Sudden sniffing death and myocardial sensitization
I will show you fear in a handful of dust. – T.S. Eliot
Little Johnny was having a hard time. Dumped by his girlfriend of eight glorious weeks, he was despondent. There wasn’t any alcohol in the house, and he didn’t have a fake ID or the facial maturity to get some. So, he turned to the internet and learned that he could forget everything (including her) by bagging keyboard duster, aka getting dusted. After running to the local Home Despot, he went back to his room and began to experiment. He sprayed some duster in a bag and inhaled deeply. At first, he used it sparingly but soon gave into the release it brought. One day, during a particularly long session, Johnny’s mom came home early. She went up and knocked on his door. She heard a thud and pushed through the locked door to find Johnny unconscious and pulseless on the ground . . .
Pain x Resistance = Suffering
The enlightened person does not deny the existence of pain. The goal is to not put any resistance to it. When we put resistance to the pain, that is the suffering. Dhamma Wiki
There are many different ways to lower our resistance to suffering, and some are less helpful than others. Given the way that most nations deal with traditional drugs of abuse and alcohol, there are few options for the aspiring teen to alter their resistance. Thus, they turn to what has been termed “alternative” drugs of abuse.1 Alternatives are essentially legal, and often easily obtained, agents that get people high. Inhalant abuse, also known as volatile substance abuse, is an example of an alternative.2 Inhalants include compounds that contain volatile solvents, typically hydrocarbons and halogenated hydrocarbons. They are found in paints, duster, fuels, solvents and lots of other products.3
Sniffing, Huffing, Bagging
Let’s explore the various means by which people abuse inhalants.4 All of these are inhaled, and the way you inhale them lends the method its name.
Sniffing is exactly what it sounds like: taking a big inhalation through your nose. Not an uncommon practice in school when copies were produced by a mimeograph or old school rubber cement, which was a “drying adhesive” kept in a liquid state through the use of a volatile solvent, such as toluene.5
Huffing is a step up, utilizing a cloth impregnated with the solvent, which is then held up to the nose like someone committing a crime using a rag soaked in chloroform.
What is bagging? It is not the dance that the Hobbits did after destroying the One Ring. Instead, this is a method of capturing the aerosolized solvent in an easy inhalation device. Think of it as the AeroChamber® for inhalant abuse. For those whose solvent of choice is toluene in spray paint, bagging has the added benefit of separating out the desired solvent from the undesired paint. One sprays a plastic bag with paint, the paint sticking to the far wall of the bag, the bag filled or inflated with the remaining volatile solvent, which then can be held to the mouth and inhaled. As you can imagine, this is not a perfect separation, and much of the paint winds up on the user’s hands and mouth. This is Patrick Tribett. He’s one of the most famous faces in toxicology.6,7 He likes bagging . . .
Sudden Sniffing Death
So what ultimately lead to Little Johnny’s demise? The answer lies in the transmutation of meatloaf into spam . . . through myocardial sensitization. Sensitization refers to a heart that is more susceptible to electrical impulses occurring where and when they shouldn’t (triggered beats) and has undergone a change that allows for the propagation of these impulses in ways that are not good (reentrant rhythms).
The Cardiac Cell Cycle
This discussion is going to get heavy in lingo about the electrophysiology of the heart.8 In order to make this clearer, there will be lots of pictures, as well as a lot of words. I want to define a few things first, which will all be a review, so that the fifth time you see the term afterdepolarization it won’t make your eyes cross.
Meatloaf is better than Spam™
The heart is a beautiful combination of plumbing, electricity and mechanical pump. We’re going to focus mostly on the wiring here, and how inhalants affect the normally orderly propagation of impulses. The heart is like a homemade meatloaf; it is a layered structure in which each layer is slightly different from the adjacent one. A bit of carrot here, potato and onion there. So how do these layers result in the orderly march of an electrical signal through the heart? The electrical layering is like sequential insulation, the insulating part being the period of repolarization. During repolarization (when the heart is getting its ions back where they belong) each electrical layer has a refractory period. During a refractory period, try as you might, the cardiac cells cannot propagate a new impulse. I’m gonna go old school here and talk about PacMan. During the game, once PacMan has eaten a power pellet, there is a period of time the ghosts cannot harm him. Similarly, during the refractory period, a reentrant rhythm cannot occur. The “electrical layering” is referred to as the dispersion of repolarization.9,10
Much of what controls repolarization is the outward potassium current through the IKr channel. On the surface ECG, repolarization is represented as the S-T segment. This is why drugs that block IKr channels cause prolongation of Q-T interval (which contains the S-T).11 Halogenated hydrocarbons (like the difluoroethane in little Johnny’s duster) are just such potassium channel blockers.12–16 When these channels are blocked, you disrupt this organized, linear pattern of impulse propagation and create a pathway that allows for abnormal, multidirectional impulse propagation. So instead of an electrical signal marching orderly through the heart, you get chaos with signals going every which way. You take your lovely homemade meatloaf and turn the heart into electrical spam; no matter how you slice it, the pathways all look the same.17 There is no layering, and an impulse can be transmitted anywhere.
