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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Hemodynamic tolerability and anti-ischemic efficacy of high dose intravenous diltiazem in patients with normal versus impaired ventricular function.

OBJECTIVES. This study was designed to compare the acute systemic and coronary hemodynamic effects of high doses of intravenous diltiazem in patients with normal versus impaired left ventricular function, investigate the safety of this drug and compare its anti-ischemic potential in these two patient groups during pacing-induced stress. BACKGROUND. Because coronary hemodynamic effects and negative inotropic properties of diltiazem are dose related, high dose intravenous diltiazem may improve anti-ischemic efficacy but may not be tolerated in patients with impaired cardiac function. METHODS. High dose intravenous diltiazem, 0.4 mg/kg for 5 min followed by 0.4 mg/kg for 10 min, was administered to 23 normotensive patients with coronary artery disease, 11 (group A) with normal and 12 (group B) with impaired ventricular function (ejection fraction < 45%) during two identical arterial pacing stress tests performed 30 min before (pacing test I) and immediately after diltiazem (pacing test II). RESULTS. Diltiazem was well tolerated despite high peak plasma levels, 869 +/- 152 micrograms/liter (group A) and 926 +/- 169 micrograms/liter (group B). It resulted in immediate but similar reductions in systemic resistance from 1,321 +/- 136 (control value) to 963 +/- 113 (group A) and from 1,267 +/- 106 to 865 +/- 58 (group B) and in mean arterial pressure from 107 +/- 3 to 93 +/- 4 mm Hg (group A) and from 103 +/- 4 to 86 +/- 4 mm Hg (group B), at 5 min after diltiazem (all p < 0.05 vs. control value). Diltiazem improved stroke output from 36 +/- 3 (control value) to 46 +/- 4 ml/beat per m2 in group B and from 44 +/- 4 (control value) to 49 +/- 5 ml/beat per m2 in group A, an effect that was significantly greater and more prolonged in group B than in group A. Although neither heart rate nor contractility was affected in either group, left ventricular end-diastolic pressure increased in group A (9 +/- 2 mm Hg to 12 +/- 1 mm Hg, p < 0.05) but not in group B. Despite similar reductions in coronary resistance and improvements in coronary flow, diltiazem consistently reduced myocardial oxygen extraction, but only in group B. Also, the anti-ischemic effects of diltiazem were more pronounced in group B. During pacing test II, myocardial lactate extraction normalized in group B (7 +/- 5% vs. -6 +/- 12% [pacing test I]) but not in group A, contractility indexes improved more and the increase in left ventricular filling pressure was reduced to a greater extent in group B. Moreover, the ischemia-induced increase in arterial pressures, observed in both groups during pacing test I, was prevented in group B but recurred in group A during pacing test II. CONCLUSIONS. High dose intravenous diltiazem is well tolerated, augments coronary flow and improves left ventricular pump function, particularly in patients with preexisting ventricular dysfunction. As its anti-ischemic effects also appear more pronounced in the latter group, high dose diltiazem may be particularly useful when ventricular function is depressed, for example, during prolonged ischemia at rest.[1]


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