The list is probably shorter for what Ketamine is not given for. It’s a ubiquitous drug and for that reason, it’s important to understand how it works to better discern in what clinical situations it's beneficial and when it may be deleterious.
Is Ketamine really a sympathomimetic? Where did this thought originate from? How can we mitigate emergence?
Read up for the next series of “Pharmacology Not Taught in Medic School: Ketamine Edition”.
I. Mechanism of Action
Ketamine is an NMDA antagonist. Remember our CNS is composed of two primary receptors – our inhibitory receptor and our excitatory receptor. Both are balanced very similarly to how our sympathetic and parasympathetic nervous system is in a state of constant balance. Our primary inhibitory receptor is the GABA receptor, and our excitatory receptor is the NMDA receptor.
NMDA receptors are heteromeric, meaning it is composed of multiple subunits. Different variations of the individual subunits can exist in different combinations (Laube et al., 1997). What is important to understand is no matter the combination, the center channel is an ion pore that allows the passage of ions into the cell. When NMDA is activated, since it is excitatory, it allows the passage of cations into the cell (namely sodium and calcium). These cations push the cellular membrane potential to above threshold and result in depolarization of the neuronal cell – hence excitatory.
Normal activation of the NMDA receptor results when the neurotransmitter glutamate and glycine attach to the receptor. This induces a conformational change of the receptor to open the central ion pore and allow the influx of sodium and calcium into the cell to result in depolarization.
However, Ketamine is an NMDA antagonist, so the role of Ketamine is to shut down the activity of this receptor. It does so in a “non-competitive” way, meaning it binds to a separate site on the receptor (known as an allosteric site). Once Ketamine binds to its allosteric site on the NMDA receptor it keeps that central pore closed so no further influx of cations occurs and thus, no depolarization occurs.
II. Ketamine and its Hemodynamic Profile
Ketamine is the “go-to” agent for any RSI with a patient presenting in shock and hypotensive. At least this is how most of our protocols paint the narrative - if the blood pressure is above 90 mmHg then give drug X. If below 90 mmHg, then give Ketamine because it will “boost your blood pressure”. What we have come to realize is this approach is very black and white and rarely ever in emergency medicine do we operate in black and white. We live in the gray area and Ketamine and its hemodynamics is no different.
....A quick history lesson.....
Let’s go back to 1969, when Ketamine wasn’t called Ketamine but rather compound number CI-581. This compound at the time was extracted from Phencyclidine and tested on lab animals to determine the exact mechanism of how Ketamine purportedly had a “pressor-like” effect. This all stemmed from a 1965 trial in which 20 healthy prison volunteers received doses of Ketamine and they found them to be hypertensive after administration (Domino et al., 1965). Here is where things started to get interesting – In the rats the researchers anesthetized, ketamine lowered their blood pressure and heart rate. However, in the “pithed” rats (severed spinal cord), they saw an increase in blood pressure. They further tested the pithed rats and gave them adrenergic blockade medications that abolished the vasopressor effect seen with CI-581. The authors concluded then that, CI-581 does in fact have a sympathetic effect and they theorized that it was due to peripheral release of catecholamines and not mediated by the central nervous system (CHANG et al., 1969).
Fast forward to 1979, by now CI-581 is making its rounds and is coined “Ketamine”. It is touted as being a preferred agent for shocked and critically ill patients with most of these recommendations coming from studies on animal models. The 1979 study looked at the mechanism by which Ketamine induces peripheral sympathetic activation. Researchers removed several rat hearts and bathed them in a solution containing Ketamine. What they found was that Ketamine showed a direct inhibition of noradrenaline uptake in the synapse. This meant that if noradrenaline was not taken back up but rather left in the synapse it could therefore be more physiologically active. More noradrenaline in the synapse, more sympathetic activity (SALT et al., 1979).
The theoretical mechanism seems great, right? Well, let’s look at some trials where Ketamine was used in the shocked patient:
1980: 12 shocked patients, mostly GI bleeds or sepsis, were induced with ketamine and the aim was to see what their hemodynamic profile did in response. What they found in this small sample was that Ketamine behaved rather erratically in these shocked patients. Only one patient experienced a true increase in cardiac output, 4 had a drop in MAP, and 3 of these had a precipitous drop to a MAP less than 60 mmHg (Waxman et al., 1980). What this study showed was some degree of skepticism in Ketamine in the very shocked patient – it seemed to behave in the opposite direction.
1983: Lippmann et al looked at 22 septic or trauma patients undergoing surgery. They received one dose of Ketamine and were re-evaluated at several intervals after. No other medications were administered during this time. As the authors denoted, “Critically ill patients frequently react adversely to anesthesia which induction is poorly tolerated by patients with minimal physiologic reserve. This is particularly true for the patient who already is maximally compensating for hypovolemia, hypoxemia, fluid-electrolyte, acid-base, and nutritional problems” (LIPPMANN et al., 1983).
