Question 3

College answer

Not available.

Discussion

This is not a new theme, but a new way of asking about the same (important) theme, a laudable development from the viewpoint of good assessment design. Beta blocker overdose digoxin toxicity and  tricyclic antidepressant overdose are covered in detail elsewhere, and local anaesthetic toxicity is one of the syllabus items from the First Part exam, but it is good to see it migrate into the Fellowship papers because - let's face it - a first year ICU trainee is not going to be left to manage local anaesthetic toxicity with "haemodynamic collapse" on their own, i.e. one might argue that these topics belong in a senior curriculum.

Digoxin: Digoxin-specific Fab fragments are used as a "pharmacological intervention", and the article in UpToDate recommends that digoxin antibodies be used in every poisoning, even those who do not present with "haemodynamic collapse". Incidentally, that's obviously a colloquialism without any sort of a precise AHA/ESC definition, but we can let that slide because most intensivists will intuitively grasp it and relate. For example, in the case of digoxin, "haemodynamic collapse" looks like life-threatening arrhythmias and bradycardia.

Rationale for digoxin-specific Fab fragments in digoxin overdose:

• Remove free digoxin from the active target sites: the Fab has a 100 – 1000 times higher affinity for digoxin than does Na+/K+ ATPase.
• Increase removal from tissues: The circulating Fab acts as a digoxin sink, increasing the gradient for free digoxin to enter the circulation; this increases the renal clearance of digoxin by 20-30% (Chan and Buckley, 2014).
• Increase renal clearance: Digoxin/Fab complexes are removed by both renal clearance and hepatic metabolism, but it's mainly renal: the digoxin-antibody complexes are filtered through the glomeruli  (which is surprising, consider their size) and reabsorbed in the proximal tubules while the digoxin is excreted. 
• The serum digoxin assay will thereafter measure both the free drug and the Fab-bound fraction, and is therefore not to be believed.

Rationale for sodium bicarbonate in tricyclic antidepressant overdose:

• Increase protein binding of TCAs in an alkaline bloodstream, thus decreasing the biologically active free fraction.
• Increase the availability of sodium in sodium bicarbonate, as a substrate for the voltage-gated channels. (this corrects the QRS prolongation and prevents arrhythmias)
• Decreased binding of TCAs to the voltage-gated sodium channel - apparently this binding is affected by subtle changes in pH, and this receptor family has a greater affinity for TCAs at acidic pH. 
• Correction of metabolic acidosis  to enhance cardiac contractility by improving catecholamine sensitivity
• Volume expansion (dilutes TCA concentration)
• Cellular membrane hypopolarisation results from the bicarbonate-induced intracellular shift of potassium. Apparently, this somehow "decreases sodium channel blockade by voltage-dependent drug-binding changes".

Rationale for high dose insulin euglycaemic therapy in beta-blocker overdose:

• Inotropic effect: Insulin is a potent positive inotrope in high doses because of its effects on various calcium-handling pathways, particularly those mediated by PI3K (Engebretsen et al, 2011).
• Afterload reducing effect: Insulin produces vasodilation, which improves local microcirculation (due to enhancement of endothelial nitric oxide synthase activity) - apparently this can "achieve perfused capillary density similar to that of exercising muscle
• Metabolic effect: Insulin assists myocardial uptake of carbohydrates, which is the preferred fuel substrate of the heart under stressed conditions (whereas normally free fatty acids are preferred).

Rationale for lipid infusion in local anaesthetic toxicity:

• Lipid sink: the highly lipid-soluble local anaesthetic molecules are absorbed into the lipid emulsion droplets, which decreases the free fraction of the drug in the circulation
• Tissue extraction: because the free fraction in the circulation drops, redistribution from target tissues (CNS, myocardium) will occur, reducing toxicity in those organs
• Lipid shuttle: the fatty droplets of lipid emulsion act as a carrier which delivers the local anaesthetic to the liver, enhancing the rate of elimination (apparently this is also referred to as a "lipid subway")
• Metabolic changes in the myocardium:  the increased fatty acid supply reverses local-anaesthetic-induced reduction in fatty acid metabolism in the cardiac mitochondria
• Inoconstrictor effects though the inhibition of nitric oxide release and some positive inotropic effects, which appears to be an intrinsic property of the lipid emulsion
• Reversal of cardiac sodium channel blockade by a mechanism apparently related to fatty acid-mediated modulation of cardiac sodium channels