The patient is a 54-year-old white male. He was found dead in his pool with no drugs or paraphernalia located nearby. Elsewhere in the house, there were prescription medications and some loose pills, not otherwise identified. No sign of trauma or foul play was noted. The decedent had a history of heavy smoking intermittently for over twenty years but had been able to quit after a diagnosis of emphysema/chronic obstructive pulmonary disease (COPD). He also suffered from Type II diabetes (DMII) and substance use disorder (SUD). SUD has been defined vaguely recently because the descriptor “addiction” was deemed to have too much stigma. I do not buy into the whole “anti-woke” movement, but I must say, please stop trying to get rid of accepted descriptors because they have developed a negative connotation. Just clarify, redefine, and educate. On the other hand, I do think the term alcoholic is more productive than “drunk,” so just a little moderation in everything would be nice.
The coroner’s office has determined the death to be from “the acute effects of ketamine.” The decedent had been receiving IV ketamine infusions but not that day or even recently enough for any to be left in his system. Ketamine is an NMDA agonist, which means it binds and activates that specific type of glutamate receptor. Glutamate is the major excitatory neurotransmitter in the brain, with several subtypes of receptors, including AMPA and kainite, besides NMDA. Ketamine has several actions in the body. It is involved in the inhibition of voltage-gated sodium and potassium channels and also inhibits the reuptake of serotonin and dopamine, also being a weak agonist of nicotinic and muscarine acetylcholine receptors. Let’s break this down to a ridiculously simplistic level that will cause my psychiatric colleagues to pull their hair out. The body of anything, even the worm C. elegans, is amazingly complex, and even its 302-neuron brain is hard for us to understand. The human brain, with its about 86 billion neurons with an equal number of glial cells that we now know take part in processing, is unbelievably complex. That being said.
Think of serotonin as most related to a feeling of satisfaction, though it does many other things, including moderating pain signals in the spinal cord, while dopamine can be seen as most related to reward-seeking and pleasure, though it also plays a critical role in movement. This all gets immediately complicated just from here. A patient is depressed, and we start them on a selective serotonin reuptake inhibitor like fluoxetine, which leaves the serotonin in the synaptic cleft longer, so it has more effect. Over time, their mood may increase, more often than a placebo but less effective than a good daily morning stroll, and we have an antidepressant. Briefly, however, someone’s motivation might increase before their mood, and they might act on urges to harm themselves that many depressed people suffer from. This is a huge danger since depression affects about 15 million Americans in any one year. If only one in a thousand fell victim to this problem and went on to harm themselves, that would be 15 thousand people a year. Is there any medication that can boost mood faster to reduce this danger zone? There is… If your patient is suffering from depression with suicidal ideation, there is, and while it is called Spravato, it is an enantiomer of ketamine called esketamine.
As you know, most complex molecules come in two mirror-image forms: right-handed and left-handed, or D and S for dexter and sinister. The (Es) in ketamine stands for S-ketamine. This nasal spray was approved by the FDA for treatment-resistant depression in 2019 and is used in conjunction with an oral antidepressant. You get an immediate antidepressant response from the ketamine, and before it has faded, the traditional antidepressant medications have time to kick in. A win-win, but there is also a Boxed Warning. Use of the medication causes sedation and difficulty with attention, judgment, and thinking and may be prone to abuse and misuse, though not really true addiction. I say this because it doesn’t do much with dopamine, which is necessary for full addiction. Feeling better is reinforcing, however, and doctors should be cautious to ensure their patients aren’t “self-medication.” Self-medicating with anything other than over-the-counter medications is not smart. Doctors spend four years in school studying these issues to give you their best assessment, which turns out to be wrong about 6% of the time.
This is still often enough that some studies calculate it to be the third leading cause of death in the US. What are the odds that the average patient is going to do better? Well, that’s been calculated also. The frequency of patients not following clear instructions resulting in a medication error in prescribed medications is 19 to 59%. So, as often as doctors are wrong, the patients are much more wrong. And this does not address the “a little more is better” tendency. We see this most often with pain patients, where a medication that makes them feel better will be wanted more frequently than the doctor has prescribed, and the patient runs out. In the past, doctors would consider two scenarios: one, the patient’s pain is too severe for them to tolerate, or two, the patient cannot manage their medication safely. The DEA always thinks the answer is B, but in fact, it is sometimes A. By starting low and going slow, we know that it is unlikely our first estimate will be accurate, and human beings are good at tolerating agony.