If you want to do more of a deep dive on the concepts of Ketamine in the catecholamine-depleted states read this blog (here). Although we have a general understanding that Ketamine does in fact induce some sympathetic outflow it is arguably from animal models and otherwise healthy volunteers. In the data sets (albeit small data sets) with critically unwell patients, Ketamine did not predictably show an increase in sympathetic activity. Our protocols create a false dichotomy of Ketamine when they are written to expect a rise in blood pressure from administration in shocked patients. Recommendation: Be wary of Ketamine the sicker your patient is!
III. The Angry Ketamine Patient and Emergence
Think of Ketamine administration like a ladder - At the base of the ladder are your pain doses (0.1 – 0.3 mg/kg) then your middle rungs are like your “no man’s land” then at the top of the ladder and beyond is your dissociative doses (>1.0 mg/kg).
You’ll notice that those middle rungs do not specify much action, but we do know that emergence phenomenon occurs here. Emergence is a state of anxiety or agitation following Ketamine administration (Sener et al., 2011). Ideally, we want to avoid this situation but with how Ketamine works anesthetically, it can be difficult, and here is why:
When we administer Ketamine, it is much like climbing a ladder. We must hit every rung of the ladder on the way up. So, giving a 1 mg/kg dose IV, we traverse the pain dose rungs, then through the emergence rungs then finally off to the dissociative doses. However, how we come up the ladder is how we come down the ladder, which means coming “off” ketamine means we must pass once again through those dissociative rungs. And usually, during the descent, we see more physical manifestations of the emergence (i.e. agitation).
Emergence should not discourage us to use Ketamine but rather be mindful of this possible phenomenon of emergence. In 2011, a prospective, double-blind, placebo-controlled, 2x2 factorial trial randomized 189 ED patients to receive dissociative dose Ketamine with Versed and the other group to receive dissociative dose Ketamine with a placebo. What they found was that there were significantly more emergence-type reactions in the placebo group than with the Versed group, in fact, 8% in the Versed group and a shocking 25% in the placebo group.
So how can we manage this emergence? Low dose Versed is a great option to control the agitation seen with Ketamine! The Versed helps to supply some sedation during the emergence phase of coming out of dissociative doses of Ketamine.
Some points to remember...
1. Ketamine is an NMDA antagonist, it allosterically binds to the receptor and shuts down this excitatory CNS receptor in the brain yielding many of its anesthetic properties.
2. Ketamine has its place, but in small data sets, the sicker the patient the more erratic your Ketamine becomes.
3. Co-administration of Versed can be your friend.
References
CHANG, P., CHAN, K. E., & GANENDRAN, A. (1969). CARDIOVASCULAR EFFECTS OF 2-( O -CHLOROPHENYL)-2-METHYLAMINOCYCLOHEXANONE (CI-581) * *The approved name is ketamine. IN RATS. British Journal of Anaesthesia, 41(5), 391–395. https://doi.org/10.1093/bja/41.5.391
Domino, E. F., Chodoff, P., & Corssen, G. (1965). Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clinical Pharmacology & Therapeutics, 6(3), 279–291. https://doi.org/10.1002/cpt196563279
Jones, J., & Dillen, C. (n.d.). Special K: A review of Ketamine. https://emergency.med.ufl.edu/files/2013/02/KetamineReview-JonesVanDillen.pdf
Laube, B., Hirai, H., Sturgess, M., Betz, H., & Kuhse, J. (1997). Molecular Determinants of Agonist Discrimination by NMDA Receptor Subunits: Analysis of the Glutamate Binding Site on the NR2B Subunit. Neuron, 18(3), 493–503. https://doi.org/10.1016/s0896-6273(00)81249-0
LIPPMANN, M., APPEL, P. L., MOK, M. S., & SHOEMAKER, W. C. (1983). Sequential cardiorespiratory patterns of anesthetic induction with ketamine in critically ill patients. Critical Care Medicine, 11(9), 730–734. https://doi.org/10.1097/00003246-198309000-00012
Rosenbaum, S. B., & Palacios, J. L. (2019, February 21). Ketamine. Nih.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK470357/
SALT, P. J., BARNES, P. K., & BESWICK, F. J. (1979). INHIBITION OF NEURONAL AND EXTRANEURONAL UPTAKE OF NORADRENALINE BY KETAMINE IN THE ISOLATED PERFUSED RAT HEART. British Journal of Anaesthesia, 51(9), 835–838. https://doi.org/10.1093/bja/51.9.835
Sener, S., Eken, C., Schultz, C. H., Serinken, M., & Ozsarac, M. (2011). Ketamine With and Without Midazolam for Emergency Department Sedation in Adults: A Randomized Controlled Trial. Annals of Emergency Medicine, 57(2), 109-114.e2. https://doi.org/10.1016/j.annemergmed.2010.09.010
Waxman, K., Shoemaker, W. C., & Lippmann, M. (1980). Cardiovascular Effects of Anesthetic Induction with Ketamine. Anesthesia & Analgesia, 59(5), 355–358. https://pdfs.journals.lww.com/anesthesia-analgesia/1980/05000/Cardiovascular_Effects_of_Anesthetic_Induction.7.pdf?token=method%7CExpireAbsolute
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