Effects of delayed cord clamping on residual placental blood volume, hemoglobin and bilirubin levels in term infants: a randomized controlled trial.

OBJECTIVE: The objective of the study was to measure the effects of a 5-min delay (DCC) versus immediate cord clamping (ICC) on residual placental blood volume (RPBV) at birth, and hemoglobin and serum bilirubin at 24 to 48 h of age. STUDY DESIGN: In this prospective randomized controlled trial, 73 women with term (37 to 41 weeks) singleton fetuses were randomized to DCC (⩾5 min; n=37) or ICC (<20 s; n=36). RESULTS: Maternal and infant demographics were not different between the groups. Mean cord clamping time was 303±121 (DCC) versus 23±59 (ICC) s (P<0.001) with 10 protocol violations. Cord milking was the proxy for DCC (n=11) when the provider could not wait. Infants randomized to DCC compared with ICC had significantly less RPBV (20.0 versus 30.8 ml kg-1, P<0.001), higher hemoglobin levels (19.4 versus 17.8 g dl-1, P=0.002) at 24 to 48 h, with no difference in bilirubin levels. CONCLUSION: Term infants had early hematological advantage of DCC without increases in hyperbilirubinemia or symptomatic polycythemia.

Subgroups, treatment effects, and baseline risks: some lessons from major cardiovascular trials.

BACKGROUND: The objective of this study was to determine how subgroup analyses are performed in large randomized trials of cardiovascular pharmacotherapy. METHODS AND RESULTS: We reviewed 67 randomized, double-blind, controlled trials involving pharmacotherapy in at least 1000 patients with unstable angina, myocardial infarction, left ventricular dysfunction, or heart failure with clinical outcomes as primary end points, published between 1980 and 1997. Nine had no subgroup analyses but 43 reported on 5 or more subgroups and 31 reported subgroups without formal statistical tests for treatment-subgroup interactions. In most trials, a rationale for subgroup selection was missing. All but 6 focused on single-factor subgroups. CONCLUSIONS: Trial subgroups should ideally be defined a priori on 2 bases: single-factor subgroups with a strong rationale for biological response modification and multifactorial prognostic subgroups defined from baseline risks. However, single-factor subgroup analyses are often reported without a supporting rationale or formal statistical tests for interactions. We suggest that clinicians should interpret published subgroup-specific variations in treatment effects skeptically unless there is a prespecified rationale and a significant treatment-subgroup interaction.

Sympathetic responses to atrial natriuretic peptide in patients with congestive heart failure.

Previous studies have shown that atrial natriuretic peptide (ANP) has relative sympathoinhibitory effects that are of potential benefit in patients with congestive heart failure (CHF). In this study, cardiac and systemic sympathetic responses to ANP were evaluated and compared with responses to sodium nitroprusside (SNP) in patients with CHF. Right- and left-heart hemodynamics were obtained simultaneously with cardiac (CANESP) and total body (TBNESP) norepinephrine spillover; these were measured by using the radiotracer technique. Reductions in arterial blood pressure and cardiac filling pressures were similar with both drugs. ANP and SNP caused a significant and similar increase in TBNESP. Mean values for CANESP did not change in either group, but the response of individual patients was dependent on the effect on diastolic blood pressure (r = -0.71, p<0.01). These results do not provide evidence for a sympathoinhibitory effect of ANP, but suggest that in patients with CHF, cardiac sympathoexcitatory response to arterial baroreceptor unloading may be countered by a potential sympathoinhibitory effect caused by a reduction in cardiac filling pressures. In the setting of CHF, vasodilator therapy may decrease cardiac sympathetic activity if systemic hypotension is avoided.

ARCTIC: assessment of haemodynamic response in patients with congestive heart failure to telmisartan: a multicentre dose-ranging study in Canada.