Especially mental agony. Mood disorders are some of the hardest-to-treat conditions we find. How often do we see bipolar patients stopping their medication because they feel better and think they “don’t need it anymore?” And while almost no one takes too much of their antidepressant because they are not immediately reinforcing, ketamine is another matter. It can, after a brief paradoxical reaction, immediately make you feel better and will, therefore, be reinforcing. Still, it is very hard to overdose on ketamine. This relates to the usual effective dose and the LD50 of this medication. Ketamine can be used as a sedative for surgical procedures at up to 4.5mg/kg IV and 13mg/kg IM. For a man my size, that is a sadly easy calculation (100kg), so 450mg to 1,300mg to knock me out, administered slowly over sixty seconds if IV. There can be a boost in blood pressure so this should be monitored, and we must watch for signs of a particular cystitis related to the use of this medication. Don’t eat at least two hours before and don’t drive home.
That’s about it; follow these instructions, and the FDA has said it can be safely used. I know that a young man died after a dose of 800mg given by EMTs who were later prosecuted and convicted, but I am convinced that the sedation did not kill him so much as the compressive asphyxiation from the police kneeling on him. For some reason, American law enforcement seems to have forgotten the “Burking” method of murder and seems to think that putting about five hundred pounds (three to four people) on someone’s thorax won’t keep them from breathing. When you’re sedated, you can’t fight back and focus on protecting your ability to breathe, lifting up with your arms to get a little breathing room, etc. But the dosage for depression treatment and even chronic pain treatment, as it helps reprogram misfiring circuits, is about 1.5mg/kg so I would get 150mg. I have seen these lower doses given IV and IM and have never seen someone smile pleasantly immediately.
On the contrary, they usually become paranoid and agitated for several minutes, and the provider should be ready for this. We often use a tiny dose of Versed to counteract this effect. Within about half an hour, they feel better and have an immediate partial or complete resolution of depressive symptoms, which is what they tend to remember, forgetting that they thought you were an alien abductor for a while. This reaction is called dissociation and is on the black box label. The usual Spravato dose is 56mg intranasally once, then 56mg to 84mg intranasally twice a week for four weeks, then once a week for weeks five to eight, then every two weeks, OR once a week, depending on response. That is not going to kill anyone. Was this patient using Spravato at too high a rate? Unless he was spraying it at an insane rate, this did not lead to a death from “an overdose of ketamine.” But that’s not what the coroner said. They said, “from the acute effects.” That is NOT the same as overdose. What are the acute effects of ketamine?
Besides the dissociative effects and anxiety, the patient may also experience dizziness, spinning, sleepiness, and fainting. That last one is important when you are going into a pool. The coroner listed the effects of ketamine complicated by coronary artery disease and the effects of buprenorphine as complicating factors. Coronary artery disease is the narrowing of the heart arteries, which will reduce cardiac function and could predispose to myocardial ischemia. Buprenorphine is a partial opioid agonist that, by itself, would not cause much respiratory depression. But, when combined with other sedatives, alcohol, benzodiazepines, sleep medications, or ketamine, that low effect can be amplified. Ketamine is also available in capsule or powder form from compounding pharmacies. These are also by prescription and while almost all of us ignore the warnings on some labels, mixing sedatives outside of a physicians care is extremely dangerous. So what does it look like happened here?
It does not look like this was an overdose, so much as a passing out while in the pool. No one should use any sedating substance and then swim alone or really swim at all. Being in the water is always dangerous and, like riding a motorcycle or flying a plane, requires your full attention at all times. Physicians are famous for buying a plane, getting in enough hours to be licensed, and then getting themselves into sometimes fatal trouble by not taking the job of piloting seriously enough. Two things are unforgiving of mistakes: the air and the water. If you are going to “self-medicate” (don’t) with alcohol or anything else, don’t mix them, have sober friends around, and do not go into the water.
