Ivabradine in sepsis

Sir,

Persistent tachycardia in sepsis or multi-organ dysfunction syndrome (MODS) is an ominous sign.[1] This usually comes under control with judicious use of antibiotics, fluid resuscitation, sedation. Uncontrolled tachycardia in systemic inflammatory response syndrome and sepsis deprives the heart muscle of oxygen. As it progresses, insufficient heart muscle nutrition eventually leads to myocardial dysfunction. It can also present as heart failure, systolic heart failure or diastolic heart failure. In acute coronary syndromes, beta blockers are used to control heart rate. However in MODS, it cannot be used due to hemodynamic instability and worsened myocardial function.

Sinoatrial (SA) myocytes are the pacemaker cells in the heart.[2,3] Pacemaker activity involves several ionic currents that influences spontaneous depolarization of SA node including I_f current. The word “f” means funny” because this current has unusual properties as compared with other currents known at the time of its discovery. I_f current is carried out by sodium and potassium ions across the sarcolemma. It is one of the most important ionic current for regulating pacemaker activity in SA node.

Ivabradine is a I_f current inhibitor in SA node.[2,3] Currently, it is the only agent shown to clinically lower heart rate with no negative inotropism or effects on conduction and contractility.[2,3] Ivabradine selectively inhibits the pacemaker If current in a dose dependent manner at concentrations that do not affect other cardiac ion currents. Blocking this channel reduces cardiac pacemaker activity, slowing the heart rate and allowing more time for blood flow to the myocardium. The dosing is started at 5 mg twice daily, and if tolerated can be safely continued to 7.5 mg twice daily. Food delays the absorption of ivabradine. As metabolism involves cytochrome P4503A4 (CYP3A4), concurrent use of inhibitors of CYP3A4 (macrolide antibiotics, azole antifungals) is contraindicated. Metabolites are excreted in urine and feces. Main t ½ is 2 h (70-75% of area under the curve) in plasma and has an effective t ½ of 11 h. Total clearance is 400 ml/min and renal clearance is 70 ml/min. The various adverse effects of ivabradine includes luminous phenomenon (due to blockade of I_h channel in the retina, which resembles I_f cardiac channels), atrioventricular block, ventricular extrasystole and bradycardia.[3]