BACKGROUND: The aim of this study was to examine the acute hemodynamic and neurohormonal effects of the angiotensin II antagonist telmisartan relative to placebo in patients with chronic symptomatic (New York Heart Association class II to III) congestive heart failure and to explore the dose-response relation for these effects. METHODS AND RESULTS: After baseline hemodynamic and neurohormonal measurements made with the use of a pulmonary artery and radial arterial catheter, 82 patients were randomly assigned to placebo or 10, 20, 40, or 80 mg of telmisartan in a double-blind fashion. Hemodynamic and neurohormonal measurements were carried out over 24 hours. Telmisartan caused significant decreases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures with evidence of a dose-response relation for each of these parameters. The drug had no significant effects on heart rate, cardiac index, or systemic vascular resistance. Telmisartan did not have consistent effects on either plasma norepinephrine or plasma atrial natriuretic peptide levels, although it did cause significant increases in both plasma renin activity and angiotensin II levels at higher doses. CONCLUSIONS: The acute administration of the angiotensin II antagonist telmisartan was associated with significant dose-dependent reductions in systemic arterial blood pressure and pulmonary pressures. Long-term follow-up studies are required to translate changes in hemodynamic parameters into a clinical benefit.

Electrical and hemodynamic correlates of the maximal rate of pressure increase in the human left ventricle.

BACKGROUND: The rate of left ventricular (LV) pressure increase (LV + dP/dt) may be related to QRS duration, as well as to a number of hemodynamic parameters. METHODS AND RESULTS: We studied the relation between basal LV + dP/dt and QRS duration in 43 patients with normal LV function and 81 patients with heart failure undergoing diagnostic catheterization. We also examined the relationship between LV + dP/dt and heart rate, as well as measures of both LV preload and afterload. In patients with normal LV function, there was a strong relationship between basal LV + dP/dt and resting heart rate, whereas the relationship with QRS duration was of borderline significance. In patients with heart failure, the relationship with heart rate was lost; however, LV systolic pressure, QRS duration, and LV end-diastolic pressure all made significant contributions to a model predicting LV + dP/dt. CONCLUSIONS: These data show a strong relationship between resting heart rate and LV + dP/dt in the healthy human LV. In patients with heart failure, the relationship with heart rate is not maintained; however, there is a systematic relationship between LV + dP/dt and both the time-course of the electrical activation and measures of LV loading conditions.

Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine.

OBJECTIVES: The purpose of this study was to investigate whether therapy with nitroglycerin (GTN) would lead to abnormal coronary artery responses to the endothelium-dependent vasodilator acetylcholine. BACKGROUND: Nitroglycerin therapy is associated with specific biochemical changes in the vasculature that may lead to increased vascular sensitivity to vasoconstrictors. METHODS: Patients were randomized to continuous transdermal GTN, 0.6 mg/h (n = 8), or no therapy (n = 7), for 5 days prior to a diagnostic catheterization. Patients had similar risk factors for endothelial dysfunction. Quantitative angiography was performed in the morning to measure the mean luminal diameter of the left anterior descending coronary artery (LAD) in response to intracoronary acetylcholine (peak concentration, 10(-4) mol/liter). The transdermal preparation was removed from the GTN group, and 3 h later experimental procedures were repeated. RESULTS: In the morning, the GTN group experienced greater coronary constriction in response to acetylcholine infusion than those not receiving GTN (-19.6+/-4.2 vs. -3.8+/-3.0%; p = 0.01). Three hours later, the GTN group continued to display greater constriction to acetylcholine (-24.1+/-5.9%) as compared to the non-GTN group (-1.8+/-4.8%). When the morning and afternoon responses to acetylcholine were compared, the increase in coronary constriction in the GTN group was greater than the change observed in the non-GTN group (p < 0.05). CONCLUSIONS: This study demonstrates that therapy with GTN causes abnormal coronary vasomotor responses to the endothelium-dependent vasodilator acetylcholine, changes that were persistent for up to 3 hours after GTN discontinuation. This nitrate-associated vasomotor dysfunction has implications with respect to the development of nitrate tolerance and the potential for adverse events during nitrate withdrawal.

Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Gastro-Intestinal Therapeutic System.