Once we’ve made spam, all you need is to trigger an abnormal impulse. Cardiac nerds know this as the “R on T” phenomenon. Beta-agonism (i.e., endogenous catecholamines) is one such trigger. If you take the sensitized heart, stimulate it with a beta agonist, you can trigger an abnormal impulse that now no longer has the normal safeguards in place to prevent the storm.
Let’s talk about afterdepolarizations. This is one of the few times in medicine where the naming of the problem describes it perfectly. Afterdepolarizations are electrical events that occur after depolarization is complete. The most common, well-known example of this is PVC’s. There are essentially two types of afterdepolarizations, named depending on when they occur. They can occur early (early afterdepolarization, or EAD) or they can occur delayed or late (delayed afterdepolarization, or DAD).10 Early occurs during the process of repolarization. Delayed occur after repolarization is complete.
Remember the goal of repolarization is to pump out all the excess positive ions that built up during depolarization, making the interior of the cell more negative, setting up for the next depolarization. The longer you prolong repolarization, the longer the inside of the cell stays positive. You may remember from medical school that the heart has voltage-sensitive calcium channels (L-type). So, the more repolarization is prolonged, the more calcium channels will be at the voltage that opens them, leading to an inward calcium current. This calcium influx leads to calcium-induced calcium release from the sarcoplasmic reticulum (SR), which sounds like a Gilbert & Sullivan lyric. This excess calcium (and its damn 2+ charge) can become a depolarizing signal leading to ectopy. The calcium can come from external to the cell (through the L-type calcium channel), which typically leads to early afterdepolarizations, or, it can come from inside the cell, from an overstuffed sarcoplasmic reticulum (the U-Stor-It of the myocyte), which typically occurs from things like cardiac glycosides (e.g. digoxin), beta-agonism or myocardial ischemia. Regardless of where the signal arises, depolarization (“R”) that occurs during repolarization (“T”) is the “R on T” and leads to an ectopic beat that can trigger a dysrhythmia. Depending on when you reach the threshold for a trigger you get an early or delayed afterdepolarization.
Can we save young Johnny? Well, if there is electrical activity when he first arrives, possibly. First and foremost, a non-perfusing ventricular dysrhythmia is treated with electricity. You can’t overdrive pace spam.
After you have restored a perfusing rhythm, the next step is to try to block the triggering stimulus and restore the dispersion of repolarization. One counter-intuitive method of preventing triggered stimulus is to use a beta-adrenergic antagonist (this will be the first and only time these agents will be endorsed on this blog . . . 😉 ). This prevents the trigger, desensitizing calcium channels (no longer phosphorylated by beta agonism) and potentially can prevent recurrence. It is not common for a cardiac arrest patient to receive a beta blocker, so this goes against standard ACLS approaches. The second approach would be to utilize some form of calcium channel blockade, the easiest and safest of which would be the administration of magnesium.
But, he had torsades, we should OVERDRIVE PACE him!
Well, there is one issue with this. Chemical overdrive pacing (i.e., isoproterenol) is a beta agonist. So, on your way to speeding up the heart to shorten the QT, you are bombarding it with the very trigger that led to the dysrhythmia in the first place. Not sure that I would recommend this modality.
Amiodarone is an interesting agent. It is an “everything blocker”. It blocks inactive sodium channels, L-type calcium channels, potassium channels (in and out), it is a non-competitive beta-adrenergic blocker, it blocks gap junctions. whew. So while therapeutically it does prolong the QT interval, it also blocks the stimulus and propagation of abnormal stimulus that leads to the dysrhythmia in the first place.
So, let’s put it all together. The halogenated hydrocarbon (“dust”) changes the dispersion of repolarization (meatloaf to spam) allowing for re-entrant circuits by blocking potassium efflux from the cell, delaying repolarization, prolonging the QT interval and allowing for EAD generation. If there is a triggered stimulus, such as a catecholamine surge because mom knocks on the door, there is the potential for an R on T and propagation of an abnormal impulse through the spam. This leads to a non-perfusing ventricular dysrhythmia, such as torsades des pointes18, and the end of Johnny. So unless you live in Hawaii, stick with what mom (and DAD) made, and don’t dust your meatloaf.
- Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis, Part II - August 14, 2020
- Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis? - July 24, 2020
- The Dantastic Mr. Tox & Howard – S03E03 – Inside Out - July 6, 2020