Coronary No-Reflow Phenomenon

Coronary no reflow is inadequate myocardial perfusion after reopening of an occluded epicardial artery, without a flow limiting lesion, dissection, spasm or thrombus to explain it. It is a failure of microvascular reperfusion and is a major cause of poor outcome after percutaneous coronary intervention.

It occurs in about 2 to 5% of all interventions. It occurs in about 10 to 30% of primary intervention for ST-elevation infarction, depending on whether angiographic flow, myocardial blush or ST-segment resolution is used. It is also seen in vein graft intervention, rotational atherectomy and after fibrinolysis.

Severity is graded by TIMI flow grade: 0 (no flow), 1 (penetration without perfusion), 2 (slow or partial perfusion; slow reflow), and 3 (normal flow). Myocardial blush grade 0 to 1 (little or no blush) shows tissue level failure even with TIMI 3 flow.

Risk factors include late presentation, large thrombus burden, high Killip class, hyperglycaemia, large infarct territory, vein grafts, and rotational atherectomy. No reflow predicts larger infarct size, heart failure and death.

Pathophysiology.

Distal embolisation of thrombus and plaque debris, microvascular spasm, endothelial injury, capillary plugging by neutrophils and platelets, oedema and extrinsic compression, and oxidative reperfusion injury together obstruct the microcirculation.

Microvascular obstruction becomes permanent after about 24 hours of failed reperfusion and leads to haemorrhagic infarction, adverse remodelling and arrhythmia.

Recognition is during or immediately after reopening of the vessel. Persistent or recurrent chest pain, hypotension, bradycardia and heart block (right coronary artery), ventricular arrhythmia and ST segments that fail to resolve (under 50% resolution at 60 to 90 minutes). The patient may deteriorate into cardiogenic shock.

Rapid investigations (within minutes, during the procedure):

• Angiography: TIMI flow of 2 or less after the lesion has been opened, with no residual stenosis, edge dissection, spasm, thrombus or air. Slow contrast washout and absent blush.
• Exclude mechanical causes first: dissection, stent edge problems, distal spasm and thrombus, air embolism, wire perforation.
• ECG for ST resolution at 60 to 90 minutes and for new block or arrhythmia. Invasive pressure and activated clotting time.
• Later: cardiac MRI shows microvascular obstruction (a dark core within enhanced infarct) and intramyocardial haemorrhage. Echocardiography for ventricular function and mechanical complications.

Differential diagnosis.

• Coronary dissection and stent thrombosis.
• Vasospasm and air embolism.
• Distal wire perforation and distal occlusion by thrombus.
• Cardiogenic shock from other cause, and tamponade.

Minutes 0 to 2.

• Confirm the diagnosis and exclude mechanical causes. Check the activated clotting time (target 250 to 300 seconds, or 300 to 350 seconds without a glycoprotein IIb/IIIa inhibitor). Add unfractionated heparin 2000 to 5000 units if it is low.
• Nitroglycerin 100 to 200 microgram intracoronary to exclude epicardial spasm, repeated when systolic pressure stays over 90 mmHg.
• Stop further high pressure balloon inflations and avoid further stenting unless a mechanical problem remains.

Minutes 2 to 10: intracoronary vasodilator through a microcatheter or over-the-wire balloon lumen placed beyond the lesion (preferred), or through the guide catheter. Choose one, give it slowly over 20 to 30 seconds, flush, and repeat angiography after each dose:

• Adenosine 100 to 200 microgram bolus, repeated every 1 to 2 minutes to a usual total of 1 mg. It causes transient bradycardia and block, so pacing back up is needed. Avoid in severe asthma and in high degree block without a pacemaker.
• Sodium nitroprusside 50 to 100 microgram bolus (maximum 200 microgram a dose), repeated to a total of 1 mg. Avoid with systolic pressure under 100 mmHg.
• Verapamil 100 to 200 microgram bolus every 1 to 2 minutes, to a total of 1 mg (or diltiazem 0.5 to 2.5 mg). Avoid with high degree block, left ventricular failure and bradycardia.
• Nicardipine 100 to 200 microgram bolus to a total of 1 mg, where available.
• Adrenaline 50 to 100 microgram intracoronary (maximum single dose 200 microgram) when no reflow comes with hypotension, since it also supports pressure.

Minutes 5 to 15: adjunctive antithrombotic therapy.

• Intracoronary tirofiban 25 microgram/kg bolus, followed by intravenous infusion of 0.15 microgram/kg/min for 12 to 24 hours (halve the dose when creatinine clearance is under 30 mL/min). Alternative: eptifibatide 180 microgram/kg bolus, repeated after 10 minutes, then 2 microgram/kg/min (1 microgram/kg/min when creatinine clearance is under 50 mL/min). Reduce the unfractionated heparin bolus to 60 units/kg when a glycoprotein IIb/IIIa inhibitor is used.
• Ensure P2Y12 inhibitor loading: ticagrelor 180 mg orally or crushed (or prasugrel 60 mg, or clopidogrel 600 mg).
• Thrombus aspiration is used only for a large residual thrombus burden, since it does not improve outcome routinely. Distal protection devices are of value in saphenous vein grafts.

Minutes 5 to 30: haemodynamic support.

• Noradrenaline 0.05 to 0.5 microgram/kg/min to keep mean arterial pressure over 65 mmHg. Dobutamine 2.5 to 10 microgram/kg/min (maximum 20) for low output.
• Atropine 0.5 mg intravenously every 3 to 5 minutes to a maximum of 3 mg for bradycardia. Temporary pacing for persistent high degree block. Defibrillation at 200 J biphasic and amiodarone 300 mg intravenously for ventricular fibrillation or tachycardia.
• Intra-aortic balloon pump, a percutaneous ventricular assist device or veno arterial extracorporeal membrane oxygenation for refractory shock.

Prevention in later procedures. Adequate P2Y12 loading, selective thrombus aspiration in large thrombus burden, avoiding oversizing and excessive high pressure post-dilatation, using distal protection in vein grafts, flush of the rotablator line with heparin, nitroglycerin and verapamil, and deferred stenting in selected high thrombus cases.

Monitoring. Admit to a coronary care unit for at least 48 to 72 hours. Continuous ECG, repeat ECG at 60 to 90 minutes for ST resolution, troponin peak, creatinine and potassium daily, echocardiography at 24 to 48 hours, MRI at 3 to 7 days where available. Start heart failure and secondary prevention therapy (atorvastatin 40 to 80 mg daily, ramipril 2.5 mg daily titrated to 10 mg, metoprolol succinate 25 mg daily titrated to 200 mg once stable, eplerenone 25 to 50 mg daily when ejection fraction is 40% or under).

Referral and escalation. Call the shock team and prepare mechanical support when hypotension, arrhythmia or flow does not recover within 10 to 15 minutes. Transfer to a centre with mechanical support if it is not available.

Special groups.

• Older adults: lower vasodilator boluses and watch for hypotension and block.
• Kidney impairment: halve tirofiban and adjust eptifibatide; limit contrast.
• Diabetes: control glucose (target 7.8 to 10 mmol/L) as hyperglycaemia worsens no reflow.
• Pregnancy: rare; spontaneous coronary artery dissection is the usual cause and adjunct drugs are used with caution.