AIMS: To present the design of ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS), an ongoing multicentre clinical outcome trial with nifedipine GITS (Gastro-Intestinal Therapeutic System) in patients with stable angina pectoris. METHODS: At least 6000 patients with optimally treated stable angina without depressed left ventricular function are randomized in equal proportions to either nifedipine GITS or matching placebo (starting dose 30 mg, maintenance dose 60 mg once daily). Patients are followed for at least four years. The primary end-point, to be analyzed by assigned treatment, includes all-cause mortality, acute myocardial infarction, emergency coronary angiography for refractory angina, overt heart failure, debilitating stroke and peripheral revascularization. For this end-point, the trial has a power of 95% to detect a relative risk reduction of 18% at the 5%, level of significance, and is large enough to exclude an excess mortality caused by nifedipine GITS of 3.1 deaths per 1000 years of treatment or greater. The pre-specified early termination rule is more conservative in the case of a beneficial effect than in the case of an adverse effect of nifedipine GITS. The first patient was randomized on 29 November, 1996. By the end of April 1998, about 5200 patients had been started on study medication. CONCLUSIONS: Results will be available in the autumn of 2003.

The effect of hydralazine on the development of tolerance to continuous nitroglycerin.

It has been reported that nitroglycerin (GTN) tolerance can be prevented by the concurrent administration of hydralazine. Although the mechanism of this effect remains unknown, it is possible that hydralazine modifies counter-regulatory responses to nitrate administration. To address this question, we examined the impact of hydralazine therapy on the development of tolerance during sustained therapy with GTN. Twenty normal volunteers and 18 patients with chronic heart failure (mean ejection fraction 30 +/- 2%) were treated for 1 week with hydralazine or placebo in a randomized double-blind fashion. Hydralazine therapy (or placebo) was continued, and subjects then received continuous transdermal GTN for 5 to 7 days. On the first and last day of transdermal GTN therapy, standing HR, systolic blood pressure and hematocrit responses were assessed. HR and blood pressure responses to sublingual GTN (0.6 mg) were also evaluated before and during sustained transdermal GTN therapy. Significant loss of the hemodynamic effects of transdermal GTN occurred during sustained therapy in both the normal volunteer and heart failure groups. Hydralazine had no effect on the development of tolerance to the hemodynamic effect of GTN in either group. In both, transdermal GTN therapy was associated with a significant fall in hematocrit that persisted for the entire treatment period. Hydralazine had no effect on this response. These data suggest that hydralazine therapy does not prevent loss of systemic arterial effects or prevent plasma volume expansion during sustained transdermal GTN therapy.

Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle.

The objective of this study was to evaluate the effect of muscarinic receptor modulation on basal and beta-adrenergic stimulated left ventricular function in patients with heart failure. 21 heart failure patients and 14 subjects with normal ventricular function were studied. In Protocol 1 intracoronary acetylcholine resulted in a 60+/-8% inhibition of the left ventricular +dP/dt response to intracoronary dobutamine in the normal group, and a similar 70+/-13% inhibition in the heart failure group. Acetylcholine also attenuated the dobutamine-mediated acceleration of isovolumic relaxation (Tau) in both groups. Acetylcholine alone had no effect on Tau in the normal group, while it prolonged Tau in the heart failure group. In Protocol 2 intracoronary atropine resulted in a 35+/-10% augmentation of the inotropic response to dobutamine in the normal group, versus a non-significant 12+/-15% augmentation of the dobutamine response in the heart failure group. In Protocol 3, in 6 heart failure patients, both effects of acetylcholine, the slowing of ventricular relaxation and the inhibition of beta-adrenergic responses, were reversed by the addition of atropine. Therefore, in the failing human left ventricle muscarinic stimulation has an independent negative lusitropic effect and antagonizes the effects of beta-adrenergic stimulation.

Effects of diuretic therapy on the development of tolerance to nitroglycerin and exercise capacity in patients with chronic stable angina.

