: The aim of this study was to evaluate the predictive factors of return to work after coronary bypass graft surgery, for the subgroup of professionally active patients aged less than 60 years included in the PERISCOP study. METHODS: In the principal, prospective, multicentre study, 2065 patients were evaluated 20+/-10 days after surgery by exercise testing, echocardiogram and 24-h ambulatory ECG monitoring. A questionnaire was completed one year after surgery. We studied a subgroup of this population, consisting of 530 patients previously defined (94.5% men; mean age: 50.5+/-5.8 years). RESULTS: One year after surgery, five of these patients had died and 21 were lost to follow-up. Among the remaining patients, 340 patients (67.5%) had returned to work. Forty patients (7.9%) had retired, 45 (8.9%) were on sick leave, 22 (4.4%) were unemployed, 49 (9.7%) returned to work after the deadline of 12 months, eight (1.6%) had given insufficient information on return to work. In multivariate analysis, the independent predictors of a failure to return to work were age >51 years [OR: 0.39 (95% CI: 0.25-0.59)], being a manual worker [OR: 0.49 (95% CI: 0.31-0.79)], being from South East France [(OR: 0.42 (95% CI: 0.23-0.74)], presence of angina [OR: 0.40 (95% CI: 0.20-0.82)], dyspnoea [(OR: 0.46 (95% CI: 0.28-0.77)] and a duration of exercise <420 s [(OR: 0.50 (95% CI: 0.33-0.76)]. CONCLUSIONS: Return to work after coronary bypass graft surgery is observed in 67.5% of cases and depends essentially on socio-professional factors and residual symptoms. A regional effect was also observed, which requires further study.