Craig Cocchio, PharmD
Craig Cocchio, PharmD
Craig Cocchio, PharmD, BCPS, is an Emergency Medicine Clinical Pharmacist at Trinity Mother Frances Hospital in Tyler, Texas. Follow on Twitter @iEMPharmD and on his blog at empharmd.blogspot.com

Is Ketamine Really Sympathomimetic?

SEPTEMBER 16, 2015
Ketamine is a popular yet polarizing drug in emergency medicine.
 
For some, it's the drug of choice for any and every indication in the emergency department (ED). For others, it's avoided at all costs.
 
Health care providers often believe that ketamine should never be used in patients with cardiovascular disease (CVD) because it is common knowledge that ketamine is a sympathomimetic drug.
 
However, this shared belief is not referenced in the American College of Emergency Physicians’ guidelines for ketamine use in the ED, for instance, so it is not actually true. In fact, this misguided principle is based on data from the 1960s and 1970s that has been quoted for decades.
 
The practice of using review articles to cite other review articles is generally regarded as poor form. For instance, a review that discussed many aspects of ketamine stated the following:

With the stimulation of noradrenergic neurons and the inhibition of catecholamine uptake, ketamine provokes a hyperadrenergic state (release of norepinephrine, dopamine, and serotonin). Inhibition of norepinephrine uptake is stereo specific: R(−) isomer only inhibits its neuronal uptake, while S(+) isomer also inhibits extra-neuronal uptake. There is a prolonged synaptic action, leading to an increased transfer of norepinephrine in the circulation.1
 
The reference cited here is not a piece of literature supporting this argument, but rather another review. Searching through this review, the referenced paper for the discussion of ketamine’s “sympathetic-activating actions” is another review, but this time, it’s in German.
 
Let’s start over at the very beginning.
 
The first research on the cardiovascular effects of ketamine occurred shortly after the drug’s discovery, as far as I can tell. A study published in 1969 described the involvement of the sympathetic nervous system in the pressor response to ketamine.2
 
The investigators administered ketamine at 5 mg/kg, 10 mg/kg, or 20 mg/kg doses to 12 mechanically ventilated dogs under epidural anesthesia. They followed the effects on mean arterial pressure (MAP) as a marker of sympathetic activation.
 
While the lowest 5 mg/kg dose did not produce any change in MAP from baseline, MAPs fell to a statistically significant margin when the higher 10 mg/kg and 20 mg/kg doses were administered. Furthermore, no changes in heart rate were observed.
 
The authors concluded that the epidural anesthesia suppressed the ketamine pressor response, serving as evidence that it is mediated by the sympathetic nervous system. Later studies provided similar evidence in models without spinal epidural anesthesia.2-5
 
While the cardiovascular effects of ketamine reported in historical literature suggest a cardiovascular neutral or depressant effect at above-normal therapeutic dosing, review articles may also state that ketamine increases norepinephrine transport into the peripheral circulation by inhibiting uptake and reuptake, thereby increasing the concentration in the neuronal synapse—an argument also supported by historical data.7.8
 
The human and animal models tested did not demonstrate clinical response to the increase in plasma norepinephrine (NE) or epinephrine. Furthermore, current attitudes toward plasma NE levels suggest they are meaningless.9
 
The ultimate concern of sympathomimetic effects in a patient with CVD is that a drug such as ketamine would lead to an increase in myocardial oxygen demand and possibly lead to ischemia/necrosis.
 
A 1979 study tested this in a dog model. Six dogs were anesthetized and mechanically ventilated and subsequently given doses of 5 mg/kg or 10 mg/kg of ketamine followed by a continuous infusion in 4 of the dogs.
 
After the 5 mg/kg bolus, there was no change in heart rate or cardiac output, but there was a decrease in MAP. For the 10 mg/kg bolus, cardiac output and stroke volume both increased by approximately 90%.
 
While the investigators observed a 58% increase in myocardial oxygen consumption, there was an equal and associated increase in myocardial oxygen delivery and increased coronary blood flow.10
 
The prevailing theory is that ketamine acts on voltage-gated calcium channels in a manner similar to calcium channel blockers (CCBs).11
 
Nevertheless, the available evidence makes it difficult to draw conclusions. While some evidence suggests that ketamine is a sympathomimetic drug, the evidence against it is of equally poor quality.
 
Should ketamine be contraindicated in patients with CVD? Perhaps. Is it still often given to patients with an unknown history of such disease? Absolutely.

References
1. Mion G, Villevieille T. Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings). CNS Neuroscience & Therapeutics. 2013;19(6):370–80.
2. Traber DL, et al. Involvement of the sympathetic nervous system in the pressor response to ketamine. Anesth Analg. 1969;48(2):248-252.
3. Bidwai AV, et al. The effects of ketamine on cardiovascular dynamics during halothane and enflurane anesthesia. Anesth Analg. 1975;54(5):588-592.
4. Savege TM, et al. A comparison of some cardiorespiratory effects of althesin and ketamine when used for induction of anaesthesia in patients with cardiac disease. Br J Anaesth. 1976 Nov;48(11):1071-81.
5. Waxman K, et al. Cardiovascular effects of anesthetic induction with ketamine. Anesth Analg. 1980 May;59(5):355-8.
6. Dewhirst E, et al. Cardiac arrest following ketamine administration for rapid sequence intubation. J Intensive Care Med. 2013 Nov-Dec;28(6):375-9.
7. Baraka A, et al. Catecholamine levels after ketamine anesthesia in man. Anesth Analg. 1973; 52(2):198-200.
8. Miletich DJ, et al. The effect of ketamine on catecholamine in the isolate perfused rat heart. Anesthesiology. 1973;39(3):271-277.
9. Goldstein DS, et al. Sources and Significance of Plasma Levels of Catechols and Their Metabolites in Humans. JPET. 2003 Jun;305(3): 800-11.
10. Smith G, et al. The effects of ketamine on the canine coronary circulation. Anesthesia. 1979;34:555-61.
11. Baum, VC, et al. Ketamine inhibits transsarcolemmal calcium entry in guinea pig myocardium: direct evidence by single cell voltage clamp. Anesth Analg. 1991;73:804-807.

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