BACKGROUND: Therapy with diuretics has been reported to prevent the development of nitrate tolerance. Importantly, diuretics may have independent antianginal effects through their effects on intravascular volume. The present investigation was designed to determine whether diuretic therapy could prevent the development of tolerance to continuous transdermal nitroglycerin. The study was also designed to examine whether diuretic therapy has an independent antianginal effect. METHODS AND RESULTS: Twelve patients with chronic stable angina were studied in a randomized, double-blind, crossover trial. Patients received diuretic (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each double-blind treatment period, patients underwent treadmill exercise testing on three separate occasions. The first exercise testing was performed after 7 to 10 days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently, exercise testing was repeated on the first day of active transdermal nitroglycerin therapy and following 7 to 10 days of continuous transdermal nitroglycerin application. Therapy with a diuretic was associated with an increase in exercise capacity but had no effect on nitroglycerin tolerance. During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an increase in treadmill walking time to the development of moderate angina compared with placebo (371 +/- 26 versus 288 +/- 16 seconds, diuretic versus placebo, P < .01). Similar results were obtained during both acute and sustained nitroglycerin therapy. CONCLUSIONS: The results of this study demonstrate that therapy with a diuretic has no effect on the development of tolerance to continuous transdermal nitroglycerin. Interestingly, diuretic therapy itself has important antianginal effects and improves exercise capacity in patients with stable angina.

Usefulness of the 12-lead electrocardiogram in detection of myocardial infarction: electrocardiographic-anatomic correlations--Part II.

Part II of this two-part series on electrocardiographic-necropsy correlation of infarct location focuses on lateral and posterior ("inferior") infarctions. The value of infarct location regarding complications and prognosis is also discussed.

Usefulness of the 12-lead electrocardiogram in detection of myocardial infarction: electrocardiographic-anatomic correlations--part I.

This two-part review evaluates a 56-year period (1938-1994) of electrocardiographic-necropsy correlation studies. Part I focuses on definitions of infarct location and evaluates anterior infarctions. Part II will focus on lateral and posterior infarcts.

Intermittent transdermal nitroglycerin therapy. Decreased anginal threshold during the nitrate-free interval.

BACKGROUND: Intermittent transdermal nitroglycerin therapy is effective in the treatment of stable angina and prevents the development of tolerance. Previous investigations have suggested that removal of nitroglycerin patches may be associated with a decrease in anginal threshold. This study examines the effect of nitroglycerin patch removal on anginal threshold in a group of patients with stable angina. METHODS AND RESULTS: Twelve patients with stable angina were enrolled in a randomized, double-blind, placebo-controlled, crossover study. These patients had reproducible treadmill walking times and were taking no other long-acting antianginal medications or vasodilators. They received 0.8 mg/h transdermal nitroglycerin or wore a matching placebo patch for 5 to 7 days and then crossed over to the other treatment arm of the study. Transdermal nitroglycerin was applied at 8:00 PM and removed at 8:00 AM each day. On the last day of each treatment period, patients underwent treadmill exercise testing at 8:00 AM (before patch removal) and at 2, 4, and 6 hours after patch removal. The primary end point was the treadmill walking time until moderate angina (P2). Other end points included the treadmill walking time until onset of angina (P1), the amount of ST segment depression at P1 and P2, and treadmill walking time until the development of 1 mm ST depression. Heart rate, systolic blood pressure, and the rate-pressure product were determined at rest before exercise and at P1 and P2. At 8:00 AM P1 and P2 were not significantly affected by active nitroglycerin compared with placebo, indicating the development of tolerance. Removal of the active transdermal nitroglycerin patch was associated with a significant decrease in the time to P1 at 2, 4, and 6 hours after patch removal compared with placebo. There was also a decrease in the time to P2 after active patch removal that was statistically significant compared with placebo at 2 and 4 hours and was of borderline significance at 6 hours. There were no differences in heart rate, blood pressure, or amount of ST segment depression at either P1 or P2 after active compared with placebo patch removal. CONCLUSIONS: In patients with stable angina pectoris, intermittent transdermal nitroglycerin therapy is associated with a decrease in anginal threshold for 4 to 6 hours after patch removal. Although the cause of this phenomenon remains uncertain, it may be due to counterregulatory responses that develop during nitroglycerin patch application.